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RELATED APPLICATIONS
This application is a continuation of U.S. application Ser. No. 10/264,350, filed Oct. 3, 2002 now U.S. Pat. No. 6,784,254 which is a continuation of U.S. application Ser. No. 10/060,556 filed Jan. 30, 2002, now abandoned, which is a continuation of U.S. application Ser. No. 09/803,647 filed Mar. 9, 2001, now U.S. Pat. No. 6,433,026, which is a continuation of U.S. application Ser. No. 09/532,984 filed Mar. 22, 2000, now U.S. Pat. No. 6,225,355, which is a continuation of U.S. application Ser. No. 09/388,876 filed Sep. 2, 1999, now U.S. Pat. No. 6,066,678, which is a continuation of U.S. application Ser. No. 09/288,357 filed Apr. 8, 1999, now U.S. Pat. No. 5,981,693, which is a continuation of U.S. application Ser. No. 09/129,286 filed Aug. 5, 1998, now U.S. Pat. No. 5,917,007, which is a continuation of U.S. application Ser. No. 08/910,692 filed Aug. 13, 1997, now abandoned, which is a divisional of U.S. application Ser. No. 08/460,980 filed on Jun. 5, 1995, now U.S. Pat. No. 5,679,717, which is a continuation-in-part of U.S. application Ser. No. 08/258,431 filed Jun. 10, 1994, now abandoned. The entire teachings of all the above applications are hereby incorporated by reference.
BACKGROUND OF THE INVENTION
This invention relates to removing bile salts from a patient.
Salts of bile acids act as detergents to solubilize and consequently aid in digestion of dietary fats. Bile acids are precursors to bile salts, and are derived from cholesterol. Following digestion, bile acids can be passively absorbed in the jejunum, or, in the case of conjugated primary bile acids, reabsorbed by active transport in the ileum. Bile acids which are not reabsorbed by active transport are deconjugated and dehydroxylated by bacterial action in the distal ileum and large intestine.
Reabsorption of bile acids from the intestine conserves lipoprotein cholesterol in the bloodstream. Conversely, blood cholesterol level can be diminished by reducing reabsorption of bile acids.
One method of reducing the amount of bile acids that are reabsorbed is oral administration of compounds that sequester the bile acids and cannot themselves be absorbed. The sequestered bile acids consequently either decompose by bacterial action or are excreted.
Many bile acid sequestrants, however, bind relatively hydrophobic bile acids more avidly than conjugated primary bile acids, such as conjugated cholic and chenodeoxycholic acids. Further, active transport in the ileum causes substantial portions of sequestered conjugated primary bile acids to be desorbed and to enter the free bile acid pool for reabsorption. In addition, the volume of sequestrants that can be ingested safely is limited. As a result, the effectiveness of sequestrants to diminish blood cholesterol levels is also limited.
Sequestering and removing bile salts (e.g., cholate, glycocholate, glycochenocholate, taurocholate, and deoxycholate salts) in a patient can be used to reduce the patient's cholesterol level. Because the biological precursor to bile salt is cholesterol, the metabolism of cholesterol to make bile salts is accompanied by a simultaneous reduction in the cholesterol in the patient.
Cholestyramine, a polystyrene/divinylbenzene ammonium ion exchange resin, when ingested, removes bile salts via the digestive tract. This resin, however, is unpalatable, gritty and constipating. Resins which avoid (totally or partially) these disadvantages and/or possess improved bile salt sequestration properties are needed.
SUMMARY OF THE INVENTION
The invention relates to the discovery that a new class of ion exchange resins have improved bile salt sequestration properties and little to no grittiness, thereby improving the palatability of the composition.
The resins comprise cross-linked polyamines which are characterized by one or more hydrophobic substituents and, optionally, one or more quaternary ammonium containing substituents.
In general, the invention features resins and their use in removing bile salts from a patient that includes administering to the patient a therapeutically effective amount of the reaction product of:
(a) one or more crosslinked polymers, salts and copolymers thereof characterized by a repeat unit selected from the group consisting essentially of:
(NR—CH 2 CH 2 —NR—CH 2 CH 2 —NR—CH 2 CHOH—CH 2 ) n (4)
where n is a positive integer and each R, independently, is H or a substituted or unsubstituted alkyl group (e.g., C 1 –C 8 alkyl); and
(b) at least one alkylating agent. The reaction product is characterized in that:
(i) at least some of the nitrogen atoms in the repeat units are unreacted with the alkylating agent; (ii) less than 10 mol % of the nitrogen atoms in the repeat units that react with the alkylating agent form quaternary ammonium units; and (iii) the reaction product is preferably non-toxic and stable once ingested.
Suitable substituents include quaternary ammonium, amine, alkylamine, dialkylamine, hydroxy, alkoxy, halogen, carboxamide, sulfonamide and carboxylic acid ester, for example.
In preferred embodiments, the polyamine of compound (a) of the reaction product is crosslinked by means of a multifunctional crosslinking agent, the agent being present in an amount from about 0.5–25% (more preferably about 2.5–20% (most preferably 1–10%)) by weight, based upon total weight or monomer plus crosslinking agent. A preferred crosslinking agent is epichlorohydrin because of its high availability and low cost. Epichlorohydrin is also advantageous because of it's low molecular weight and hydrophilic nature, increasing the water-swellability and gel properties of the polyamine.
The invention also features compositions based upon the above-described reaction products.
The invention provides an effective treatment for removing bile salts from a patient (and thereby reducing the patient's cholesterol level). The compositions are non-toxic and stable when ingested in therapeutically effective amounts.
Other features and advantages will be apparent from the following description of the preferred embodiments thereof and from the claims.
DETAILED DESCRIPTION OF THE INVENTION
Compositions
Preferred reaction products include the products of one or more crosslinked polymers having the formulae set forth in the Summary of the Invention, above, and one or more alkylating agents. The polymers are crosslinked. The level of crosslinking makes the polymers completely insoluble and thus limits the activity of the alkylated reaction product to the gastrointestinal tract only. Thus, the compositions are non-systemic in their activity and will lead to reduced side-effects in the patient.
By “non-toxic” it is meant that when ingested in therapeutically effective amounts neither the reaction products nor any ions released into the body upon ion exchange are harmful. Cross-linking the polymer renders the polymer substantially resistant to absorption. When the polymer is administered as a salt, the cationic counterions are preferably selected to minimize adverse effects on the patient, as is more particularly described below.
By “stable” it is meant that when ingested in therapeutically effective amounts the reaction products do not dissolve or otherwise decompose in vivo to form potentially harmful by-products, and remain substantially intact so that they can transport material out of the body.
By “salt” it is meant that the nitrogen group in the repeat unit is protonated to create a positively charged nitrogen atom associated with a negatively charged counterion.
By “alkylating agent” it is meant a reactant which, when reacted with the crosslinked polymer, causes an alkyl group or derivative thereof (e.g., a substituted alkyl, such as an aralkyl, hydroxyalkyl, alkylammonium salt, alkylamide, or combination thereof) to be covalently bound to one or more of the nitrogen atoms of the polymer.
One example of preferred polymer is characterized by a repeat unit having the formula
or a salt or copolymer thereof; wherein x is zero or an integer between about 1 to 4.
A second example of a preferred polymer is characterized by a repeat unit having the formula
(NH—CH 2 CH 2 ) n (6)
or a salt or copolymer thereof.
A third example of a preferred polymer is characterized by a repeat unit having the formula
(NH—CH 2 CH 2 —NH—CH 2 CH 2 —NH—CH 2 CHOH—CH 2 ) n (7)
or a salt or copolymer thereof.
The polymers are preferably crosslinked prior to alkylation. Examples of suitable crosslinking agents include acryloyl chloride, epichlorohydrin, butanedioldiglycidyl ether, ethanedioldiglycidyl ether, and dimethyl succinate. The amount of crosslinking agent is typically between 0.5 and 25 weight %, based upon combined weight of crosslinking agent and monomer, with 2.5–20%, or 1–10%, being preferred.
Typically, the amount of crosslinking agent that is reacted with the amine polymer is sufficient to cause reaction of between about 0.5 and twenty percent of the amines. In a preferred embodiment, between about 0.5 and six percent of the amine groups react with the crosslinking agent.
Crosslinking of the polymer can be achieved by reacting the polymer with a suitable crosslinking agent in an aqueous caustic solution at about 25° C. for a period of time of about eighteen hours to thereby form a gel. The gel is then combined with water and blended to form a particulate solid. The particulate solid can then be washed with water and dried under suitable conditions, such as a temperature of about 50° C. for a period of time of about eighteen hours.
Alkylation involves reaction between the nitrogen atoms of the polymer and the alkylating agent (which may contain additional nitrogen atoms, e.g., in the form of amido or ammonium groups). In addition, the nitrogen atoms which do react with the alkylating agent(s) resist multiple alkylation to form quaternary ammonium ions such that less than 10 mol % of the nitrogen atoms form quaternary ammonium ions at the conclusion of alkylation.
Preferred alkylating agents have the formula RX where R is a C 1 –C 20 alkyl (preferably C 4 –C 20 ), C 1 –C 20 hydroxy-alkyl (preferably C 4 –C 20 hydroxyalkyl), C 7 –C 20 aralkyl, C 1 –C 20 alkylammonium (preferably C 4 –C 20 alkyl ammonium), or C 1 –C 20 alkylamido (preferably C 4 –C 20 alkyl amido) group and X includes one or more electrophilic leaving groups. By “electrophilic leaving group” it is meant a group which is displaced by a nitrogen atom in the crosslinked polymer during the alkylation reaction. Examples of preferred leaving groups include halide, epoxy, tosylate, and mesylate group. In the case of, e.g., epoxy groups, the alkylation reaction causes opening of the three-membered epoxy ring.
Examples of preferred alkylating agents include a C 1 –C 20 alkyl halide (e.g., an n-butyl halide, n-hexyl halide, n-octyl halide, n-decyl halide, n-dodecyl halide, n-tetradecyl halide, n-octadecyl halide, and combinations thereof); a C 1 –C 20 dihaloalkane (e.g., a 1,10-dihalodecane); a C 1 –C 20 hydroxyalkyl halide (e.g., an 11-halo-1-undecanol); a C 1 –C 20 aralkyl halide (e.g., a benzyl halide); a C 1 –C 20 alkyl halide ammonium salt (e.g., a (4-halobutyl)trimethylammonium salt, (6-halohexyl)trimethyl-ammonium salt, (8-halooctyl)trimethylammonium salt, (10-halodecyl)trimethylammonium salt, (12-halododecyl)-trimethylammonium salts and combinations thereof); a C 1 –C 20 alkyl epoxy ammonium salt (e.g., a (glycidylpropyl)-trimethylammonium salt); and a C 1 –C 20 epoxy alkylamide (e.g., an N-(2,3-eoxypropane)butyramide, N-(2,3-epoxypropane)hexanamide, and combinations thereof).
It is particularly preferred to react the polymer with at least two alkylating agents, added simultaneously or sequentially to the polymer. In one preferred example, one of the alkylating agents has the formula RX where R is a C 1 –C 20 alkyl group and X includes one or more electrophilic leaving groups (e.g., an alkyl halide), and the other alkylating agent has the formula R′X where R′ is a C 1 –C 20 alkyl ammonium group and X includes one or more electrophilic leaving groups (e.g., an alkyl halide ammonium salt).
In another preferred example, one of the alkylating agents has the formula RX where R is a C 1 –C 20 alkyl group and X includes one or more electrophilic leaving groups (e.g., an alkyl halide), and the other alkylating agent has the formula R′X where R′ is a C 1 –C 20 hydroxyalkyl group and X includes one or more electrophilic leaving groups (e.g., a hydroxy alkyl halide).
In another preferred example, one of the alkylating agents is a C 1 –C 20 dihaloalkane and the other alkylating agent is a C 1 –C 20 alkylammonium salt.
The reaction products may have fixed positive charges, or may have the capability of becoming charged upon ingestion at physiological pH. In the latter case, the charged ions also pick up negatively charged counterions upon ingestion that can be exchanged with bile salts. In the case of reaction products having fixed positive charges, however, the reaction product may be provided with one or more exchangeable counterions. Examples of suitable counterions include Cl − , Br − , CH 3 OSO 3 − , HSO 4 − , SO 4 2− , HCO 3 − , CO 3 − , acetate, lactate, succinate, propionate, butyrate, ascorbate, citrate, maleate, folate, an amino acid derivative, a nucleotide, a lipid, or a phospholipid. The counterions may be the same as, or different from, each other. For example, the reaction product may contain two different types of counterions, both of which are exchanged for the bile salts being removed. More than one reaction product, each having different counterions associated with the fixed charges, may be administered as well.
The alkylating agent can be added to the cross-linked polymer at a molar ratio between about 0.05:1 to 4:1, for example, the alkylating agents can be preferably selected to provide hydrophobic regions and hydrophilic regions.
The amine polymer is typically alkylated by combining the polymer with the alkylating agents in an organic solvent. The amount of first alkylating agent combined with the amine polymer is generally sufficient to cause reaction of the first alkylating agent with between about 5 and 75 of the percent of amine groups on the amine polymer that are available for reaction. The amount of second alkylating agent combined with the amine polymer and solution is generally sufficient to cause reaction of the second alkylating agent with between about 5 and about 75 of the amine groups available for reaction on the amine polymer. Examples of suitable organic solvents include methanol, ethanal, isopropanol, acetonitrile, DMF and DMSO. A preferred organic solvent is methanol.
In one embodiment, the reaction mixture is heated over a period of about forty minutes to a temperature of about 65° C., with stirring. Typically, an aqueous sodium hydroxide solution is continuously added during the reaction period. Preferably, the reaction period at 65° C. is about eighteen hours, followed by gradual cooling to a room temperature of about 25° C. over a period of about four hours. The resulting reaction product is then filtered, resuspended in methanol, filtered again, and then washed with a suitable aqueous solution, such as two molar sodium chloride,and then with deionized water. The resultant solid product is then dried under suitable conditions, such as at a temperature of about 60° C. in an air-drying oven. The dried solid can then be subsequently processed. Preferably, the solid is ground and passed through an 80 mesh sieve.
In a particularly preferred embodiment of the invention, the amine polymer is a crosslinked poly(allylamine), wherein the first substituent includes a hydrophobic decyl moiety, and the second amine substituent includes a hexyltrimethylammonium. Further, the particularly preferred crosslinked poly(allylamine) is crosslinked by epichlorohydrin that is present in a range of between about two and six percent of the amines available for reaction with the epichlorohydrin.
The invention will now be described more specifically by the examples.
EXAMPLES
A. Polymer Preparation
1. Preparation of Poly(vinylamine)
The first step involved the preparation of ethylidenebisacetamide. Acetamide (118 g), acetaldehyde (44.06 g), copper acetate (0.2 g), and water (300 mL) were placed in a 1 L three neck flask fitted with condenser, thermometer, and mechanical stirred. Concentrated HCl (34 mL) was added and the mixture was heated to 45–50° C. with stirring for 24 hours. The water was then removed in vacuo to leave a thick sludge which formed crystals on cooling to 5° C. Acetone (200 ML) was added and stirred for a few minutes, after which the solid was filtered off and discarded. The acetone was cooled to 0° C. and solid was filtered off. This solid was rinsed in 500 mL acetone and air dried 18 hours to yield 31.5 g of ethylidenebis-acetamide.
The next step involved the preparation of vinylacetamide from ethylidenebisacetamide. Ethylidenebisacetamide (31.05 g), calcium carbonate (2 g) and celite 541 (2 g) were placed in a 500 mL three neck flask fitted with a thermometer, a mechanical stirred, and a distilling heat atop a Vigroux column. The mixture was vacuum distilled at 24 mm Hg by heating the pot to 180–225° C. Only a single fraction was collected (10.8 g) which contained a large portion of acetamide in addition to the product (determined by NMR). This solid product was dissolved in isopropanol (30 mL) to form the crude vinylacetamide solution used for polymerization.
Crude vinylacetamide solution (15 mL), divinylbenzene (1 g, technical grade, 55% pure, mixed isomers), and AIBN (0.3 g) were mixed and heated to reflux under a nitrogen atmosphere for 90 minutes, forming a solid precipitate. The solution was cooled, isopropanol (50 mL) was added, and the solid was collected by centrifugation. The solid was rinsed twice in isopropanol, once in water, and dried in a vacuum oven to yield 0.8 g of poly(vinylacetamide), which was used to prepare poly(vinylamine as follows).
Poly(vinylacetamide) (0.79 g) was placed in a 100 mL one neck flask containing water (25 mL) and conc. HCl (25 mL). The mixture was refluxed for 5 days, after which the solid was filtered off, rinsed once in water, twice in isopropanol, and dried in a vacuum oven to yield 0.77 g of product. Infrared spectroscopy indicated that a significant amount of the amide (1656 cm −1 ) remained and that not much amine (1606 cm −1 ) was formed. The product of this reaction (˜0.84 g) was suspended in NaOh (46 g) and water (46 g) and heated to boiling (˜140° C.). Due to foaming the temperature was reduced and maintained at ˜100° C. for 2 hours. Water (100 mL) was added and the solid collected by filtration. After rinsing once in water the solid was suspended in water (500 mL) and adjusted to pH 5 with acetic acid. The solid was again filtered off, rinsed with water, then isopropanol, and dried in a vacuum oven to yield 0.51 g of product. Infrared spectroscopy indicated that significant amine had been formed.
2. Preparation of Poly(ethyleneimine)
Polyethyleneimine (120 g of a 50% aqueous solution; Scientific Polymer Products) was dissolved in water (250 mL). Epichlorohydrin (22.1 mL) was added dropwise. The solution was heated to 60° C. for 4 hours, after which it had gelled. The gel was removed, blended with water (1.5 L) and the solid was filtered off, rinsed three times with water (3 L) and twice with isopropanol (3 L), and the resulting gel was dried in a vacuum oven to yield 81.2 g of the title polymer.
3. Preparation of Poly(allylamine)hydrochloride
To a 2 liter, water-jacketed reaction kettle equipped with (1) a condenser topped with a nitrogen gas inlet, (2) a thermometer, and (3) a mechanical stirrer was added concentrated hydrochloric acid (360 mL). The acid was cooled to 5° C. using circulating water in the jacket of the reaction kettle (water temperature=0° C.). Allylamine (328.5 mL, 250 g) was added dropwise with stirring while maintaining the reaction temperature at 5–10° C. After addition was complete, the mixture was removed, placed in a 3 liter one-neck flask, and 206 g of liquid was removed by rotary vacuum evaporation at 60° C. Water (20 mL) was then added and the liquid was returned to the reaction kettle. Azobis(amidinopropane)dihydrochloride (0.5 g) suspended in 11 mL of water was then added. The resulting reaction mixture was heated to 50° C. under a nitrogen atmosphere with stirring for 24 hours. Additional azobis(amidinopropane)dihydrochloride (5 mL) suspended in 11 mL of water was then added, after which heating and stirring were continued for an additional 44 hours.
At the end of this period, distilled water (100 mL) was added to the reaction mixture and the liquid mixture allowed to cool with stirring. The mixture was then removed and placed in a 2 liter separatory funnel, after which it was added dropwise to a stirring solution of methanol (4 L), causing a solid to form. The solid was removed by filtration, re-suspended in methanol (4 L), stirred for 1 hour, and collected by filtration. The methanol rinse was then repeated one more time and the solid dried in a vacuum oven to afford 215.1 g of poly(allylamine)hydrochloride as a granular white solid.
4. Preparation of Poly(allylamine)hydrochloride Crosslinked with epichlorohydrin
To a 5 gallon vessel was added poly(allylamine)hydrochloride prepared as described in Example 3 (1 kg) and water (4 L). The mixture was stirred to dissolve the hydrochloride and the pH was adjusted by adding solid NaOH (284 g). The resulting solution was cooled to room temperature, after which epichlorohydrin crosslinking agent (50 mL) was added all at once with stirring. The resulting mixture was stirred gently until it gelled (about 35 minutes). The crosslinking reaction was allowed to proceed for an additional 18 hours at room temperature, after which the polymer gel was removed and placed in portions in a blender with a total of 10 L of water. Each portion was blended gently for about 3 minutes to form coarse particles which were then stirred for 1 hour and collected by filtration. The solid was rinsed three times by suspending it in water (10 L, 15 L, 20 L), stirring each suspension for 1 hour, and collecting the solid each time by filtration. The resulting solid was then rinsed once by suspending it in isopropanol (17 L), stirring the mixture for 1 hour, and then collecting the solid by filtration, after which the solid was dried in a vacuum oven at 50° C. for 18 hours to yield about 677 g of the cross linked polymer as a granular, brittle, white solid.
5. Preparation of Poly(allylamine)hydrochloride Crosslinked with butanedioldiglycidyl ether
To a 5 gallon plastic bucket was added poly(allylamine)hydrochloride prepared as described in Example 3 (500 g) and water (2 L). The mixture was stirred to dissolve the hydrochloride and the pH was adjusted to 10 by adding solid NaOH (134.6 g). The resulting solution was cooled to room temperature in the bucket, after which 1,4-butanedioldiglycidyl ether crosslinking agent (65 mL) was added all at once with stirring. The resulting mixture was stirred gently until it gelled (about 6 minutes). The crosslinking reaction was allowed to proceed for an additional 18 hours at room temperature, after which the polymer gel was removed and dried in a vacuum oven at 75° C. for 24 hours. The dry solid was then ground and sieved to −30 mesh, after which it was suspended in 6 gallons of water and stirred for 1 hour. The solid was then filtered off and the rinse process repeated two more times. The resulting solid was then air dried for 48 hours, followed by drying in a vacuum oven at 50° C. for 24 hours to yield about 415 g of the crosslinked polymer as a white solid.
6. Preparation of Poly(allylamine)hydrochloride Crosslinked with ethanedioldiglycidyl ether
To a 100 mL beaker was added poly(allylamine)hydrochloride prepared as described in Example 3 (10 g) and water (40 mL). The mixture was stirred to dissolve the hydrochloride and the pH was adjusted to 10 by adding solid NaOH. The resulting solution was cooled to room temperature in the beaker, after which 1,2-ethanedioldiglycidyl ether crosslinking agent (2.0 mL) was added all at once with stirring. The resulting mixture was stirred gently until it gelled (about 4 minutes). The crosslinking reaction was allowed to proceed for an additional 18 hours at room temperature, after which the polymer gel was removed and blended in 500 mL of methanol. The solid was then filtered off and suspended in water (500 mL). After stirring for 1 hour, the solid was filtered off and the rinse process repeated. The resulting solid was rinsed twice in isopropanol (400 mL) and then dried in a vacuum oven at 50° C. for 24 hours to yield 8.7 g of the crosslinked polymer as a white solid.
7. Preparation of Poly(allylamine)hydrochloride Crosslinked with dimethylsuccinate
To a 500 mL round bottom flask was added poly(allylamine)hydrochloride prepared as described in Example 3 (10 g), methanol (100 mL), and triethylamine (10 mL). The mixture was stirred and dimethylsuccinate crosslinking agent (1 mL) was added. The solution was heated to reflux and the stirring discontinued after 30 minutes. After 18 hours, the solution was cooled to room temperature, and the solid filtered off and blended in 400 mL of isopropanol. The solid was then filtered off and suspended in water (1 L). After stirring for 1 hour, the solid was filtered off and the rinse process repeated two more times. The solid was then rinsed once in isopropanol (800 mL) and dried in a vacuum oven at 50° C. for 24 hours to yield 5.9 g of the crosslinked polymer as a white solid.
8. Preparation of Poly(ethyleneimine) Crosslinked with acryloyl chloride
Into a 5 L three neck flask equipped with a mechanical stirred, a thermometer, and an addition funnel was added poly(ethyleneimine) (510 g of a 50% aqueous solution, equivalent to 255 g of dry polymer) and isopropanol (2.5 L). Acryloyl chloride crosslinking agent (50 g) was added dropwise through the addition funnel over a 35 minute period while maintaining the temperature below 29° C. The solution was then heated to 60° C. with stirring for 18 hours, after which the solution was cooled and the solid immediately filtered off. The solid was then washed three times by suspending it in water (2 gallons), stirring for 1 hour, and filtering to recover the solid. Next, the solid was rinsed once by suspending it in methanol (2 gallons), stirring for 30 minutes, and filtering to recover the solid. Finally, the solid was rinsed in isopropanol as in Example 7 and dried in a vacuum oven at 50° C. for 18 hours to yield 206 g of the crosslinked polymer as a light orange granular solid.
9. Alkylation of Poly(allylamine) Crosslinked with butanedioldiglydicyl ether with 1-iodooctane alkylating Agent
Poly(allylamine) crosslinked with butanedioldiglycidyl ether prepared as described in Example 5 (5 g) was suspended in methanol (100 mL) and sodium hydroxide (0.2 g) was added. After stirring for 15 minutes, 1-iodooctane (1.92 mL) was added and the mixture stirred at 60° C. for 20 hours. The mixture was then cooled and the solid filtered off. Next, the solid was washed by suspending it in isopropanol (500 mL), after which it was stirred for 1 hour and then collected by filtration. The wash procedure was then repeated twice using aqueous sodium chloride (500 mL of a 1 M solution), twice with water (500 mL), and once with isopropanol (500 mL) before drying in a vacuum oven at 50° C. for 24 hours to yield 4.65 g of alkylated product.
The procedure was repeated using 2.88 mL of 1-iodooctane to yield 4.68 g of alkylated product.
10. Alkylation of Poly(allylamine) Crosslinked with epichlorohydrin with 1-iodooctane alkylating Agent
Poly(allylamine) crosslinked with epichlorohydrin prepared as described in Example 4 (5 g) was alkylated according to the procedure described in Example 9 except that 3.84 mL of 1-iodooctane was used. The procedure yielded 5.94 g of alkylated product.
11. Alkylation of Poly(allylamine) Crosslinked with epichlorohydrin with 1-iodooctadecane alkylating Agent
Poly(allylamine) crosslinked with epichlorohydrin prepared as described in Example 4 (10 g) was suspended in methanol (100 mL) and sodium hydroxide (0.2 g) was added. After stirring for 15 minutes, 1-iodooctadecane (8.1 g) was added and the mixture stirred at 60° C. for 20 hours. The mixture was then cooled and the solid filtered off. Next, the solid was washed by suspending it in isopropanol (500 mL), after which it was stirred for 1 hour and then collected by filtration. The wash procedure was then repeated twice using aqueous sodium chloride (500 mL of a 1 M solution), twice with water (500 mL), and once with isopropanol (500 mL) before drying in a vacuum oven at 50° C. for 24 hours to yield 9.6 g of alkylated product.
12. Alkylation of Poly(allylamine) Crosslinked with butanedioldiglycidyl ether with 1-iodododecane alkylating Agent
Poly(allylamine) crosslinked with butanedioldiglycidyl ether prepared as described in Example 5 (5 g) was alkylated according to the procedure described in Example 11 except that 2.47 mL of 1-iodododecane was used. The procedure yielded 4.7 g of alkylated product.
13. Alkylation of Poly(allylamine) Crosslinked with butanedioldiglycidyl ether with benzyl bromide alkylating Agent
Poly(allylamine) crosslinked with butanedioldiglycidyl ether prepared as described in Example 5 (5 g) was alkylated according to the procedure described in Example 11 except that 2.42 mL of benzyl bromide was used. The procedure yielded 6.4 g of alkylated product.
14. Alkylation of Poly(allylamine) Crosslinked with epichlorohydrin with benzyl bromide alkylating Agent
Poly(allylamine) crosslinked with epichlorohydrin prepared as described in Example 4 (5 g) was alkylated according to the procedure described in Example 11 except that 1.21 mL of benzyl bromide was used. The procedure yielded 6.6 g of alkylated product.
15. Alkylation of Poly(allylamine) Crosslinked with epichlorohydrin with 1-iododecane alkylating Agent
Poly(allylamine) crosslinked with epichlorohydrin prepared as described in Example 4 (20 g) was alkylated according to the procedure described in Example 11 except that 7.15 g of 1-iododecane and 2.1 g of NaOH were used. The procedure yielded 20.67 g of alkylated product.
16. Alkylation of Poly(allylamine) Crosslinked with epichlorohydrin with 1-iodobutane alkylating Agent
Poly(allylamine) crosslinked with epichlorohydrin prepared as described in Example 4 (20 g) was alkylated according to the procedure described in Example 11 except that 22.03 g of 1-iodobutane and 8.0 g of NaOH were used. The procedure yielded 24.0 g of alkylated product.
The procedure was also followed using 29.44 g and 14.72 g of 1-iodobutane to yield 17.0 g and 21.0 g, respectively, of alkylated product.
17. Alkylation of Poly(allylamine) Crosslinked with epichlorohydrin with 1-iodotetradecane alkylating Agent
Poly(allylamine) crosslinked with epichlorohydrin prepared as described in Example 4 (5 g) was alkylated according to the procedure described in Example 11 except that 2.1 mL of 1-iodotetradecane was used. The procedure yielded 5.2 g of alkylated product.
The procedure was also followed using 6.4 mL of 1-iodotetradecane to yield 7.15 g of alkylated product.
18. Alkylation of Poly(allylamine) Crosslinked with epichlorohydrin with 1-iodooctane alkylating Agent
Poly(allylamine) crosslinked with epichlorohydrin prepared as described in Example 8 (5 g) was alkylated according to the procedure described in Example 11 except that 1.92 mL of 1-iodooctane was used. The procedure yielded 5.0 g of alkylated product.
19. Alkylation of a Copolymer of diethylene triamine and epichlorohydrin with 1-iodooctane alkylating Agent
A copolymer of diethylene triamine and epichlorohydrin (10 g) was alkylated according to the procedure described in Example 11 except that 1.92 mL of 1-iodooctane was used. The procedure yielded 5.3 g of alkylated product.
20. Alkylation of Poly(allylamine) Crosslinked with epichlorohydrin with 1-iodododecane and glycidyl-propyltrimethylammonium chloride alkylating Agents
Poly(allylamine) crosslinked with epichlorohydrin prepared as described in Example 4 (20 g) was alkylated according to the procedure described in Example 11 except that 23.66 g of 1-iodododecane, 6.4 g of sodium hydroxide, and 500 mL of methanol were used. 24 grams of the alkylated product was then reacted with 50 g of 90% glycidylpropyltrimethylammonium chloride in methanol (1 L). The mixture was stirred at reflux for 24 hours, after which it was cooled to room temperature and washed successively with water (three times using 2.5 L each time). Vacuum drying afforded 22.4 g of dialkylated product.
Dialkylated products were prepared in an analogous manner by replacing 1-iodododecane with 1-iododecane and 1-iodooctadecane, respectively, followed by alkylation with glycidylpropyltrimethylammonium chloride.
21. Alkylation of Poly(allylamine) Crosslinked with epichlorohydrin with glycidylpropyltrimethylammonium chloride alkylating Agent
Poly(allylamine) crosslinked with epichlorohydrin prepared as described in Example 4 (5 g) was reacted with 11.63 g of 90% glycidylpropyltrimethylammonium chloride (1 mole equiv.) in methanol (100 mL). The mixture was stirred at 60° C. for 20 hours, after which it was cooled to room temperature and washed successively with water (three times using 400 mL each time) and isopropanol (one time using 400 mL). Vacuum drying afforded 6.93 g of alkylated product.
Alkylated products were prepared in an analogous manner using 50%, 200%, and 300% mole equiv of 90% glycidylpropyltrimethylammonium chloride.
22. Alkylation of Poly(allylamine) Crosslinked with epichlorohydrin with (10-bromodecyl)trimethylammonium bromide alkylating Agent
The first step is the preparation of (10-bromodecyl)trimethylammonium bromide as follows.
1,10-dibromodecane (200 g) was dissolved in methanol (3 L) in a 5 liter three neck round bottom flask fitted with a cold condenser (−5° C.). To this mixture was added aqueous trimethylamine (176 mL of a 24% aqueous solution, w/w). The mixture was stirred at room temperature for 4 hours, after which is was heated to reflux for an additional 18 hours. At the conclusion of the heating period, the flask was cooled to 50° C. and the solvent removed under vacuum to leave a solid mass. Acetone (300 mL) was added and the mixture stirred at 40° C. for 1 hour. The solid was filtered off, resuspended in an additional portion of acetone (1 L), and stirred for 90 minutes.
At the conclusion of the stirring period, the solid was filtered and discarded, and the acetone fractions were combined and evaporated to dryness under vacuum. Hexanes (about 1.5 L) were added and the mixture then stirred for 1 hour, after which the solid was filtered off and then rinsed on the filtration funnel with fresh hexanes. The resulting solid was then dissolved in isopropanol (75 mL) at 40° C. Ethyl acetate (1500 mL) was added and the temperature raised to about 50° C. to fully dissolve all solid material. The flask was then wrapped in towels and placed in a freezer for 24 hours, resulting in the formation of solid crystals. The crystals were filtered off, rinsed in cold ethyl acetate, and dried in a vacuum oven at 75° C. to yield 100.9 g of (10-bromodecyl)trimethyl-ammonium bromide as white crystals.
Poly(allylamine) crosslinked with epichlorohydrin prepared as described in Example 4 (10 g) was suspended in methanol (300 mL). Sodium hydroxide (3.3 g) was added and the mixture stirred until it dissolved. (10-bromodecyl)trimethylammonium bromide (20.7 g) was added and the mixture was refluxed with stirring for 20 hours. The mixture was then cooled to room temperature and washed successively with methanol (two times using 1 L each time), sodium chloride) two times using 1 L of 1 M solution each time), water (three times using 1 L each time), and isopropanol (one time using 1 L). Vacuum drying yielded 14.3 g of alkylated product.
23. Alkylation of Poly(allylamine) Crosslinked with epichlorohydrin with (10-bromodecyl)trimethylammonium bromide and 1,10-dibromodecane alkylating Agents
1,10-dibromodecane (200 g) was dissolved in methanol (3 L) in a 5 liter round bottom flask fitted with a cold condenser (−5° C.). To this mixture was added aqueous trimethylamine (220 mL of a 24% aqueous solution, w/w). The mixture was stirred at room temperature for 4 hours, after which it was heated to reflux for an additional 24 hours. The flask was then cooled to room temperature and found to contain 3350 mL of clear liquid.
Poly(allylamine) crosslinked with epichlorohydrin prepared as described in Example 4 (30 g) was suspended in the clear liquid (2 L) and stirred for 10 minutes. Sodium hydroxide (20 g) was then added and the mixture stirred until it had dissolved. Next, the mixture was refluxed with stirring for 24 hours, cooled to room temperature, and the solid filtered off. The solid was then washed successively with methanol (one time using 10 L), sodium chloride (two times using 10 L of a 1 M solution each time), water (three times using 10 L each time), and isopropanol (one time using 5 L). Vacuum drying afforded 35.3 g of dialkylated product.
24. Alkylation of Poly(allylamine) Crosslinked with epichlorohydrin with (10-bromodecyl)trimethylammonium bromide and 1-bromodecane alkylating Agents
Poly(allylamine) crosslinked with epichlorohydrin prepared as described in Example 4 (10 g) was suspended in methanol (300 mL). Sodium hydroxide (4.99 g) was added and the mixture stirred until it dissolved. (10-bromodecyl)trimethylammonium bromide prepared as described in Example 22 (20.7 g) and 1-bromodecane were added and the mixture was refluxed with stirring for 20 hours. The mixture was then cooled to room temperature and washed successively with methanol (two times using 1 L each time), sodium chloride (two times using 1 L of a 1 M solution each time), water (three times using 1 L each time), and isopropanol (one time using 1 L). Vacuum drying yielded 10.8 g of dialkylated product.
Dialkylated products were also prepared in analogous fashion using different amounts of 1-bromodecane as follows: (a) 3.19 g 1-bromodecane and 4.14 g sodium hydroxide to yield 11.8 g of dialkylated product; (b) 38.4 g 1-bromodecane and 6.96 g sodium hydroxide to yield 19.1 g of dialkylated product.
Dialkylated products were also prepared in analogous fashion using the following combinations of alkylating agents: 1-bromodecane and (4-bromobutyl)trimethylammonium bromide; 1-bromodecane and (6-bromohexyl)trimethylammonium bromide; 1-bromodecane and (8-bromooctyl)trimethylammonium bromide; 1-bromodecane and (2-bromoethyl)trimethylammonium bromide; 1-bromodecane and (3-bromopropyl)trimethylammonium bromide; 1-bromohexane and (6-bromohexyl)trimethylammonium bromide; 1-bromododecane and (12-bromododecyl)trimethyl-ammonium bromide; and 1-bromooctane and (6-bromohexyl)trimethylammonium bromide.
25. Alkylation of Poly(allylamine) Crosslinked with epichlorohydrin with 11-bromo-1-undecanol alkylating Agent
Poly(allylamine) crosslinked with epichlorohydrin prepared as described in Example 4 (5.35 g) was suspended in methanol (100 mL). Sodium hydroxide (1.10 g) was added and the mixture stirred until it dissolved. 11-bromo-1-undecanol (5.0 g) was added and the mixture was refluxed with stirring for 20 hours, after which it was cooled to room temperature and washed successively with methanol (one time using 3 L), sodium chloride (two times using 500 mL of a 1 M solution each time), and water (three times using 1 L each time). Vacuum drying yielded 6.47 g of alkylated product.
The reaction was also performed using 1.05 g sodium hydroxide and 10 g 11-bromo-1-undecanol to yield 8.86 g of alkylated product.
26. Alkylation of Poly(allylamine) Crosslinked with epichlorohydrin with N-(2,3-epoxypropane)butyramide alkylating Agent
The first step is the preparation of N-allyl butyramide as follows.
Butyroyl chloride (194.7 g, 1.83 mol) in 1 L of tetrahydrofuran was added to a three neck round bottom flask equipped with a thermometer, stir bar, and dropping funnel. The contents of the flask were then cooled to 15° C. in an ice bath while stirring. Allylamine (208.7 g, 3.65 mol) in 50 mL of tetrahydrofuran was then added slowly through the dropping funnel while maintaining stirring. Throughout the addition, the temperature was maintained at 15° C. After addition was complete, stirring continued for an additional 15 minutes, after which the solid allylamine chloride precipitate was filtered off. The filtrate was concentrated under vacuum to yield 236.4 g of N-allyl butyramide as a colorless viscous liquid.
N-allyl butyramide (12.7 g, 0.1 mol) was taken into a 1 L round bottom flask equipped with a stir bar and air condenser. Methylene chloride (200 mL) was added to the flask, followed by 3-chloroperoxybenzoic acid (50–60% strength, 200 g) in five portions over the course of 30 minutes and the reaction allowed to proceed. After 16 hours, TLC analysis (using 5% methanol in dichloromethane) showed complete formation of product. The reaction mixture was then cooled and filtered to remove solid benzoic acid precipitate. The filtrate was washed with saturated sodium sulfite solution (two times using 100 mL each time) and then with saturated dosium bicarbonate solution (two times using 100 mL each time). The dichloromethane layer was then dried with anhydrous sodium sulfate and concentrated under vacuum to yield 10.0 g of N-(2,3-epoxypropane)butyramide as a light yellow viscous liquid.
Poly(allylamine) crosslinked with epichlorohydrin prepared as described in Example 4 (10 g, −80 sieved) and methanol (250 mL) were added to a 1 L round bottom flask, followed by N-(2,3-epoxypropane)butyramide (0.97 g, 0.0067 mol, 5 mol %) and then sodium hydroxide pellets (0.55 g, 0.01375 mol). The mixture was stirred overnight at room temperature. After 16 hours, the reaction mixture was filtered and the solid washed successively with methanol (three times using 300 mL each time), water (two times using 300 mL each time), and isopropanol (three times using 300 mL each time. Vacuum drying at 54° C. overnight yielded 9.0 g of the alkylated product as a light yellow powder.
Alkylated products based upon 10 mol %, 20 mol %, and 30 mol % N-(2,3-epoxypropane)butyramide were prepared in analogous fashion except that (a) in the 10 mol % case, 1.93 g (0.013 mol) N-(2,3-epoxypropane)butyramide and 1.1 g (0.0275 mol) sodium hydroxide pellets were used to yield 8.3 g of alkylated product, (b) in the 20 mol % case, 3.86 g (0.026 mol) N-(2,3-epoxypropane)butyramide and 2.1 g (0.053 mol) sodium hydroxide pellets were used to yield 8.2 g of alkylated product, and (c) in the 30 mol % case, 5.72 g (0.04 mol) N-(2,3-epoxypropane)butyramide and 2.1 g (0.053 mol) sodium hydroxide pellets were used to yield 8.32 g of alkylated product.
27. Alkylation of Poly(allylamine) Crosslinked with epichlorohydrin with N-(2,3-epoxypropane)hexanamide alkylating Agent
The first step is the preparation of N-allyl hexanamide as follows.
Hexanoyl chloride (33 g, 0.25 mol) in 250 mL of tetrahydrofuran was added to a three neck round bottom flask equipped with a thermometer, stir bar, and dropping funnel. The contents of the flask were then cooled to 15° C. in an ice bath while stirring. Allylamine (28.6 g, 0.5 mol) in 200 mL of tetrahydrofuran was then added slowly through the dropping funnel while maintaining stirring. Throughout the addition, the temperature was maintained at 15° C. After addition was complete, stirring continued for an additional 15 minutes, after which the solid allylamine chloride precipitate was filtered off. The filtration was concentrated under vacuum to yield 37 g of N-allyl hexanamide as a colorless viscous liquid.
N-allyl hexanamide (16 g, 0.1 mol) was taken into a 1 L round bottom flask equipped with a stir bar and air condenser. Methylene chloride (200 mL) was added to the flask, followed by 3-chloroperoxybenzoic acid (50–60% strength, 200 g) in five portions over the course of 30 minutes and the reaction allowed to proceed. After 16 hours, TLC analysis (using 5% methanol in dichloromethane) showed complete formation of product. The reaction mixture was then cooled and filtered to remove solid enzoic acid precipitate. The filtrate was washed with saturated sodium sulfite solution (two times using 100 mL each time) and then with saturated sodium bicarbonate solution (two times using 100 mL each time). The dichloromethane layer was then dried with anhydrous sodium sulfate and concentrated under vacuum to yield 14.2 g of N-(2,3-epoxypropane)hexanamide as a light yellow viscous liquid.
Poly(allylamine) crosslinked with epichlorohydrin prepared as described in Example 4 (10 g, −80 sieved) and methanol (250 mL) were added to a 1 L round bottom flask, followed by N-(2,3-epoxypropane)hexanamide (4.46 g, 0.026 mol, 20 mol %) and then sodium hydroxide pellets (2.1 g, 0.053 mol). The mixture was stirred overnight at room temperature. After 16 hours, the reaction mixture was filtered and the solid washed successively with methanol (three times using 300 mL each time), water (two times using 300 mL each time), and isopropanol (three times using 300 mL each time. Vacuum drying at 54° C. overnight yielded 9.59 g of the alkylated product as a light yellow powder.
An alkylated product based upon 30 mol % N-(2,3-epoxypropane)hexanamide was prepared in analogous fashion except that 6.84 g (0.04 mol) N-(2,3-epoxypropane)hexanamide was used to yield 9.83 g of alkylated product.
28. Alkylation of Poly(allylamine) Crosslinked with epichlorohydrin with (6-bromohexyl)trimethylammonium bromide and 1-bromodecane alkylating Agent
To a 12-1 round bottom flask equipped with a mechanical stirrer, a thermometer, and a condenser is added methanol (5 L) and sodium hydroxide (133.7 g). The mixture is stirred until the solid has dissolved and crosslinked poly(allylamine) (297 g; ground to −80 mesh size) is added along with additional methanol (3 L). (6–Bromohexyl)trimethylammonium bromide (522.1 g) and 1-bromodecane (311.7 g) are added and the mixture heated to 65° C. with stirring. After 18 hours at 65° C. the mixture is allowed to cool to room temperature. The solid is filtered off and rinsed by suspending, stirring for 30 minutes, and filtering off the solid from: methanol, 12 L; methanol, 12 L; 2 M aqueous NaCl, 22 L; 2 M aqueous NaCl, 22 L; deionized water, 22 L; deionized water, 22 L; deionized water, 22 L and isopropanol, 22 L. The solid is dried in a vacuum oven at 50° C. to yield 505.1 g of off-white solid. the solid is then ground to pass through an 80 mesh sieve.
Testing of Polymers
Preparation of Artificial Intestinal Fluid
Sodium carbonate (1.27 g) and sodium chloride (1.87 g) were dissolved in 400 mL of distilled water. To this solution was added either glycocholic acid (1.95 g, 4.0 mmol) or glycochenodeoxycholic acid (1.89 g, 4.0 mmol) to make a 10 mM solution. The pH of the solution was adjusted to 6.8 with acetic acid. These solutions were used for the testing of the various polymers.
Polymers were tested as follows.
To a 14 mL centrifuge tube was added 10 mg of polymer and 10 mL of a bile salt solution in concentrations ranging from 0.1–10 mM prepared from 10 mM stock solution (prepared as previously described) and buffer without bile salt, in the appropriate amount. The mixture was stirred in a water bath maintained at 37° C. for three hours. The mixture was then filtered. The filtrate was analyzed for total 3-hydroxy steroid content by an enzymatic assay using 3a-hydroxy steroid dehydrogenase, as described below.
Enzymatic Assay for Total Bile Salt Content
Four stock solutions were prepared.
Solution 1—Tris-HCl buffer, containing 0.133 M Tris, 0.666 mM EDTA at pH 9.5.
Solution 2—Hydrazine hydrate solution, containing 1 M hydrazine hydrate at pH 9.5.
Solution 3—NAD solution, containing 7 mM NAD+ at pH 7.0.
Solution 4—HSD solution, containing 2 units/mL in Tris-HCl buffer (0.03 M Tris, 1 mM EDTA) at pH 7.2.
To a 3 mL cuvette was added 1.5 mL of Solution 1, 1.0 mL of Solution 2, 0.3 mL of solution 3, 0.1 mL of Solution 4 and 0.1 mL of supernatant/filtrate from a polymer test as described above. The solution was placed in a UV-VIS spectrophotometer and the absorbance (O.D.) of NADH at 350 nm was measured. The bile salt concentration was determined from a calibration curve prepared from dilutions of the artificial intestinal fluid prepared as described above.
All of the polymers previously described were tested in the above manner and all were efficacious in removing bile salts from the artificial intestinal fluid.
Use
The polymers according to the invention may be administered orally to a patient in a dosage of about 1 mg/kg/day to about 10 g/kg/day; the particular dosage will depend on the individual patient (e.g., the patient's weight and the extent of bile salt removal required). The polymer may be administrated either in hydrated or dehydrated form, and may be flavored or added to a food or drink, if desired to enhance patient acceptability. Additional ingredients such as other bile acid sequestrants, drugs for treating hypercholesterolemia, atherosclerosis or other related indications, or inert ingredients, such as artificial coloring agents may be added as well.
Examples of suitable forms for administration include pills, tablets, capsules, and powders (e.g., for sprinkling on food). The pill, tablet, capsule, or powder can be coated with a substance capable of protecting the composition from the gastric acid in the patient's stomach for a period of time sufficient to allow the composition to pass undisintegrated into the patient's small intestine. The polymer may be administered alone or in combination with a pharmaceutically acceptable carrier substance, e.g., magnesium carbonate, lactose, or a phospholipid with which the polymer can form a micelle.
While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. | 1a
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CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser. No. 11/166,817 filed on Jun. 24, 2005 the entire disclosure of which is incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] This invention relates to the treatment of acne vulgaris, commonly known simply as “acne.” Acne is a disease of the skin in which the pilosebaceous structures of the skin become inflamed, leading to the formation of comedones, pustules and nodules. Acne can lead to permanent scarring in severe cases.
[0003] It is generally believed that acne arises when hyperkeratosis of the pilosebaceous structure wholly or partially blocks the opening of the structure, resulting in comedones filled with sebum, keratin, and Propionibacterium acnes . These lesions are commonly identified as acne. P. acnes naturally occurs in normal skin, but is especially and characteristically present in acne lesions. It is believed that metabolic byproducts and waste from P. acnes within the pilosebaceous structures cause or contribute to the inflammation of acne lesions.
[0004] Conventional acne treatments have taken many forms. Topical keratolytic agents, such as salicylic acid are sometimes used. Keratolytic agents are thought to encourage the opening up of blocked pilosebaceous structures, thereby reducing conditions that are favorable to inflammation. Benzoyl peroxide, an anti-microbial, remains a popular and effective treatment. Topical antibiotics, such as clindamycin, which are effective against P. acnes , have also been used with a view towards preventing the formation of metabolic byproducts from this organism. Topical retinoids such as tretinoin have also been used in the treatment of acne.
[0005] Systemic (i.e. non-topical) treatments for acne include the use of oral antibiotics in more serious cases. These treatments are directed towards the reduction in the amount P. acnes in the skin, especially the pilosebaceous structures, and seek to reduce the inflammation caused by waste materials and metabolic byproducts from these organisms. Tetracycline antibiotics are most commonly used for this purpose. These include tetracycline, minocycline and doxycycline. Erythromycinis also sometimes used.
[0006] Standard oral minocycline therapy for acne in pediatric patients calls for the administration of a 4 mg/kg initial loading dose, and a 2 mg/kg dose every 12 hours thereafter. This results in a dose of 6 mg/kg on the first day of treatment and a 4 mg/kg dose each day thereafter. In adults, a 200 mg initial dose is followed by a 100 mg dose every 12 hours thereafter. In a typical patient, this results in about a 4.5 mg/kg dose on the first day of treatment, and 3.0 mg/kg dose each day thereafter.
[0007] In cases where acne does not respond to oral antibiotic treatment, oral isotretinoin is sometimes used. While effective, isotretinoin is also powerfully teratogenic, and women of childbearing age are required to use multiple methods of contraception while taking the drug.
[0008] While oral tetracycline antibiotics remain a highly favored and widely used treatment for more serious cases of acne, it is not without side effects. Vestibular side effects, including extreme dizziness and concomitant nausea, can be so severe as to result in discontinuance of tetracycline therapy. Long term use can sometimes result in vaginal candidisis, esophageal erosions and in antibiotic resistant infections.
[0009] Some recent research has indicated that very low doses of oral tetracycline can result in some improvement of acne even though the dose of tetracycline is too low to have an antibiotic effect. This observation has been attributed to an anti-inflammatory effect of tetracycline compounds. This effect has been reported to have been observed even where a chemically modified tetracycline that have no antibiotic properties are used. The use of tetracycline antibiotics at a dose too low to have an antibiotic effect or the use of modified tetracycline having no antibiotic properties as treatments for acne has never been approved by any drug regulatory agency.
SUMMARY OF THE INVENTION
[0010] According to the present invention, a method is provided for the treatment of acne in which an antibiotically effective dose of an oral tetracycline, such as minocycline, is provided. This dose is approximately 1 milligram per kilogram of body weight (1 mg/kg), without an initial loading dose of antibiotic. This antibiotic dosing regimen has been found to be as effective as a conventional dosing regimen incorporating a significant initial loading dose and higher subsequent doses. However, the dosing method of the current invention produces far fewer side effects.
[0011] In another aspect of this invention, the oral tetracycline is provided in a dosage form that provides for the continued release of the antibiotic between doses, as opposed to an immediate or nearly immediate release of the drug.
DETAILED DESCRIPTION OF THE INVENTION
[0012] According to the present invention, acne vulgaris is treated by the use of an oral tetracycline antibiotic, preferably minocycline. This antibiotic is administered in an antibiotically effective amount of approximately 1.0 milligram per kilogram of body weight per day (1.0 mg/kg/day). While this may be accomplished by the use of divided doses, it is preferred that the tetracycline antibiotic be delivered in a single daily dose. This treatment regime is initiated without a loading dose, and is continued until resolution or substantial resolution of the patient's acne. The course of treatment typically lasts 12 to up to 60 weeks, but will be adjusted according to the disease status and other medical conditions of each patient in the exercise of ordinary good clinical judgment by the patient's health care provider.
[0013] Controlled, double-blinded studies were undertaken to determine the effectiveness of this invention. Treatment of 473 patients with acne was undertaken according to the present invention. Placebos were provided to 239 patients. The effectiveness of the invention in treating acne vulgaris is shown in Table 1.
TABLE 1 Total Lesion Counts Total Lesions Total Lesions (as Percent of Baseline) Baseline (mean) 169.3 100 Day 28 (mean) 134.0 78 Day 56 (mean) 119.3 69 Day 84 (mean) 112.3 66 Inflammatory Lesion Counts Inflammatory Inflammatory Lesions Lesions (as Percent of Baseline) Baseline (mean) 77.4 100 Day 28 (mean) 52.1 66 Day 56 (mean) 44.3 56 Day 84 (mean) 41.9 53
[0014] While effective as a treatment for acne, this resulted in almost no side effects above those observed with a placebo, as shown in Table 2.
TABLE 2 % Subjects with Adverse Events Minocycline Placebo At least One Adverse Event 56.2 54.1 At Least One Serious 0.4 0 Adverse Event Blood/Lymphatic System 0.3 0.3 Disorders Cardiac Disorders 0.3 0 Ear and Labyrinth Disorders 3.6 3.3 Endocrine Disorders 0.3 0 Eye Disorders 2.2 2.7 Gastrointestinal Disorders 21.2 26.1 General Disorders and 13.8 10.4 Administrative Site Conditions Immune System Disorders 0.7 2.5 Infections and Infestations 9.3 11.0 Laboratory Blood 0.7 1.1 Abnormalities Metabolism and Nutrition 0.6 0.3 Disorders Musculoskeletal and 4.6 3.6 Connective Disorders Neoplasms Benign, 0.1 0 Malignant and Unspecified Nervous System Disorders 29.2 25.8 Psychiatric Disorders 6.4 7.1 Renal and Urinary Disorders 0.3 0.5 Reproductive System and 0.7 0.3 Breast Disorders Respiratory, Thoracic and 5.3 6.9 Mediastinal Disorders Skin and Subcutaneous 8.6 7.1 Tissue Disorders Vascular Disorders 1.0 0.3
[0015] The effectiveness of this invention can be seen by comparing the above efficacy data with published data on the effectiveness of conventional tetracycline treatments for acne in the reduction of total acne lesions and in the reduction of inflammatory lesions. See, e.g. Hersel & Gisslen, “Minocycline in Acne Vulgaris: A Double Blind Study,” Current Therapeutic Research, 1976.
[0016] Because of the variations in body weight encountered in clinical practice, in the actual practice of this invention it is not practical to provide every patient with exactly 1 mg/kg/day of oral tetracycline antibiotic. However, it is acceptable to approximate this dose by providing the patient with from 0.5 to 1.5 mg/kg/day although from 0.7 to 1.3 mg/kg/day is preferred, and 1.0 mg/kg/day is ideal.
[0017] While it can be effective to provide the oral tetracycline antibiotic in divided doses taken over the course of a day (e.g. twice or three times a day), it is preferable to provide the oral tetracycline antibiotic in a dosage form that releases the antibiotic slowly during the course of a day so that once-a-day dosing is possible. While delayed release dosage forms are known in the art, the formulation of them is far from predictable and the selection of a specific delayed release formulation is accomplished more by trial and error than by mathematical prediction based on known properties of delay release agents. No delayed release product useful in the present invention has been known heretofore.
[0018] It has been discovered that the ratio of fast dissolving carriers to slow dissolving carriers in the core caplet is important in obtaining a dissolution profile that enables once-a-day dosing in accordance with the present invention. By keeping the ratio of these components within a certain range, one may obtain this result.
[0019] The fast dissolving carrier is any binder, vehicle, or excipient that quickly dissolves in an aqueous physiological medium, such as gastric fluid, thereby tending to quickly release the active ingredient. Lactose, its salts and hydrates are good examples of such components. It has been observed that sometimes a portion of the fast dissolving components are formulated in a manner that results in the complete or partial encapsulation or inclusion or coating of these fast-dissolving materials in granules of slow-dissolving materials. These encapsulated materials are excluded from the calculation of the above mentioned ratio of fast-dissolving to slow dissolving components.
[0020] A slow dissolving carrier is any binder, vehicle, or excipient that dissolves slowly over the course of hours and perhaps a day, thereby slowing the release of the active ingredient. Examples of such components are polyvinyl pyrrolidone, polyvinyl acetate, microcrystalline cellulose, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, or waxy or lipid-based tableting agents such as magnesium stearate or calcium stearate. Outer “enteric” coatings are excluded from this amount when calculating the above-mentioned ratio.
[0021] Insoluble carriers are binders, vehicles, or excipients that are practically insoluble in physiological fluids, such as gastric fluid, and includes compounds, such as silicon dioxide and talc.
[0022] While the exact formulation of these dosage forms can vary, it has been observed that it is advantageous to formulate them so that the ratio of fast dissolving carriers to slow dissolving carriers is from 0.30 to 0.50, and preferably from 0.35 to 0.45. A ratio of about 0.36 to 0.40 is particularly preferable.
[0023] Dosage forms, such as capsules, tablets, and caplets that release 25 to 52% of the antibiotics within 1 hour, 53 to 89% in 2 hours, and at least 90% within 4 hours are suited to the once-a-day dosage regimen contemplated by the current inventories. More preferably, 30 to 52% of the antibiotic is released within 1 hour, 53 to 84% within 2 hours, and at least 85% within 4 hours.
[0024] Alternatively, the oral tetracycline antibiotic may be delivered in a dosage form that releases the antibiotic in such a way that the maximum blood concentration of the antibiotic (C max ) is reached at about 3.5 hours after administration (T max ). In actual practice of the invention, the C max should be reached between 2.75 and 4.0 after administration, more preferably between 3.0 and 3.75 after administration.
[0025] As examples of such a once-a-day formulation, one may use the following:
Quantity Component (mg) 135 mg Caplet Minocycline (as 145.8 hydrochloride) (dry weight) Lactose 107.4 Monohydrate (intragranular) Lactose 43.8 Monohydrate (extragranular) Total Lactose 151.2 Monohydrate HPMC 94 Silicon Dioxide 3 Mg. Stearate 6 45 mg Caplet Minocycline (as 48.6 hydrochloride) (dry weight) Lactose 192.2 Monohydrate (intragranular) Lactose 42.2 Monohydrate (extragranular) Total Lactose 234.40 Monohydrate HPMC 108 Silicon Dioxide 3 Mg. Stearate 6
[0026] Each of these components is combined in a conventional fashion, compressed in a tabletting apparatus, and then provided in a conventional manner with a suitable coating, such as, without limitation Opadry II and optional coloring. | 1a
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CROSS REFERENCE TO RELATED APPLICATION
This application claims the filing benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 60/405,659, filed Aug. 26, 2002, which is included herein by reference.
TECHNICAL FIELD
The present invention pertains generally to electro-muscle stimulation (EMS), and more particularly to a method and system for applying a varying level of EMS as a user activates an exercise apparatus.
BACKGROUND OF THE INVENTION
Electro-muscle stimulation (EMS) is well known in the medical art. This technology utilizes a conductive pad or electrode to externally apply a very weak current to a muscle or group of muscles and thereby cause them to contract. The electrode receives an electric stimulation signal from an external voltage/current source, such as an EMS machine. The stimulation signal can be adjusted in amplitude, polarity, frequency, waveform, etc. EMS is commonly used in physical or occupational therapy to strengthen atrophied muscles or paralyzed limbs. It is also used to exercise muscles that are immobilized for long periods of time as a result of muscular or neurological disorders, or extended periods of bed rest arising from injury, surgery, or illness. EMS is also useful for the general exercise of functional muscles to improve muscle tone and strength. For example, athletes can use EMS to treat muscle injuries as a supplement to conventional conditioning exercises. EMS can also be used to recondition muscles or muscle groups which have, for whatever reason, lost their tone and/or strength, have been injured, or are in need of reconditioning to effect cosmetic improvements. An operator who has been trained in the principles of EMS can analyze the areas which are of concern and select the proper muscles to exercise and train.
For example, U.S. Pat. No. 6,341,237 illustrates a device for administrating EMS which includes a flexible covering having a plurality of spaced apart electrodes. In a preferred embodiment, the flexible covering is shaped like a band or belt, and is designed to encircle and be connected around a portion of a patient's body. The band or belt is fabricated from an elastic material so that the electrodes are pressed against the skin of the patient to promote better electrical conduction. Electrodes are selectively positionable to different locations on the flexible covering so they may be placed directly over a selected muscle or muscle group. Each electrode has its individual control for adjusting the level of the electrical stimulation signal so that different muscles can receive different levels of stimulation and the level of stimulation may be changed during the course of treatment. A master adjustment control can be used to adjust the stimulation signal level applied to all electrodes. In a preferred embodiment, the individual adjustment controls are located adjacent their respective electrodes on the flexible covering. U.S. Pat. No. 4,480,830 illustrates a method and apparatus for exercising paralyzed muscles. The method and apparatus make use of a set of transcutaneous electrodes which are placed upon the skin of the subject over muscles which are to be stimulated. A computer controlled stimulator generates a pair of alternately pulsed stimulation signals which are applied across different pairs of stimulation electrodes to produce controlled muscle contraction. Muscle movement is resisted by a dynamic load and a position sensor provides a feedback signal indicating the movement actually achieved. The computer uses the feedback signal for modifying the control signal applied to the stimulator. U.S. Pat. No. 4,499,990 shows a system and method for treating persons with paralyzed legs. The apparatus and method include four sets of transcutaneous electrodes which are placed above the iliac and quadriceps muscles of the paralyzed person. The person is seated upon an exercycle and a series of pulsed stimulation signals are applied to the electrodes to cause coordinated contraction of the iliac and quadriceps muscles. This causes pedaling of the exercycle by the paralyzed legs. A position sensor senses the position of the pedals and transmits an indication thereof to a computer which generates control signals for stimulation driving circuits connected to the stimulation electrodes. U.S. Pat. No. 4,586,495 illustrates an apparatus and method for stimulating muscular activity in an acutely injured patient. A leg which is to be stimulated is strapped into a brace and the leg muscles are stimulated to work isometrically against the brace. The effort exerted by the muscles is measured by load cells which generate feedback signals for a control computer. The computer adjusts the stimulation signals in accordance with the received feedback signals. U.S. Pat. No. 4,586,510 discloses an apparatus for exercising a paralyzed limb by functional electrical stimulation. The system utilizes simple analog devices including a reference signal generator, a position sensor, and an error signal generator. The error signal is integrated to produce a stimulation driving signal for application to the stimulation electrodes mounted on the limb. In the disclosed embodiment, the paralyzed person may be seated in an exercise chair which is equipped with a pair of loading assemblies which are attachable to the legs of the person so as to yieldingly resist the stimulated movement. U.S. Pat. No. 4,724,842 shows a method and apparatus for muscle stimulation. An exercise machine or dynamometer is provided with control apparatus for ascertaining the physical position of a patient during an exercise. The patient is then electrically stimulated over selected ranges of motion in order to aid in the exercise. U.S. Pat. No. 5,070,873 includes a method of and apparatus for electrically stimulating quadriceps muscles of an upper motor unit paraplegic. Muscle fatigue of an electrically stimulated quadriceps muscle of an upper motor neuron paraplegic is detected and compensated for by monitoring the myoelectric (EMG) signal produced by the stimulated muscle and controlling one or more of the following parameters of the electrical stimulation (ES) signal: pulse repetition rate, amplitude, and pulse width. U.S. Pat. No. 5,507,788 illustrates a method and apparatus for controlling skeletal muscle fatigue during electrical stimulation. Electrical stimulation signals are applied to muscles at a frequency which is varied in response to a detected ripple signal in an output tension or torque record which corresponds to the fusion of the multiple muscle contractions. An average torque amplitude is first determined when a stimulation signal is applied at an initial frequency. The amplitude of the ripple on the torque output is then determined and compared to the average torque amplitude to provide a ripple percentage. The measured ripple percentage is compared to a selected ripple percentage corresponding to the desired fusion of the multiple muscle contractions. And the stimulation frequency is adjusted by a feedback loop until the measured ripple percentage conforms to the selected value. U.S. Pat. No. 5,628,722 shows a method for maintaining knee stability of a user suffering from damage to a knee ligament. The method includes a sensor feedback system for measuring abnormal physical relationships between the tibia and femur. The sensor feedback system determines whether selected conditions have been met warranting the application of electrical stimulation and provides information regarding the determination to an electronic stimulator. Electrodes are spaceably mounted on the hamstring and/or quadriceps muscles in electrical communication with the electronic stimulator for causing contraction of the thigh muscles at selected levels, thus providing a posteriorly and/or anteriorly directed force to the upper tibial bone and thereby preventing its instability.
SUMMARY OF THE INVENTION
The present invention is directed to a method and associated system for applying varying electro-muscle stimulation. The method can be practiced on any exercise apparatus which has a rotational element upon which the user exerts a force during the course of exercising. A transducer senses the rotation of the exercise apparatus, and delivers an output signal to an EMS covering such as a belt which is placed on a target muscle group of the user. As the user works to rotate the apparatus, the output signal of the transducer increases from zero at no rotation to a maximum value as a function of the amount of rotation. In this fashion the electro-muscle stimulation rises smoothly as the muscle moves during flexion and peaks upon full contraction or end phase of motion.
A preferred name for the present invention is electro-augmented myociser. The electro-augmented myociser is to be used concurrently with an electro myociser belt, which consists of a belt having electrodes strategically placed to stimulate specific muscles of the body. Electrical signals, directed by the location of the electrodes within the belt, are emitted causing contraction of targeted muscles.
The purpose of the electro-augmented myociser is to augment and enhance natural exercise by encouraging maximum muscle contraction of those muscles that are easily exercised. It also isolates and enhances contraction of targeted muscle groups that are difficult to exercise. Controls allow the user to establish the level of difficulty that is comfortable and change the level during use. Additionally, the user may change the stimulus to specific sites within a muscle group during use.
The present invention may be incorporated in a vast variety of exercise apparatus including but not limited to equipment used to exercise the abdomen, deltoids, biceps, hamstrings, and quadriceps. It operates under the principle of voltage application being supplied only as the person contracts or actuates his or her muscles. As the person exercises activating a range of motion, the exercise apparatus moves or pivots. The movement or rotation of the equipment is mechanically coupled to a transducer that controls the output of the electrical stimulus. The voltage rises smoothly as the muscle moves causing contraction to peak upon full contraction. In the opposite direction, the voltage reduces smoothly as the muscle is relaxed. When the muscle is at rest, or fully elongated, the voltage is zero. In the process of performing active exercise with augmented electro muscle stimulation, the tendons and bones realize a healthier benefit than merely administering passive muscle stimulus alone. What is completely unique about the present invention is that the voltage surge is not controlled by the machine, but is instead controlled by the actions of the individual performing the exercise. The present invention will further induce motivation by enabling the person to perform a greater number of repetitions with less effort, thereby providing enhanced muscle development in a shorter time span.
Alternately, the user may have the option of putting the electrical stimulation from the voltage source to the belt on automatic to a predesignated mode and rate when he becomes fatigued and unable to continue exercising. The preferred mode is a surge mode. For example, a surge of eight seconds on and five seconds off may be selected. This provides a constricting action on the abdominals with a rest or recovery period. The surge mode tends to give a better result than using a pulse mode.
In accordance with a preferred embodiment of the invention, a method for applying variable electro-muscle stimulation, includes:
(a) providing a flexible electro-muscle stimulation covering having a plurality of spaced apart electrodes, the electrodes disposed in a pattern upon the flexible covering which matches a predetermined group of human muscles, so that when the flexible covering is placed upon a patient, the electrodes are proximate to the predetermined group of muscles, wherein the pattern matches predetermined groups of muscles, the muscles being the upper portion of the rectus abdominus, the lower portion of the rectus abdominus, the right obliques, and the left obliques.
(b) providing an exercise system having (1) an exercise apparatus having a member which is rotatable about an axis by an exercising user, and (2) a transducer communicating with the axis, so that as the member is rotated, the transducer generates an output signal which is a function of an angular position of the member;
(c) providing an electro-muscle stimulation system which delivers a voltage to the transducer;
(d) providing electrical emphasis to certain regions over other regions within the muscle group;
(e) placing the electro-muscle stimulation covering upon a target muscle group of the user;
(f) causing the output signal to be delivered to the electro-muscle stimulation covering;
(g) the user rotating the member in a first direction thereby causing the output signal to increase thereby causing increased electro-muscle stimulation to be applied to the user; and,
(h) the user rotating the member in an opposite direction thereby causing the output signal to decrease thereby causing decreased electro-muscle stimulation to be applied to the user.
In accordance with another preferred embodiment of the invention, a method for applying variable electro-muscle stimulation, includes:
(a) providing an electro-muscle stimulation device having:
a flexible covering having a plurality of spaced apart electrodes; the electrodes including:
a first positive electrode; a second positive electrode; and, a return electrode disposed between the first and second positive electrodes;
a voltage source connected between the positive electrodes and the return electrode; and, an adjustment control which simultaneously applies a first positive voltage to the first positive electrode and a second positive voltage to the second positive electrode, so that as the first positive voltage increases, the second positive voltage decreases, and as the first positive voltage decreases, the second positive voltage increases;
(b) providing an exercise system having:
an exercise apparatus having a member which is rotatable about an axis by an exercising user; a transducer communicating with the axis; and, so that as the member is rotated, the transducer generates an output signal which is a function of an angular position of the member;
(c) providing an electro-muscle stimulation system which delivers a voltage to the transducer;
(d) placing the electro-muscle stimulation covering upon the user;
(e) causing the output signal to be delivered to the electro-muscle stimulation covering;
(f) the user rotating the member in a first direction thereby causing the output signal to increase thereby causing increased electro-muscle stimulation to be applied to the user; and,
(g) the user rotating the member in an opposite second direction, thereby causing the output signal to decrease thereby causing decreased electro-muscle stimulation to be applied to the user.
Other aspects of the present invention will become apparent from the following detailed description, taken in conjunction with the accompanying drawings, which illustrate, by way of example, the principles of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a top plan view of a prior art exercise apparatus;
FIG. 2 is a side elevation view of the prior art exercise apparatus;
FIG. 3 is a side elevation view of the prior art exercise apparatus rotated to a second position;
FIG. 4 is a top plan view of a system for applying electro-muscle stimulation in accordance with the present invention;
FIG. 5 is a side elevation view of the system;
FIG. 6 is an enlarged view of area 6 — 6 of FIG. 4 ;
FIG. 7 is an enlarged view of area 7 — 7 of FIG. 5 ;
FIG. 8 is an electrical schematic diagram of the present invention;
FIG. 9 is a graph which illustrates an output signal V θ as a function of rotational angle θ;
FIG. 10 is a reduced side elevation view of the system of the present invention being used by an exercising user in an initial position;
FIG. 11 is a reduced side elevation view of the system of the present invention being used by an exercising user in a rotated position;
FIG. 12 is a front elevation view of a user;
FIG. 13 is a side elevation view of a user;
FIG. 14 is a top plan view of the outside of an abdominal covering;
FIG. 15 is a top plan view of a second abdominal covering;
FIG. 16 is a top plan view of a third abdominal covering;
FIG. 17 is a top plan view of a second prior art exercise apparatus;
FIG. 18 is a side elevation view of the second prior art exercise apparatus;
FIG. 19 is a side elevation view of the second prior art exercise apparatus rotated to a second position;
FIG. 20 is a top plan view of a second system for applying electro-muscle stimulation in accordance with the present invention;
FIG. 21 is a side elevation view of the second system;
FIG. 22 is a side elevation view of the second system of the present invention being used by an exercising user in an initial position;
FIG. 23 is a side elevation view of the second system of the present invention rotated to a second position;
FIG. 24 is a top plan view of another covering; and,
FIG. 25 is a schematic diagram of the covering of FIG. 24 .
DETAILED DESCRIPTION OF THE INVENTION
FIGS. 1 and 2 are top plan and side elevation views, respectively, of a prior art exercise apparatus, generally designated as 500 . In the shown embodiment, exercise apparatus 500 comprises an abdominal roller which is used to exercise the abdominal muscles of an exercising user. Exercise apparatus 500 includes a member 502 which is rotatable about an axis 504 such as an axle by the exercising user. Member 502 rotates about base 506 which resides on a support surface 700 .
FIG. 3 is a side elevation view of prior art exercise apparatus 500 rotated through an angle θ to a second position.
FIGS. 4 and 5 illustrate top plan and side elevation views, respectively, of a system for applying variable electro-muscle stimulation in accordance with the present invention, generally designated as 40 . System 40 includes exercise apparatus 500 having a member 502 which is rotated about an axis 504 by an exercising user. A transducer 20 communicates with axis 504 , so that as member 502 is rotated about axis 504 , transducer 20 generates an output signal which is a function of an angular position of member 502 .
FIG. 6 is an enlarged view of area 6 — 6 of FIG. 4 . In the shown embodiment, transducer 20 is an angular position-to-voltage transducer, such as a potentiometer. Transducer 20 is connected by shaft 22 to axis of rotation 504 of member 502 , so that as member 502 is rotated, shaft 22 of transducer 20 also rotates. The housing of transducer 20 is attached to a bracket 25 which is in turn attached to base 506 . In this manner, as member 502 is rotated about axis of rotation 504 , shaft 22 rotates and changes the output signal V θ of transducer 20 (refer also to FIG. 9 ). It is noted that a plurality of transducers 20 may communicate with axis 504 , such as the two shown in the FIG. 6 . It may be appreciated that other shaft position transducers such as shaft angle encoders, digitizers, etc. could be utilized to convert the rotation of member 502 into an output signal.
FIG. 7 is an enlarged view of the area 7 — 7 of FIG. 5 . It is noted that the terminals of transducer 20 are routed to an EMS system (machine) and an EMS covering which is placed upon an appropriate part of the exercising user's body (refer also to FIGS. 8 , 10 , and 11 ).
FIG. 8 is an electrical schematic diagram of the present invention. An EMS system delivers a voltage V 1 to transducer 20 . In the shown embodiment voltage V 1 is referenced to ground, however other reference arrangements are also possible. As member 502 of exercise apparatus 500 is rotated through angle θ, the wiper of transducer 20 generates an output signal (voltage V 1 θ ) which is routed to an EMS covering such as a belt which is placed upon a part of the user's body (refer to EMS covering 550 in FIGS. 10 and 11 ). Output signal V 1 θ increases from a minimum value for θ=zero, to a value of V 1 for θ=a maximum rotational value. In the shown embodiment, two transducers 20 comprise two separate channel inputs ( 1 and 2 ) to the EMS covering. In one embodiment, the two channels deliver EMS to different muscle groups of the user. In an embodiment of the invention, a voltage level control 21 is provided on each of the two channels. The voltage level control 21 includes a potentiometer which controls the voltage (V 1 or V 2 ) delivered to transducer 20 , and thereby the intensity of the electro-muscle stimulation. The mechanical placement of the voltage level control 21 is shown in FIGS. 4 , 5 , 10 , 11 , and 20 - 23 . The voltage level control is placed so a user can conveniently control the intensity of the EMS during exercise without breaking the exercise rhythm.
FIG. 9 is a graph which illustrates the output signal V θ as a function of rotational angle θ of member 502 . The output signal V θ rises smoothly as the exercise apparatus 500 is rotated. The output signal V θ could be linear as shown in I, or nonlinear as shown in II or III.
FIGS. 10 and 11 are side elevation views of system 40 being used by an exercising user. In FIG. 10 the user is initially reclining on his or her back, and in FIG. 11 the user has rotated to the shown position. An EMS covering 120 is disposed around the user's abdomen. The output signal V θ from transducer 20 is delivered to the EMS covering 120 . As the user rotates member 502 from the position of FIG. 10 in a first direction 30 , output signal V θ increases thereby causing increasing electro-muscle stimulation. Conversely, as the user rotates member 502 in an opposite second direction 31 , output signal V θ decreases thereby causing decreasing electro-muscle stimulation. It is noted that the output signal V θ increases as the user is using his or her abdominal muscles to rotate member 502 . Applying increasing electro-muscle stimulation as the user is using his or her muscles, enhances the benefits of the exercise. Voltage level control 21 is conveniently located on member 502 adjacent the hands of the user so that the intensity of the EMS can be adjusted during exercise without breaking the exercise rhythm.
FIG. 12 is a front elevation view of a patient 706 showing the muscles of the rectus abdominis divided at the umbilical area 712 into an upper portion 708 and a lower portion 710 . The rectus abdominis includes two distinct muscles on opposite sides of the linea alba. But for purposes of this invention, they work together and are stimulated together. Line 714 defines the junction of the right and left obliques 716 with the upper portion 708 and lower portion 710 of the rectus abdominis (refer also to FIG. 13 ).
FIG. 13 is a side elevation view of the patient 706 showing the right obliques 716 . The left obliques are on the opposite side. Line 714 defines the junction of the right obliques 716 with the upper portion 708 and lower portion 710 of the rectus abdominis.
FIG. 14 illustrates a top plan view of the outside of the abdominal covering 120 of FIGS. 10 and 11 . The abdominal covering or belt is specifically designed to encircle the abdomen and stimulate the muscle groups of the central torso. Abdominal covering 120 includes a flexible covering or band 124 , selectively positionable electrodes 146 , 148 , 150 , and 152 , and connector 130 . Some of the electrodes receive a positive stimulation signal 134 and some receive a negative stimulation signal 138 . The stimulated muscles ( FIGS. 12 and 13 ) are the upper portion 708 and the lower portion 710 of the rectus abdominis, the right obliques 716 , and the left obliques. Abdominal covering 120 includes a first positive electrode 140 which, when placed upon a patient, is proximate to the upper portion 708 of the rectus abdominis, a second positive electrode 142 which, when placed upon a patient, is proximate to the lower portion of the rectus abdominis, and a third negative return or common electrode 144 disposed between first 140 and second 142 positive electrodes in the umbilical region 712 . Return electrode 144 provides a conduction path for both first positive electrode 140 and second positive electrode 142 . It is noted that second positive electrode 142 has a truncated shape, in the form of edge 143 , so as to avoid stimulation of the femoral nerve.
A fourth positive electrode 146 is placed on the left obliques on the side of the abdomen above the iliac crest and a fifth return electrode 148 is placed proximate to the junction 714 of the left obliques 716 and the upper and lower portions 708 and 710 of the rectus abdominis. The fifth return electrode 148 is disposed between the fourth positive electrode 146 and third return electrode 144 . By placing the return electrodes 144 and 148 adjacent to each other, the electrodes which stimulate the rectus abdominis are electrically isolated from the electrodes which stimulate the obliques thereby minimizing stimulation interaction. A sixth positive electrode 150 is placed on the right obliques on the side of the abdomen above the iliac crest and a seventh return electrode 152 is placed proximate to the junction 714 of the right obliques 716 and the upper and lower portions 708 and 710 of the rectus abdominis. The seventh return electrode 152 is disposed between the sixth positive electrode 150 and third return electrode 144 in order to again minimize stimulation interaction.
A voltage source such as an EMS machine provides the signals 134 and 138 . An overall control box 121 can be attached to the covering 120 , located nearby, or attached to an exercise device such as an ab roller exerciser. Individual adjustment controls 131 , 132 , and 133 determine the voltage delivered to first positive electrode 140 , fourth and sixth positive electrodes 146 and 150 , and second positive electrode 142 , respectively. A master adjustment control 135 provides overall voltage control to the individual controls 131 , 132 , and 133 . An adjustment control 136 simultaneously applies a first positive voltage 137 to fourth positive electrode 146 and a second positive voltage 138 to sixth positive electrode 150 . As first positive voltage 137 increases, second positive voltage 138 decreases. And as first positive voltage 137 decreases, second positive voltage 138 increases.
FIG. 15 illustrates a top plan view of the outside of a second abdominal covering 320 similar to abdominal covering 120 of FIG. 14 but having dual channels. Abdominal covering 320 includes a flexible covering or band 324 , selectively positionable electrodes 346 , 348 , 350 , and 352 , and connector 330 . Abdominal covering 320 includes a first positive electrode 340 which, when placed upon a patient, is proximate to the upper portion 708 of the rectus abdominis, a second positive electrode 342 which, when placed upon a patient, is proximate to the lower portion of the rectus abdominis, and a third negative return or common electrode 344 disposed between first 340 and second 342 positive electrodes in the umbilical region 712 . Return electrode 344 provides a conduction path for both first positive electrode 340 and second positive electrode 342 . It is noted that second positive electrode 342 has a truncated shape, in the form of edge 343 , so as to avoid stimulation of the femoral nerve.
A fourth positive electrode 346 is placed on the left obliques on the side of the abdomen above the iliac crest and a fifth return electrode 348 is placed proximate to the junction 714 of the left obliques 716 and the upper and lower portions 708 and 710 of the rectus abdominis. The fifth return electrode 348 is disposed between the fourth positive electrode 346 and third return electrode 344 . By placing the return electrodes 344 and 348 adjacent to each other, the electrodes which stimulate the rectus abdominis are electrically isolated from the electrodes which stimulate the obliques thereby minimizing stimulation interaction. A sixth positive electrode 350 is placed on the right obliques on the side of the abdomen above the iliac crest and a seventh return electrode 352 is placed proximate to the junction 714 of the right obliques 716 and the upper and lower portions 708 and 710 of the rectus abdominis. The seventh return electrode 352 is disposed between the sixth positive electrode 350 and third return electrode 344 in order to again minimize stimulation interaction.
A voltage source such as an EMS machine provides the channel signals 334 and 335 . The covering 320 has two channels. One channel 335 provides stimulation and intensity control to the upper, mid, and lower rectus abdominis. The other channel 334 provides stimulation and intensity control to the right and left obliques. Each channel operates independently from the other providing respective input to these muscle groups. The two diverging or balance controls 331 , 336 are mounted on the covering or belt 320 . Potentiometers may be used as the diverting devices. However, other diverting systems may also be used for example separate channels or multiple EMS units.
The first diverging control 331 distributes the electrical input 335 between the first positive electrode 340 placed over the upper rectus abdominis and the second positive electrode 342 placed over the lower rectus abdominis. The third electrode 344 located at the umbilicus acts as a return. This control facilitates the concentration of stimulation to either the upper or lower rectus abdominis. As the first positive voltage 332 to the first electrode 340 increases, the second positive voltage 333 to the second electrode 342 decreases. And as the first positive voltage decreases, the second positive voltage increases.
The second diverging control 336 distributes the electrical input 334 between the fourth positive electrode 346 over the right obliques and sixth positive electrode 350 over the left obliques. The fifth electrode 348 and sixth electrode 352 located along each junction of the obliques and rectus abdominis serve as returns. This control facilitates balance and equal stimulation of the right and left obliques. As the third positive voltage 337 to the sixth positive electrode 350 increases, the fourth positive voltage 338 to the seventh positive electrode 346 decreases. And as the third positive voltage decreases, the fourth positive voltage increases.
FIG. 16 illustrates a top plan view of the outside of a third abdominal covering 460 similar to abdominal covering 320 of FIG. 15 but having a single channel. Abdominal covering 420 includes a flexible covering or band 424 , selectively positionable electrodes 444 , 446 , 448 , 450 , and 452 , and connector 430 . The control and versatility of the covering or belt is less than the dual channel covering or belt but it is more economical. The first return electrode 444 is placed on the rectus abdominis at the umbilical region. It is adjustable with respect to placement allowing the user to target any region between the umbillical and lower rectus abdominis. The second positive electrode 452 is placed at the junction of the rectus abdominis and left oblique muscles. The third positive electrode 448 is placed at the junction of the rectus abdominis and right oblique muscles. A diverting device 431 controls the intensity balance between the second and third positive electrodes. The fourth positive electrode 450 is placed at the most lateral portion of the left obliques between the iliac crest and lower ribs. The fifth positive electrode 446 is placed at the most lateral portion of the right obliques between the iliac crest and lower ribs. Diverting device 431 simultaneously applies a first positive voltage 432 to second positive electrode 452 and a second positive voltage 433 to third positive electrode 448 . As the first positive voltage 432 increases, the second positive voltage 433 decreases. And as the first positive voltage decreases, the second positive voltage increases. A diverting device 436 controls the intensity balance between the fourth and fifth positive electrodes. Diverting device 436 simultaneously applies a third positive voltage 437 to fourth positive electrode 450 and a fourth positive voltage 438 to fifth positive electrode 446 . As the third positive voltage increases, the fourth positive voltage decreases. And as the third positive voltage decreases, the fourth positive voltage increases. A toggle switch 460 enables the user to alternatively stimulate the region between the rectus abdominis and medial obliques to target the anterior abdomen versus stimulating the region between the rectus abdominis and lateral obliques to target the lateral obliques. Generally, the lateral most aspects of the obliques are more responsive to electrical stimulation than the medial portions. A resistor 462 is therefore preferred to reduce the voltage to the lateral obliques when the toggle switch 460 is changed. This eliminates the sudden surge that may otherwise be experienced when the toggle switch is switched from the medial to lateral obliques.
FIGS. 17 and 18 illustrate top plan and side elevation views, respectively, of a second prior art exercise apparatus, generally designated as 600 . In the shown embodiment, exercise apparatus 600 comprises a chair like device which is used to exercise the legs muscles of an exercising user. Exercise apparatus 600 includes a member 602 which is rotated about an axis 604 by the leg of the exercising user. A weight 608 provides rotational resistance. Member 602 rotates about base 606 which resides on a support surface 700 .
FIG. 19 is a side elevation view of prior art exercise apparatus 600 rotated through an angle θ to a second position.
FIGS. 20 and 21 illustrate top plan and side elevation views, respectively, of a second system for applying electro-muscle stimulation in accordance with the present invention, generally designated as 140 . System 140 includes exercise apparatus 600 having a member 602 which is rotatable about an axis 604 by an exercising user. A transducer 20 communicates with axis 604 , so that as member 602 is rotated about axis 604 , transducer 20 generates an output signal which is a function of an angular position of member 602 .
FIGS. 22 and 23 are side elevation views of system 140 being used by an exercising user. In FIG. 22 the leg of the user is initially at rest and hooked under a padded roller 610 . In FIG. 23 the user has rotated member 602 to the shown position. An EMS covering 220 is disposed around the user's thigh. The output signal V θ from transducer 20 is delivered to EMS covering 220 . As the user rotates member 602 from the position of FIG. 22 in a first direction 30 , output signal V θ increases thereby causing increasing electro-muscle stimulation. Conversely, as the user rotates member 602 in an opposite second direction 31 , output signal V θ decreases thereby causing decreasing electro-muscle stimulation. It is noted that the output signal V θ increases as the user is using his or her leg muscles to rotate member 602 . Applying increasing electro-muscle stimulation as the user is using his or her muscles, enhances the benefits of the exercise. Voltage level control 21 is conveniently located adjacent the hand of the user so that the intensity of the EMS can be adjusted during exercise without breaking the exercise rhythm.
FIG. 24 is a top plan view of the covering 220 of FIGS. 22 and 23 . FIG. 25 is a schematic diagram of the covering 220 . Covering 220 includes a first positive electrode 222 and a second positive electrode 224 . A return electrode 226 is disposed between first positive electrode 222 and second positive electrode 224 . An adjustment control 228 simultaneously applies a first positive voltage 230 to first positive electrode 222 and a second positive voltage 232 to second positive electrode 224 . As first positive voltage 230 increases, second positive voltage 232 decreases. And as first positive voltage 230 decreases, second positive voltage 232 increases. A voltage/current source 500 applies an electrical stimulation signal input. Covering 220 is designed for the application of traverse stimulation. In this application, a single covering 220 is utilized in which the positive and return electrodes are placed on the same covering. The central return electrode 226 is somewhat larger in surface area than the positive electrodes 222 and 224 . This design allows the concentration of stimuli to the return electrode to become dispersed in order to dilute the intensity of the stimulation feed from both positive electrodes 222 and 224 . It may be readily appreciated that the positive and return negative or ground electrodes may be reversed.
In terms of use, a method for applying electro-muscle stimulation, includes:
(a) providing a flexible electro-muscle stimulation covering 120 having a plurality of spaced apart electrodes 140 , 142 , 144 , 146 , 148 , 150 , and 152 , said electrodes disposed in a pattern upon said flexible covering which matches a predetermined group of human muscles, so that when said flexible covering is placed upon a patient, said electrodes are proximate to the predetermined group of muscles, wherein said pattern matches predetermined groups of muscles, the muscles being the upper portion of the rectus abdominis, the lower portion of the rectus abdominis, the right obliques, and the left obliques.
(b) providing an exercise system 40 having:
an exercise apparatus 500 having a member 502 which is rotatable about an axis 504 by an exercising user; a transducer 20 communicating with axis 504 ; and, so that as member 502 is rotated, transducer 20 generates an output signal V θ which is a function of an angular position of member 502 ;
(c) providing an electro-muscle stimulation system (EMS) which delivers a voltage V 1 (and/or V 2 ) to transducer 20 ;
(d) providing electrical emphasis to certain regions over other regions within the muscle group;
(e) placing electro-muscle stimulation covering 550 upon the user;
(f) causing output signal V θ to be delivered to electro-muscle stimulation covering 550 ;
(g) the user rotating member 502 in a first direction 30 thereby causing output signal V θ to increase thereby causing increased electro-muscle stimulation to be applied to the user; and,
(h) the user rotating member 502 in an opposite direction 31 thereby causing output signal V θ to decrease thereby causing decreased electro-muscle stimulation to be applied to the user.
The method further including in step (b), transducer 20 being a potentiometer. The method further including in step (b), providing a plurality of tranducers 20 . The method further including in step (c), a voltage level control 21 connected between electro-muscle stimulation system EMS and transducer 20 ; and, so that the voltage to the transducer may be adjusted.
In terms of use, an alternate method for applying electro-muscle stimulation, includes:
(a) providing an electro-muscle stimulation device having:
a flexible covering 320 having a plurality of spaced apart electrodes 340 , 342 , 344 , 346 , 348 , 350 , and 352 ; the electrodes including:
a first positive electrode 340 ; a second positive electrode 342 ; and, a return electrode 344 disposed between the first and second positive electrodes;
a voltage source 334 connected between the positive electrodes and the return electrode; and, an adjustment control 331 which simultaneously applies a first positive voltage 332 to the first positive electrode 340 and a second positive voltage 333 to the second positive electrode 342 , so that as the first positive voltage increases, the second positive voltage decreases, and as the first positive voltage decreases, the second positive voltage increases;
(b) providing an exercise system 40 having:
an exercise apparatus 500 having a member 502 which is rotatable about an axis 504 by an exercising user; a transducer 20 communicating with the axis 504 ; and, so that as the member 502 is rotated, the transducer 20 generates an output signal V 1 which is a function of an angular position of the member 502 ;
(c) providing an electro-muscle stimulation system which delivers a voltage to the transducer;
(d) placing the electro-muscle stimulation covering 320 upon the user;
(e) causing the output signal V 1 to be delivered to the electro-muscle stimulation covering 320 ;
(f) the user rotating the member 502 in a first direction 30 thereby causing the output signal to increase thereby causing increased electro-muscle stimulation to be applied to the user; and,
(g) the user rotating the member 502 in an opposite second direction 31 , thereby causing the output signal to decrease thereby causing decreased electro-muscle stimulation to be applied to the user.
The preferred embodiments of the invention described herein are exemplary and numerous modifications, variations, and rearrangements can be readily envisioned to achieve an equivalent result, all of which are intended to be embraced within the scope of the appended claims. | 1a
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority from U.S. Provisional Patent Application Ser. No. 60/994,188 filed Sep. 18, 2007.
FIELD OF THE INVENTION
[0002] The invention relates to medical devices and more particularly to devices for use in insertion or implantation of catheters and the like into the vasculature of patients.
BACKGROUND OF THE INVENTION
[0003] Catheters are used in numerous medical procedures. In particular, catheters are used for the introduction or removal of fluids from various venous regions and vessels throughout the body, such as for hemodialysis. The procedure by which these catheters are introduced to the body is delicate and complex. One particularly intricate challenge to catheterization is enlarging a hole in the flesh and vessel to be catheterized while minimizing blood loss and trauma to the patient. Generally, to insert any catheter in a blood vessel, the vessel is identified by aspiration with a long hollow needle in accordance with the Seldinger technique. When blood enters a syringe attached to the needle, indicating that the vessel has been found, a thin guide wire is then introduced, typically through the syringe needle or other introducer device, into the interior of the vessel. The introducer device is then removed, leaving the guide wire within the vessel. The guide wire projects beyond the surface of the skin.
[0004] At this point, several options are available to a physician for catheter placement. The simplest option is to pass a catheter into the vessel directly over the guide wire. The guide wire is then removed. However, use of this technique is only possible in cases where the catheter is of a relatively small diameter, made of a stiff material and not significantly larger than the guide wire. If, however, the catheter is of a relatively large diameter and/or not made of a soft material, one preferable method of inserting the catheter into the vessel is through an introducer sheath. The introducer sheath is simply a large, stiff, thin-walled tube, which serves as a temporary conduit for the catheter that is being placed. The sheath is positioned by placing a dilator, which has a hollow passageway along its longitudinal axis, inside of the sheath and passing both the dilator and the sheath together into the vessel over the guide wire. The dilator expands the opening in the blood vessel to allow for catheter insertion into the vessel. The guide wire and dilator are then removed, leaving the thin-walled sheath in place. The catheter is then inserted into the vessel through the sheath.
[0005] In a setting where a catheter with a hub or other attachment at the proximal end of the catheter has a feature which is larger than that of the inner diameter of the sheath, it is necessary to have a tear-away sheath that can be split away from the catheter as the sheath is being removed from the patient. An example of such a tear-away, or splittable or peelable, sheath, with dilator is set forth in U.S. Pat. No. 6,796,991, which is depicted herein in PRIOR ART FIGS. 1 and 2 hereof. By splitting the sheath along its longitudinal axis as the sheath is being removed from the patient, the inserting physician will be able to pull out the sheath in such a way that the portion removed from the patient is split, thereby not interfering with any encumbrances on the catheter. Generally, tear-away sheaths are manufactured in a way that aids in the tearing of the sheath at two opposing points on the circumference of the sheath, thereby splitting the sheath into two halves separated longitudinally through the center of the sheath.
[0006] A sheath is generally constructed with a hub at its proximal end. This hub serves as a handle, a mating point for a dilator, and a flat surface to aid in the prevention of blood loss or contamination. When a sheath needs to be split apart in order to be successfully withdrawn from the body while leaving the catheter in place, the hub will also have to be split apart in order to clear the catheter. Preferably, the hub will split along the same lines as the sheath. To accomplish this, the hub must be designed with reveals or other weaknesses along two longitudinal lines aligned with the weaknesses in the sheath. Some previous examples of these weaknesses are tabs or webs which connect two halves of the hub, or recesses in the material comprising the hub. The weaknesses in the hub will help the inserting physician to break apart the hub in line with the tear seams on the sheath.
[0007] Another important facet of the hub is a set of tabs or wings that protrude from the center. These tabs not only help the inserting physician to align, insert and withdraw the sheath, but also to pull the sheath so that the sheath can be removed from around a catheter while still leaving the catheter in place. There are a number of different tab configurations, but it is important to have one which allows for easy maneuverability, control, and leverage. One design includes a hub wherein the tabs protrude from the hub perpendicular to a plane which includes the tear seams in the sheath and the longitudinal axis of the sheath. In this design, the tabs are diametrically opposed from each other and are spaced in such a way that when the tabs are grasped and pulled apart from each other, the sheath and its hub will split down the middle. Another desirable feature of the tabs is that the tabs provide leverage for breaking apart the hub in a manner that does not cause trauma to the incision in the body.
[0008] During insertion, especially in the time between the removal of the dilator from the sheath and the insertion of the catheter through the sheath, it is possible for blood loss through the sheath, or the introduction of contaminants or air through the sheath and into the vessel. For this reason, it is desirable that measures be taken to prevent blood, air or contaminants from traveling through the sheath. In the past, inserting physicians have simply held their thumb over the opening in the proximal end of the sheath; however, a more permanent and reliable means for preventing blood, air or contaminants from traveling through the sheath is desirable. It is therefore desirable for the hub to include a valve located in the sheath. Such a valve would facilitate the insertion of objects such as a catheter, dilator or syringe through the sheath while restricting blood loss and reducing the chance of contaminants entering the patient's bloodstream when the sheath is not engaged with a dilator or a catheter.
[0009] In the case where a sheath does not have a small diameter or a narrow point, the dilator is often used to aid in the insertion of the sheath. The dilator has a long tubular section, the outside diameter of which is slightly smaller than the inside diameter of the sheath. The dilator also has a pointed tip on its distal end and a hollow center, which runs along the entire length of the dilator. The dilator is inserted into the body with the guidewire running through its center, thereby allowing the tip of the dilator to follow the guidewire to the place that is to be catheterized. On its proximal end, the dilator may have a hub. Like the hub of the sheath, this hub can also serve a number of purposes, such as providing a stable handle to aid in guiding the dilator into the vein, and as a mechanism which can mate with the sheath hub to form a locked connection.
[0010] In PRIOR ART FIGS. 1 and 2 , a releasably locking dilator and sheath assembly and methods for releasing the dilator from the sheath and longitudinally splitting the sheath are provided. The assembly includes a dilator having a dilator hub and a sheath having a sheath hub. The sheath hub has a valve and two opposing winged tabs, each tab having a perpendicular portion and an angled portion as well as a female threaded portion. The dilator hub has a male threaded portion designed to engage the female threaded portion of the sheath hub. The dilator is released from the sheath by rotating the dilator 90° in relation to the sheath and pulling the dilator out of the sheath. The sheath is longitudinally split by creating a coupling moment on each of the winged tabs thereby forcing the sheath and the sheath hub to split longitudinally. With the sheath, the valve and the sheath hub split longitudinally, the sheath is removed from around a catheter while leaving the catheter in place.
[0011] It is desired to provide a hemostasis valve for a splittable sheath, and to provide a sheath assembly with hemostasis valve and sheath hub for use therewith, that are splittable for facilitating removal of the sheath from about an inserted catheter.
BRIEF SUMMARY OF THE INVENTION
[0012] The present invention is a hemostasis tearaway sheath assembly having a splittable sheath tube and a splittable hub affixed thereto, with the hub being at the proximal end of the sheath assembly, the sheath tube extending to a smaller diameter distal sheath end, a passageway extending through the assembly from the proximal end to the distal end and defining a longitudinal axis therethrough. The sheath tube includes frangible longitudinal lines of weakness (or seams) therealong to facilitate peeling or splitting during the tearaway procedure once splitting has been initiated by splitting apart of the hub by the practitioner. The assembly of the present invention also includes an easily split hemostasis valve contained and affixed within the hub.
[0013] The hub comprises two opposing sections joined to each other at frangible joints or webs until intentionally split apart, so that the hub remains an integral one-piece unit until split by the practitioner after insertion of the catheter into a patient's vasculature has been accomplished, with a grippable wing joined to each hub section for handling and for initiating splitting in a manner known in the art. The hub also provides distinct opposing gaps between the two opposing sections that are joined at frangible sections within the gaps, and upon splitting of the hub by the practitioner, the sheath tube also splits apart as the tearaway procedure continues. The easily split hemostasis valve contained within the proximal end of the hub is, prior to splitting, selectively openable to permit insertion therethrough of a dilator and later of a catheter forming a seal therewith and therearound, but otherwise remains closed to prevent blood effusion.
[0014] In a preferred embodiment, the split valve includes a distal slit partially across a transverse valve section, the slit being openable only to permit receipt therethrough of a dilator, syringe or catheter when same is pushed against the transverse valve section, and then closing sealingly when the device is withdrawn therethrough, and also closing sealingly about a guidewire remaining in place until catheter insertion. Also, preferably, the valve comprises two opposing halves, either molded separately or, as is preferable, that are formed from an integrally molded valve that is bisected and then fused together to form a weak bond that is easily broken during splitting of the sheath assembly as mentioned above. Each valve half includes a mounting flange or ear extending laterally from its proximal end, which ear includes a post-receiving aperture. Correspondingly, the sheath hub includes a valve-receiving recess at its proximal end that includes a pair of anchor posts beside the passageway that will extend through the two post-receiving apertures of the valve. Further, the assembly includes a cap comprising a pair of cap halves, which remain unfixed to each other, that are fastened to the proximal hub end in a force fit so as to compress the ears of the valve.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] The accompanying drawings, which are incorporated herein and constitute part of this specification, illustrate the presently preferred embodiments of the invention, and, together with the general description given above and the detailed description given below, serve to explain the features of the invention. In the drawings:
[0016] FIGS. 1 and 2 are isometric views of a PRIOR ART sheath/dilator assembly, and the sheath of the assembly shown with the dilator removed;
[0017] FIG. 3 is an enlarged isometric view of the tearaway sheath assembly of the present invention, showing the sheath hub and valve cap at the proximal end of the sheath tube and the hub's gaps aligned with lines of weakness of the sheath tube;
[0018] FIG. 4 is an exploded isometric view of the assembly of FIG. 3 in which are seen the valve and two separate cap halves spaced proximally from the sheath hub proximal end;
[0019] FIG. 5 is a plan view of the split valve of FIG. 4 after the two valve portions are fused together;
[0020] FIG. 6 is a cross-sectional view of the valve of FIG. 5 taken along lines 6 - 6 thereof;
[0021] FIG. 7 is an isometric view of a half valve portion prior to valve fusion;
[0022] FIG. 8 is a cross-sectional view of the hub assembly with valve, with a dilator extending therethrough;
[0023] FIG. 9 is an isometric view of a sheath assembly with dilator locked in position; and
[0024] FIGS. 10 and 11 are, respectively, isometric views of an alternative embodiment of a complete valve and a valve half.
DETAILED DESCRIPTION OF THE INVENTION
[0025] In the drawings, like numerals indicate like elements throughout. Certain terminology is used herein for convenience only and is not to be taken as a limitation on the present invention. The terms “distal” and “proximal” refer, respectively, to directions closer to and away from the vascular insertion site on the patient. The terminology includes the words specifically mentioned, derivatives thereof and words of similar import. The embodiments illustrated below are not intended to be exhaustive or to limit the invention to the precise form disclosed. These embodiments are chosen and described to best explain the principle of the invention and its application and practical use and to enable others skilled in the art to best utilize the invention.
[0026] In PRIOR ART FIGS. 1 and 2 , a sheath assembly 10 is shown comprising a dilator 12 and a sheath 14 , and having a longitudinal axis “L”. Dilator 12 has a dilator hub 16 at its proximal end, and its distal end portion 18 extends beyond the distal end 20 of sheath 14 to a distal tip 22 . Sheath 14 includes a sheath tube 24 and a sheath hub 26 at the proximal end of the sheath tube, and is seen in FIG. 2 with the dilator removed. Sheath hub 26 is seen to have grippable wings 28 to facilitate the initiation of splitting by the practitioner to peel away the sheath from an inserted catheter (not shown). To facilitate splitting of the sheath 14 from around the catheter, the sheath tube has a pair of opposed frangible seams 30 , and sheath hub 26 includes frangible webs along opposed gaps 32 that are aligned with seams 30 . The proximal end 34 of sheath 14 includes a threaded locking arrangement for locking with the dilator hub 12 prior to removal of the dilator.
[0027] Sheath assembly 100 of the present invention is illustrated in FIGS. 3 and 4 . The sheath assembly includes a sheath tube 102 with a proximal end portion 104 and extending to a distal end, with a passageway extending therebetween defining a longitudinal axis. The sheath tube 102 preferably is extruded of polytetrafluoroethylene (PTFE) having longitudinal polymeric orientation providing inherent lines of weakness represented as lines 106 , for splitting therealong once splitting is initiated at the hub seams by the practitioner after completion of the insertion of the catheter's distal portion into the vasculature of a patient (not shown). Alternatively, as is shown in PRIOR ART FIGS. 1 and 2 , the sheath hub can having a conventional pair of opposed seams or frangible sections 106 that define weaknesses along which the sheath tube is easily split by the practitioner.
[0028] Referring primarily first to FIG. 3 , a sheath hub 110 is affixed to the proximal end portion 104 of the sheath tube, the sheath hub being affixed to the sheath tube along the distal end portion 112 of the hub. A pair of wings or tabs 114 extend from respective opposed sections 116 , 118 of hub 110 at its proximal end 120 , for gripping by the practitioner for initiating the splitting of the sheath assembly for tearing it away from the catheter, by their being pried toward the sheath distal end such that the splitting of the hub begins at its proximal end 120 and separating hub sections 116 , 118 completely from each other along a pair of opposed gaps 122 . A dilator 200 is disposed through the sheath with its proximal end portion 202 extending proximally from the sheath hub 110 and including a dilator hub 212 . Also seen in FIG. 3 is a frangible section 124 disposed along the inside edge of gap 122 of sheath hub 110 ; the frangible section or webs on both sides of the hub join together the two hub sections 116 , 118 .
[0029] Now referring to FIG. 4 , valve 150 is shown exploded from hub 110 , the two halves 182 of cap 180 are shown exploded from hub 110 and valve 150 , and dilator hub 212 is withdrawn from the sheath enabling showing of the dilator's elongate tube 204 and clearly showing detail of the cap 180 and valve 150 . Hub 110 includes a large diameter cylindrical portion 126 extending to its proximal end 120 and to a smaller diameter distal end portion 112 whereat it is affixed to a proximal end of sheath tube 102 . A passageway extends through the hub 110 in fluid communication with the elongate passageway of the sheath tube 102 . Proximal end 120 of hub 110 includes a proximally extending wall 128 defining therewithin a valve-receiving recess 130 having extended lateral recess portions 132 to either side of the passageway 126 . Extending proximally from the recess bottom in each lateral recess portion 132 is an anchor post 136 that is generally centered with respect to the respective lateral recess portion 132 and is associated with a respective valve half. Shown just laterally outwardly of the opposite ends of wall 128 are a pair of apertures 138 for securing the cap to the hub 110 , discussed later.
[0030] Hemostasis valve 150 will now be described with reference to FIGS. 4 to 7 . Valve 150 includes opposing halves or portions 152 A, 152 B that preferably are heat-fused together along a weak but sealed interfacial joint 154 ; alternatively, the opposing halves 152 A, 152 B can be bonded with a weak silicone adhesive. At its distal end, valve 150 includes a transverse distal section 156 . Distal section 156 includes a slit 158 therethrough extending partially to the peripheral portions thereof. Valve 150 also includes a proximal cavity 160 for receipt of the distal end of a dilator or catheter and may include an annular ridge 162 for engaging the side surfaces of the device inserted thereinto. Each valve portion 152 A, 152 B includes a lateral flange or ear 164 A, 164 B at its proximal end, which further includes a post-receiving aperture 166 A, 166 B therethrough; preferably, a thick flange extends from the lateral flanges to surround the entrance to proximal cavity 160 . The valve 150 may be initially molded in two separate sections or halves, or, as is preferable, initially molded as an integral whole that is bisected into opposing halves. The valve halves 152 A, 152 B may be made of silicone and may be fused together by a weak but sealed interfacial joint 154 such as by placing the valve halves into a common conforming mold of the shape of an integral valve body and maintained at 400° F. for 1.25 hours. Optionally, an additional slit 168 can be formed through transverse distal valve section 156 partially along the weak interfacial joint 154 , thus being orthogonal to slit 158 .
[0031] Referring now to FIG. 4 , cap 180 preferably comprises two completely separate but identical halves 182 , for securing valve 150 within valve-receiving recess 130 of sheath hub 110 . The interface 184 between the cap halves 182 is aligned with gaps 122 of hub 110 and seams 108 of sheath tube. Cap 180 defines a passageway 186 extending therethrough from a beveled lead-in at the cap's proximal end, with passageway 186 sufficiently large in inner diameter for a dilator and a catheter to be movably inserted therethrough. An outer cap wall 188 extends distally to be received around wall 128 surrounding valve-receiving recess 130 of hub 110 , and securing posts 190 of the cap halves are snap-fitted and/or friction fitted into apertures 138 of hub 110 ; optionally, each cap half may also be affixed to a respective hub half-portion by adhesive. Also, optionally, the cap halves 182 may include respective protuberances and apertures along their interface 184 for precise co-alignment when assembled paired together to the hub 110 .
[0032] Cap 180 may include a locking section for lockingly engaging the dilator hub 202 of the dilator 200 . The locking section is shown to comprise a pair of locking pins 192 extending proximally from a proximal surfaces of the respective cap halves, each locking pin 192 including an enlarged head 194 on the end of a pin shaft 196 . A distal end 206 of the dilator hub 202 includes a cooperating locking section adapted to grip the locking pins to secure the dilator in position assembled to the introducer sheath assembly 100 . The cooperating locking section is shown to comprise a pair of hooks 208 that extend first radially outwardly from the side of the dilator hub distal end 204 and then circumferentially a selected small distance in a common direction, thus defining a pair of post-receiving slots 210 that are each sufficiently large to receive in a snug fit thereinto the shafts 196 of the cap's posts 192 distally of their enlarged heads when the dilator 200 is fully inserted into the sheath assembly and abutting the cap, and then rotated a small angular distance in the common direction thus moving the hooks about the locking pins.
[0033] The interrelationship of the various associated portions of the hub, valve and cap is best explained with respect to FIGS. 3 and 4 . Valve 150 is seated within valve-receiving recess 130 of sheath hub 110 . The anchor posts 136 of the hub 110 extending through the apertures 166 A, 166 B of the valve ears assures that the valve halves will become separated from each other and remain with the respective hub portions when the hub is split for peeling the sheath assembly from about the catheter after catheter insertion. Similarly, the respective cap halves 182 will also remain with the respective hub portions upon splitting of the sheath hub 110 .
[0034] Frangible sections or webs 124 of hub 110 that join hub sections 116 , 118 are formed adjacent the inside surface of the passageway of the hub and are very thin. It is preferred that, mainly for manufacturing reasons, the gaps 122 of hub 110 extend radially inwardly from hub outer surfaces to inner gap end portions that are U-shaped converging at the frangible webs 124 , in order for the mold inserts to remain relatively thick, robust and durable over many molding cycles and also to carefully control the thickness of the frangible webs. The webs may have a thickness, for example, of about 0.005 in (0.127 mm), and the width of the gaps 122 at the outer surfaces can be, for example, about 0.010 in (0.254 mm).
[0035] It can be discerned from FIG. 6 that the transverse distal section 156 of the valve would be abutted by a proximal end of a guide wire (not shown) during initial placement of the sheath assembly over the guide wire after the guide wire is placed in the vasculature, later by the dilator distal tip inserted through the hub and valve and later by the catheter distal tip, with the slit 158 permitting an opening therethrough in response to guide wire, dilator or catheter insertion, with the valve maintaining engagement with the outer surfaces of the guide wire, dilator or catheter as it passes therethrough; and the slit will also close against the guide wire upon withdrawal of the dilator from the sheath assembly, forming a hemostasis seal and preventing effusion of blood. The hub and the cap may be made of polyethylene or polypropylene.
[0036] An enlarged cross-section of the proximal end of the assembly 100 , 200 is depicted in FIG. 8 , wherein the sheath hub 110 contains the split hemostasis valve 150 seated therewithin, the cap half members 182 , 182 and the dilator 200 locked to the cap half members so that the dilator tube 202 extends through the valve 150 and into the sheath tube 102 . The half portions of valve 150 are secured in place by posts 136 extending proximally through apertures 166 A, 166 B. Cap posts 190 are fitted into holes in the hub half portions. Dilator hub 204 is secured to cap members 182 when hooks 208 are rotated and post-receiving slots 210 thereof are snap-fitted around locking pins 192 of the cap members. An opening 220 in the proximal portion of dilator hub 204 permits insertion therethrough of a guidewire (not shown).
[0037] A view of the entire assembly is shown in FIG. 9 , partly in cross-section to show another embodiment of valve 250 in its open state, with a valve 250 and a valve half 252 illustrated in FIGS. 10 and 11 , respectively. Two or more rib portions 268 are provided along outer surfaces of the converging distal end portions 270 of the valve halves 252 to enhance the closing of slit 258 either entirely, if no medical device extends therethrough, or tightly around a medical device extending therethrough, by virtue of the stiffness of the added material.
[0038] It will be appreciated by those skilled in the art that changes could be made to the embodiments described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the particular embodiments disclosed, but it is intended to cover modifications within the spirit and scope of the present invention as defined by the appended claims. | 1a
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RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Application No. 60/283,934 filed Apr. 17, 2002 and U.S. Provisional Application No. 60/284,232 filed Apr. 18, 2002 both incorporated herein by reference.
FIELD OF THE INVENTION
[0002] This invention relates to methods for inhibiting the initiation or progression of a pathological condition associated with atherosclerotic plaque (plaques) formation. The invention also relates to methods for promoting the regression of plaques associated with atherosclerosis. The methods further relate to inhibiting the proliferation of smooth muscle cells in one or more arteries, and inhibiting the formation and expansion of fat and protein deposits within one or more arteries.
[0003] The method comprises administering an amount of IL-9 to a subject in need thereof wherein the amount of IL-9 is sufficient to prevent or inhibit the initiation of atherosclerotic plaques, inhibit the progression of plaques, and/or to promote the regression of plaques. In one embodiment the IL-9 is administered in an amount sufficient to inhibit the proliferation of smooth muscle cells in one or more arteries and/or to inhibit the formation and expansion of fat and protein deposits within one or more arteries. The methods of this invention also relate to administering IL-9 in an amount sufficient to inhibit the infiltration of monocytes, to inhibit activation of macrophages and to inhibit activation of macrophage derived foam cells within the atherosclerotic plaque.
BACKGROUND OF THE INVENTION
[0004] Atherosclerosis is a general term for the thickening and hardening of arteries. Arteries comprise three main layers. The outside layer (the external elastic lamina or the adventitia) supports the artery and is composed predominantly of loose connective tissue. The middle layer (between the lamina elastica interna and externa), comprises predominantly smooth muscle (in mice this layer is very thin: 1-2 cells). The muscle cells provide for contraction and relaxation of the artery which controls the rate of blood flow. The inner layer of the artery is itself composed of three layers: an elastic layer (the internal elastic lamina), a basement layer (the intima) and an innermost layer (the endothelium). Atherosclerosis involves changes in the intima the inner layer of the artery.
[0005] Atherosclerosis is characterized by deposits of fatty substances, cholesterol, cellular waste products, calcium, proteins, deposits of extracellular matrix proteins, such as collagen, and other various specific proteins such as metallo proteases and the accumulation of intimal foam cells in medium and large sized arteries. Atherosclerosis appears to be a response to an initial injury to the inner lining of the artery and may be initiated by high serum cholesterol levels (Ross, R (1999) N. Engl. J Med. 340, 115-126). In response to high serum cholesterol levels in the blood, endothelial cells secrete factors which attract monocytes. Once the monocytes attach to the endothelium, they migrate through the endothelium and lodge just beneath the endothelial layer in the intima. After lodging in the artery, the monocytes mature to tissue macrophages and take up lipids and lipoproteins from the blood and become lipid filled foam cells. This process results in the formation of the initial atherosclerotic plaque The macrophage-derived foam cells release various mediators, e.g., cytokines and chemokines, free radicals, bioactive lipids, proteases, protease inhibitors and coagulation cascade components, which stimulate the migration and growth of smooth muscle cells. The smooth muscle cells may also take up lipids and transform into foam cells. During this process T lymphocytes infiltrate into the plaque and produce pro-inflammatory mediators thus contributing to the inflammatory process in the plaque. The initial lesion develops during the aforementioned processes through intermediate lesions to complex, advanced lesions (Ross, R (1999) N. Engl. J. Med. 340, 115-126) Lusis et al., “Atherosclerosis.” Nature 407, 233-241 (2000) Finally, damage to the endothelium, whether by the action of monocytes or other physical injury to the endothelium, attracts platelets. Often a blood clot forms and blocks the artery, stopping the flow of blood. Reducing the blood supply to the heart muscle may result in a heart attack. Reducing the blood supply to the brain may result in a stroke. Reducing the blood supply to a limb can result in gangrene.
[0006] Several reports suggest that atherosclerosis is a multifactorial disease with a large/major inflammatory component. (Ross, (1999) N. Engl. J. Med. 340, 115-126). Down regulation of the inflammatory component leads to a decreased level of atherosclerosis, e.g., adenoviral IL-10 gene therapy in low density lipoprotein (LDL) receptor knockout mice induces high levels of IL-10 and IL-10 significantly reduces the initiation of atherosclerosis (Terkeltaub, Artherioscler Thromb Vasc Biol 19:2823-2825 (1999); Pinderski et al, Arterioscler Thromb Vasc Biol 19:2847-2853 (1999); Mallat et al., Circ. Res, 85:1-8 (1999), and von der Thüsen, FASEB J., 15:2730-2732 (2000)).
[0007] Several models have been used to study atherosclerosis. Local lesion induction has been achieved by transluminal or extravascular arterial manipulation (Fishman et al., “Endothelial regeneration in the rat carotid artery and the significance of endothelial denudation in the pathogenesis of myointimal thickening”, Lab Invest., 32:339-351 (1975), and; Booth et al. “Rapid development of atherosclerotic lesions in the rabbit carotid artery induced by perivascular manipulation”, Atherosclerosis, 76:25 7-268 (1989)). Diet-induced hypercholesterolemina and genetically modified rabbits have also been used to study atherosclerosis (see, e.g., Finking and Hanke, “Nikolaj Nikolajewitsch Anitschkow (1885-1964) established the cholesterol-fed rabbit as a model for atherosclerosis research”, Atherosclerosis, 135:1-7 (1997); Fujiwara and Shiba, “Mechanisms of augmented vascular responses to histamine in atherosclerotic common carotid arteries”, Eur J Pharmacol., 258:195-201 (1994), and; Matthys et al., “Local application of LDL promotes intimal thickening in the collared carotid artery of the rabbit” Arterioscler Thromb Basc Biol., 17:2423-2429 (1997)). Mouse models for atherosclerosis include, e.g., LDL receptor knockout mice described by Ishibashi et al. infra, apolipoprotein E knockout mice (apoE−/−) described by Nakashima et al. infra and apolipoprotein E3-Leiden transgenic mice described by van den Maagdenberg infra ((Ishibashi et al., “Massive xanthomatosis and atherosclerosis in cholesterol-fed low density lipoprotein receptor-negative mice”, J Clin Invest. 93:1885-1893 (1994); Nakashima et al. “ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree”, Arterioscler Thromb., 14:133-140 (1994), and; van den Maagdenberg et al., “Transgenic mice carrying the apolipoprotein E3-Leiden gene exhibit hyperlipoproteinemia”, J Biol Chem., 268:10540-10545 (1993)).
[0008] Using the LDL receptor deficient mice we established a rapid model for atherosclerosis, which was used in these studies (von der Thüsen, et al. Circulation, 103, 1164-1170 (2001)). These models have been useful in analyzing the role of diet, environmental factors, and genetics in the initiation and progression of atherosclerosis. Described herein are the effects of IL-9 on the initiation, progression and regression of plaques associated with atherosclerosis and the effect of IL-9 on the proliferation of smooth muscle cells and the formation and enlargement of fat and/or protein deposits in one or more arteries.
BRIEF DESCRIPTION OF THE FIGURES
[0009] FIGS. 1 A-D depict the effect of intraperitoneal administered IL-9 (lug/mouse/day) on collar-induced atherosclerosis in LDL receptor deficient male mice.
[0010] [0010]FIG. 2 depicts the effect of IL-9 on atherosclerosis ( 2 A, plaque size μm 2 ; 2B, median size, μm 2 ) in LDL receptor deficient female mice treated for 4 weeks with daily injections of 1 μg IL-9. The extent of atherosclerosis was determined in the carotid artery after collar placement.
[0011] [0011]FIG. 3 depicts the effect of IL-9 on TNF-α production in whole blood of LDL receptor deficient mice treated for 5 days with 1 μg IL-9 per day. The TNF-α production ex vivo was determined in response to increasing amounts of lipopolysaccharide (LPS).
[0012] [0012]FIG. 4 depicts the extent of atherosclerosis ( 4 A, plaque size, μm 2 ; 4 B, median size, μm 2 ) in LDL receptor deficient mice immunized with IL-9 ovalbumin conjugates (IL-9-OVA). The extent of atherosclerosis was determined in the carotid artery after collar placement.
SUMMARY OF THE INVENTION
[0013] This invention relates to methods for preventing or inhibiting the progression of a pathologic condition associated with atherosclerotic plaque formation. Pathologic conditions associated with atherosclerotic plaque formation include e.g., atherosclerosis, stroke, heart attacks, unstable angina and gangrene due to blocked blood vessels. The methods of this invention also relate to inhibiting the initiation of atherosclerotic plaques, inhibiting the progression of plaques, or promoting the regression of plaques associated with atherosclerosis in a subject in need thereof. The methods are useful for the treatment and prevention of vulnerable plaques, unstable plaques or rupture prone plaques (Stary, et al., Arterioscl. Thromb., 14, 840-856 (1994) and Stary, et al., Arteriscl. Thromb. Vasc. Biol., 20, 1177-1178 (2000)). This invention relates to methods useful for inhibiting the formation and enlargement of fat and protein deposits and to inhibiting the proliferation of smooth muscle cells in one or more arteries in an animal.
[0014] The methods comprise administering an amount of IL-9 to a subject in need thereof wherein the amount is sufficient to prevent the formation of an atherosclerotic plaque, to inhibit the progression of the plaque and eventually to promote the regression of an atherosclerotic plaque. The administration of IL-9 inhibits the initiation or progression of atherosclerotic plaque formation, which is manifested as a reduction in the average size of plaques as compared to a control that is not treated with IL-9. Also an embodiment of this invention is a method for promoting the regression of plaques by administering an amount of IL-9 to promote regression of plaques. This may be manifested in a reduction in the size or number of already existing plaques.
[0015] In one embodiment of the invention the amount of IL-9 administered to the subject is sufficient to inhibit or prevent the proliferation of foam cells and smooth muscle cells and monocytes or monocyte derived macrophages in arteries, and/or to inhibit the formation of fat deposits or protein deposits in one or more arteries. Preferably the amount of IL-9 is sufficient to inhibit the initiation or progression of plaques or to promote the regression of plaques, e.g., vulnerable plaques, unstable plaques and rupture prone plaques.
[0016] Preferably the IL-9 is an autologous IL-9, e.g., an IL-9 of the species of the subject to which it is administered, e.g., if the subject is a human the administered IL-9 is a human IL-9 or if the subject is a dog the administered IL-9 is a dog IL-9. The IL-9 may be isolated from a natural source, e.g., from serum or it may be produced recombinantly. Preferably the IL-9 is produced recombinantly. Those of skill in the art appreciate that there are a variety of commercially available sources for cytokines such as IL-9 and that there are a variety of methods available that are suitable for producing a recombinant IL-9 that is useful in the methods of this invention. See, e.g., Druez, et al., “Functional and biochemical characterization of mouse P40/IL-9 receptors” J. Immunol., 145:2494-2499(1990) for methods for producing a murine IL-9 in insect cells under the control of a baculovirus promoter. IL-9 produced in insect cells under the control of baculovirus promoters has a short half life, which may be the consequence of a high mannose content and lack of terminal sialic acid. IL-9 isolated from the serum of IL-9 transgenic mice, display a substantially stronger effect than the baculovirus produced IL-9, e.g., 50 ηg of IL-9 isolated from the serum of the transgenic mice display a stronger effect than 4 μg baculovirus produced IL-9.
[0017] Also useful in the methods of this invention is a conjugate of IL-9 and a conjugation partner e.g. polyethylene glycol. Preferably the conjugation partner does not promote an immune response to itself or to the IL-9 such that repeated treatments with IL-9 or the conjugated IL-9 are possible. Conjugates of IL-9 and polyethylene glycol have been shown to increase the activity of IL-9 in vitro. Methods for preparing conjugates of cytokines and polyethylene glycol are well known in the art. See, e.g., Cunningham-Rundles et al., “Long-term low-dose IL-2 enhances immune function in common variable immunodeficiency”, Clin. Immunol, 100(2):181-90 (August, 2001) and Meyers et al., “A phase I study including pharmacokinetics of polyethylene glycol conjugated interleukin-2 ”, Clin. Pharmacol. Ther., 49(3):307-13 (March, 1991).
[0018] Other forms of IL-9 are also useful in the methods of this invention, e.g., any fragment of IL-9 that binds to cellular IL-9 receptors and induces an IL-9 response by those cells would be suitable for use in the methods of this invention. The binding of an IL-9 to IL-9 receptor may be assayed by any method known in the art. The induction of a response by a suitable IL-9 fragment may be determined by a variety of assays, e.g., by assaying for proliferation of PHA plus IL- 4 stimulated human lymphoblast lines (Yang et al., Blood, 74:1880-1884 (1989, incorporated herein by reference).
[0019] IL-9 may be administered to the subject with any pharmaceutically acceptable carrier and in any pharmaceutically acceptable manner. For example, IL-9 may be administered e.g., intramuscularly, intradermally, intra-arterially, subcutaneously, intraperitoneally, intravenously and intraventricularly. Preferably, IL-9 is administered subcutaneously.
[0020] Gene therapy methods for delivering IL-9 to a subject in need thereof to inhibit the initiation and progression of artherosclerotic plaques are also contemplated herein. A nucleic acid molecule encoding an IL-9 may be introduced into cells ex vivo, wherein harvested cells are transformed with the IL-9-encoding nucleic acid molecule and then the transformed cells reintroduced into a subject, or the polynucleotide may be introduced into cells in vivo via a vector. For example, an IL-9 encoding sequence can be incorporated into naked DNA vectors, e.g., plasmids, and introduced into cells by using e.g., cationic lipids or liposomes. Alternatively the nucleic acid molecule encoding IL-9 may be introduced into cells, in vivo and ex vivo via viral vectors, e.g., adenoviral vectors, adeno associated viral vectors, lentiviral vectors or retroviral vectors, and the vectors, and expressed at levels that are sufficient to inhibit the initiation or progression of atherosclerotic plaque formation. The vectors may be introduced into a subject directly, e.g., by injection of the vectors either locally or systemically and the vectors may be designed for constitutive or inducible IL-9 expression and the vectors may be designed for their transient presence, e.g., not incorporated within the genome of a cell, or a their permanent presence, e.g., integrated into a cell genome. Gene therapy has been used to introduce a variety of therapeutic genes into subjects in need thereof, see for example, Tolstoshev, Ann. Rev. Pharm. Toxicol., 32:573-596 (1993); Morgan et al. Ann Rev. Biochem 62:191-217 (1993) for a review and also U.S. Pat. Nos. 6 , 538 , 915 issued Mar. 19, 2002, 5,981,501 issued Nov. 9, 1999 and 5,656,465 issued Aug. 12, 1997 all incorporated herein by reference. Gene therapy vectors are also commercially available from different laboratories, e.g., Chiron, Inc., Emeryville, Calif.; Genetic Therapy, Inc., Gaithersburg, Md.; Genzyme, Cambridge, Mass.; Targeted Genetics, Seattle, Wash., and; Viagene, San Diego Calif.
[0021] IL-9 may be administered monthly, weekly or daily for a predetermined period of time.
[0022] Suitable carriers include but are not limited to pharmaceutically acceptable diluents of various buffer content (e.g., Tris-HCl, acetate, phosphate), pH and ionic strength; and may include additives such as detergents and solubilizing agents (e.g., Tween 80, Polysorbate 80), antioxidants (e.g., ascorbic acid, sodium metabisulfite), and preservatives (e.g., Thimersol, benzyl alcohol) and bulking substances (e.g., lactose, mannitol). IL-9 may be incorporated into particulate preparations of polymeric compounds such as polylactic acid, polyglycolic acid, etc. or into liposomes. Hylauronic acid may also be used. Such compositions may influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance. See, e.g., Remington's Pharmaceutical Sciences, 18th Ed. (1990, Mack Publishing Co., Easton, Pa. 18042) pages 1435-1712 which are herein incorporated by reference.
[0023] Those of skill in the art appreciate that the amount of IL-9 sufficient to prevent, inhibit or promote regression of plaques associated with atherosclerosis, or sufficient to inhibit smooth muscle cell proliferation, or inhibit the deposition and accumulation of fats and proteins in one or more arteries can readily be determined using routine methods available in the art. Preferably the effective amount is about 40 ug/kg body weight, equivalent to about 2.1-3.2 mg per patient. Those of skill in the art are well aware of methods useful for detecting arterial plaques and assaying their size and progression or regression (von der Thüsen et al., “Induction of Rapid Atherogenesis by Perivascular Carotid Collar Placement in Apolipoprotein E-Deficient and Low-density Lipoprotein Receptor-Deficient Mice”, Circulation 103:1164-1170 (2001) incorporated herein by reference). Thus one of skill in the art could assay the size of arterial plaques before and after treatment with IL-9 to determine the dose of IL-9 needed to be increased or decreased. A decrease in the size or number of arterial plaques would indicate that a suitable dose of IL-9 is being administered.
[0024] The methods of this invention are applicable to any subject in need thereof. The subject in need thereof may be any mammal which has a predilection for developing atherosclerosis, for example a subject who has a family history of developing atherosclerotic plaques, a subject having Familial Hypercholesteremia, which is an inherited disorder that leads to high cholesterol levels, or a subject having high plasma cholesterol levels without a family history of high cholesterol, or any mammal already having atherosclerotic plaques in one or more arteries. By inhibiting the initiation and progression of plaque formation, the initiation and progression of pathologic conditions associated with plaque formation, e.g., atherosclerosis, stroke, heart attacks, unstable angina and gangrene associated with a blocked blood vessel, are also inhibited. Those of skill in the art are well aware of methods used to determine if a subject harbors atherosclerotic plaques or has an increased chance of developing atherosclerotic plaques (see, e.g., Williams Hematology, 2d edition, Beutler et al. eds., (2001), chapter 30;Ross, N. Engl. J Med. 340, 115-126 (1999), Lusis, “Atherosclerosis.” Nature 407, 233-241 (2000) (all incorporated herein by reference). The atherosclerotic plaques may be end stage plaques, e.g., vulnerable plaques, unstable plaques or rupture prone plaques or any combination thereof. Preferably the mammal is a human, a mouse, a guinea pig, a cat, a dog, a horse, a cow or a pig. More preferably the subject is a human.
[0025] Also an aspect of the invention is a method for inducing the production of IL-9 in a subject in need thereof, wherein IL-9 production or activity is induced to a level that is sufficient to prevent the formation of atherosclerotic plaques, to inhibit the progression of plaques, and/or to promote the regression of plaques associated with atherosclerosis. In another embodiment of the invention IL-9 production or activity is induced to sufficient levels to prevent the proliferation of smooth muscle cells in arteries and to prevent the deposition of fat and proteins in arteries. Such methods comprise, e.g., administering an agent that promotes the synthesis of IL-9, or enhances the activity of IL-9, to the subject. Also envisioned is the production of IL-9 from a gene introduced into a subject via gene therapy using either viral vectors, e.g., adenoviral vectors, lentiviral vectors or retroviral vectors or naked DNA vectors, e.g., plasmids.
[0026] Because administration of IL-9 reduces plaque formation in the mouse model, a low level of IL-9 as compared to a predetermined control level may be indicative of a subject's predilection for the development of atherosclerotic plaques and could be used to suggest measures that would decrease the risk of developing plaques, e.g., a change in diet to one that is low in cholesterol or increasing the subjects level of exercise. Thus, a further aspect of this invention are methods for assessing the predilection of a subject for the development of atherosclerotic plaques by assaying the subject for a reduced level of IL-9 wherein a reduced level of IL-9, as compared to a predetermined control level, is indicative of a predilection of said subject for the development of atherosclerotic plaques. Levels of IL-9 may be determined in a variety of assays. For example, one could measure IL-9 production by assaying peripheral blood lymphocyte in vitro response to polyclonal stimulation with anti-CD3, or PHA or with LDL or a modified LDL.
[0027] Also an aspect of this invention is the use of an IL-9 in the manufacture of a medicament for treating a pathologic disorder associated with arterial plaque formation in a subject in need thereof. Such pathological disorders include, e.g., atherosclerosis, heart attack, unstable angina, stroke or gangrene due to blocked blood vessel. Another aspect of this invention is the use of a vector comprising a sequence encoding IL-9 in the manufacture of a medicament for use in gene therapy of a pathologic disorder associated with arterial plaque formation. The vectors may be a viral vector e.g., a retroviral vector, an adenoviral vector, an adeno associated viral vector or a lentiviral vector or a nucleic acid vector e.g., a plasmid. The vectors may be designed such that they are for temporary expression of IL-9, constitutive expression of IL-9 or permanent expression of IL-9. The IL-9 may be a naturally occurring IL-9, an autologous IL-9, a recombinant IL-9, or an IL-9 conjugate, e.g., pegylated IL-9, wherein the conjugation partner does not promote antibody production to itself or to the IL-9. The IL-9 may also be a fragment of IL-9 that binds to cellular IL-9 receptors and induces an IL-9 response by those cells would be suitable for use in the methods of this invention. The IL-9 may be produced in culture, for example in mammalian cell culture or in insect cell culture. The subject in need thereof may be a mammal, e.g., a mouse, a rat, a guinea pig, a cat, a dog, a pig, a cow, a horse or a human. A subject in need thereof may be one who displays a predilection for developing arterial plaques, has a family history of developing atherosclerotic plaques, a subject having Familial Hypercholesteremia, which is an inherited disorder that leads to high cholesterol levels, or a subject having high plasma cholesterol levels without a family history of high cholesterol, or one who already has a plaque, e.g., a vulnerable plaque, an unstable plaque or a rupture prone plaque, in one or more arteries. A subject in need thereof may have reduced levels of LDL receptors or apolipoprotein E.
DETAILED DESCRIPTION OF THE INVENTION
EXAMPLE 1
[0028] LDL receptor deficient mice, transgenic mice developed essentially as described in Ishibashi et al., “Massive Xanthomatosis And Atherosclerosis In Cholesterol Fed Low Density Lipoprotein Receptor-Negative Mice”, J. Clin. Invest., 93:1885-1893 (1994), incorporated herein by reference, were used in these examples. The LDL deficient mice are currently used as a model for the development of atherosclerosis (see von der Thüsen et al., Circulation (2001) supra).
[0029] Male LDL receptor deficient mice were put on a cholesterol rich diet (type W diet containing 0.25% cholesterol, 15% cocoa butter). After 14 days, collars were placed around the left and the right carotid artery (as described in von der Thüsen Circulation 2001 , supra ). The mice were then treated with IL-9 with daily intraperitoneal injection with 1 μg baculovirus recombinant IL-9 (Druez, et al., J. Immunol., 145:2494-2499(1990) incorporated herein by reference) per mouse per day from day 21 to day 56. Control animals received daily injections with vehicle alone (PBS containing 1% autologous mouse serum).
[0030] Body weight, cholesterol levels and lipoprotein profile were monitored throughout the experiment. At the end of the experiment (day 56 after the last dose of IL-9), animals were anesthetized and exsanguinated by femoral artery transection. In situ perfusion fixation through the left cardiac ventricle was performed by PBS instillation for 15 minutes, followed by constant-pressure infusion (at 80 mm Hg) of 10% neutral buffered formalin for 30 minutes. Subsequently, both carotid bifurcations and common carotid arteries were removed. No differences were observed between the body weight of IL-9-treated and vehicle-treated mice. In addition, IL-9 treatment did not affect the cholesterol levels as compared to the control mice. Throughout the experiments the mice, regardless of treatment, maintained a level of approximately 3000 mg cholesterol/dl. IL-9 treatment did not alter the lipoprotein profile of the treated mice as compared to the control mice (80% of the total cholesterol is recovered in both groups in the VLDL fraction).
[0031] The collar-induced atherosclerosis in treated and untreated mice was assayed by determining plaque size (surface area at the point where the size/area of the plaque is maximal) media size (between the intima (plaque) and the smooth muscle layer), intima/media ratio and intima/lumen ratio (FIG. 1 A-D) essentially as described in von der Thüsen ( Circulation 2001 supra). Briefly, hematoxylin and eosin-stained sections were assessed in cross-section at 3 levels: 0.5 mm proximal, in the mid-section and 0.5 mm distal to the collar. The intimal surface area was calculated by subtracting the patent lumen area from the area circumscribed by the internal elastic lamina. The medial surface area was defined as the area between the internal elastic lamina and the external elastic lamina. The intima/media ratio and the intima/lumen ratio were determined by dividing the intimal area by the medial area and the total area confined by the internal elastic lamina, respectively.
[0032] The results are set forth in FIGS. 1A through 1D and indicate that IL-9 significantly reduced plaque size without effect on the size of the media. These results clearly demonstrate that daily treatment of mice with IL-9 significantly reduces the initiation of atherosclerosis.
EXAMPLE 2
[0033] Example 1 was repeated in female LDL receptor deficient mice and the effects of IL-9 on atherosclerotic plaque formation was evaluated. On Day 1 , two groups of mice (Group A (IL-9 treated, n=9) and Group B (control, n=8)) were put on a western type diet containing 0.25% cholesterol and 15% cocoa butter. At Day 15 collars were placed around the left and right carotid artery (as described by von der Thüsen et al., Circulation (2001) supra). From Day 16 through Day 42 the Group A mice were injected daily (intra-peritoneal) with 1 μg baculovirus produced IL-9 dissolved in 100 μl of PBS (containing 1% normal autologous mouse serum). The Group B control mice received a daily intra-peritoneal injection of 100 μl of PBS (containing 1% normal autologous mouse serum).
[0034] At Day 42, both groups of mice were anaesthetized and exsanguinated by femoral artery transection, and in situ perfusion fixation through the left cardiac ventricle was performed by PBS instillation for 15 minutes, followed by constant-pressure infusion (at 80 mm Hg) of 10% neutral buffered formalin for 30 minutes. Subsequently, both carotid bifurcations and common carotid arteries were removed. Formalin fixation was omitted for arteries that were to be stained for von Willebrand Factor “vWF”; these were immediately snap-frozen in liquid nitrogen after having been embedded in OCT compound (Tissue-Tek; Sakura Finetek), whereas the remaining arteries were left in 10% formalin overnight before freezing. The specimens were stored at −20° C. until further use. Transverse 5-mm cryosections were prepared in a proximal direction from the carotid bifurcation and mounted in order on a parallel series of slides.
[0035] [0035]FIG. 2 depicts the effects of baculovirus-produced IL-9 on the development of atherosclerotic plaques. The mice of Group A, which were treated with IL-9, showed a clear diminishment in the extent of atherosclerosis. The significant reduction in the extent of atherosclerosis was 58.6% in comparison to the control group (p<0.05).
EXAMPLE 3
[0036] The effect of IL-9 on TNF-A production by blood monocytes in response to LPS was determined in a whole blood assay.
[0037] Mice (Group A: IL-9 treated, n=9)) received a daily intra-peritoneal injection of recombinant IL-9 dissolved in 100 μl of PBS (containing 1% normal autologous mouse serum) for five days. Control mice (Group B, n=8) received a daily i.p. injection of 100 μl of PBS (containing 1% normal autologous mouse serum) for five days. At day 5 blood was collected from the tail vein of all mice. Whole blood was obtained by tail vein transection and diluted 25 fold in Dulbecco's modified Eagle's medium supplemented with L-glutamine, penicillin and streptomycin, which contained varying concentration so lipopolysaccharide (Re 595, List Biological Laboratories, Campbell, Calif.). Following incubation overnight at 37° C., 50 μl of the supernatent was analyzed for TNF-α content by ELISA.
[0038] The results are depicted in FIG. 3. The TNF-α production in the whole blood assay after LPS stimulation was not significantly different in the IL-9 treated animals as compared to the control treated animals.
EXAMPLE 4
[0039] The effect of endogenous interleukin 9 on atherosclerosis was also assayed by vaccinating mice with IL-9 ovalbumin conjugates (IL-9-OVA) prior to placing the mice on a diet containing 0.25% cholesterol and 15% cocoa butter.
[0040] On Day 1, 10 female LDL receptor mice (Group A) were vaccinated in both footpads using 1 μg of IL-9-ovalbumin conjugate in the presence of complete Freund's adjuvant as described by Richard et al., (“Anti-IL-9 vaccination prevents worm expulsion and blood eosinophilia in Trichuris muris -infected mice”, PNAS 97 767-772 (2000) incorporated herein by reference). Control mice were 10 female LDL receptor mice vaccinated with ovalbumin in the presence of complete Freund's adjuvant (Group B).
[0041] On Days 15, 29 and 43, the Group A mice were vaccinated with 1 μg of IL-9-ovalbumin conjugate in the presence of incomplete Freund's adjuvant. On Days 15, 29 and 43, the control Group B mice were vaccinated with ovalbumin in the presence of incomplete Freund's adjuvant.
[0042] On Day 57 the two groups of mice were put on a western type diet (0.25% cholesterol, 15% cocoa butter) and assayed for the production of IL-9 specific antibodies. Anti-IL-9 titers of the vaccinated mice were tested in a TS1 assay. The titers are the reciprocal dilutions of the sera that produce 50 % inhibition of IL-9 (50 pg/ml). The only Group A mice that were included in the experiment were those that had a significant level of anti-IL-9 antibodies (6/10 mice). The control mice vaccinated with OVA did not produce IL-9 antibodies.
[0043] Two weeks later (Day 71) collars were placed around the left and right carotid artery (as described by von der Thüsen et al. 2001 supra) of the control mice and the mice with the significant levels of anti-IL-9 antibody.
[0044] On Day 113, both groups of mice were anaesthetized, and in situ perfusion fixation through the left cardiac ventricle was performed by PBS instillation for 15 minutes, followed by constant-pressure infusion (at 80 mm Hg) of 10% neutral buffered formalin for 30 minutes. Subsequently, both carotid bifurcations and common carotid arteries were removed. Formalin fixation was omitted for arteries that were to be stained for vWF; these were immediately snap-frozen in liquid nitrogen after having been embedded in OCT compound (Tissue-Tek; Sakura Finetek), whereas the remaining arteries were left in 10% formalin overnight before freezing. The specimens were stored at −20° C. until further use. Transverse 5-mm cryosections were prepared in a proximal direction from the carotid bifurcation and mounted in order on a parallel series of slides.
[0045] [0045]FIG. 4 demonstrates that the Group A mice, which were vaccinated with IL-9-OVA conjugates and had significant levels of IL-9 specific antibodies, had a clear increase in the extent of atherosclerosis. The level of atherosclerosis was more than double (2.05 fold) the level in control mice which were vaccinated ovalbumin (p<0.05).
[0046] The results set forth herein demonstrate that administration of IL-9 to a subject inhibits formation and progression of atherosclerotic plaques. The increase in atherosclerosis as a result of IL-9-OVA immunization demonstrates that endogenous IL-9 plays a role in inhibiting atherosclerosis and that IL-9 does not prevent the subsequent production of TNF by blood monocytes in response to LPS in vitro.
[0047] The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or any portions thereof, it being recognized that various modifications are possible within the scope of the invention. | 1a
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BACKGROUND OF THE INVENTION
This invention relates to an article display stand and particularly to a stand that can be easily assembled and disassembled for ease of storage.
The display of articles for sale in a retail establishment such as a florist or a jewelry store is an important part of proper merchandising. Also, the use of appropriate display stands for floral centerpieces is an important factor in contributing to the overall aesthetics of social events such as banquets, weddings, etc. In both of the above-mentioned uses, it is advantageous to have display stands that can be easily assembled or disassembled so that each display stand requires only a minimum of storage space. This is particularly important for florists that may have need for a multitude of centerpiece stands.
Additionally, with respect to centerpiece stands, it is preferable that the stand be made of a transparent material to permit persons on opposite sides of a banquet table to view each other. As generally in use at the present time, centerpiece floral arrangements are placed in the table center causing great difficulty for persons on opposite sides to see and converse with each other.
There is thus a need for a knockdown type of article display stand that can be formed of transparent plastic material and that can provide a stable, solid and firm support for an article.
OBJECTS OF THE INVENTION
It is an object of the invention to provide an article display stand that can be readily assembled and disassembled.
It is another object of the invention to provide an article display stand that has a pleasing appearance and is made of transparent plastic material.
It is still another object of the invention to provide an article display stand that can be molded of plastic material with use of only two different molds.
It is still a further object of the invention to provide an article display stand that requires four molded parts and that can be assembled and disassembled without any fasteners.
SUMMARY OF THE INVENTION
The above outlined objectives as well as other objects and features of the present invention are accomplished by an article display stand formed of one pair of identical vertical support members and one pair of identical horizontal support members. The horizontal support members have means thereon to hold the vertical support members in position. The vertical support members are preferably formed of transparent material to permit viewing therethrough and may also include a coloring material to vary the overall aesthetic effect of the article display stand.
BRIEF DESCRIPTION OF THE DRAWINGS
For a full understanding of the nature and objects of the invention, reference should be had to the following detailed description taken in conjunction with the accompanying drawings in which:
FIG. 1 is a perspective view showing the article display stand in accordance with the present invention;
FIG. 2 is an exploded view of the article display stand showing the parts in unassembled condition; and
FIG. 3 is a sectional view taken along the line 3--3 of FIG. 1 looking in the direction of the arrows.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring now to the drawings in detail, wherein like reference numerals indicate like parts throughout the several figures, reference numeral 10 indicates the article display stand of the present invention. The article display stand 10 comprises just two types of components with two of each type used to assemble the stand.
The first type of component utilized in the stand 10 is the vertical support member 12 generally formed in a semicylindrical shape having an inner concave surface 14, an outer convex surface 16, side edges 18, 18 and top and bottom edges 20, 20. The side edges are preferably formed in a slight concave configuration to enhance the overall aesthetic effect of the stand 10.
As seen best in FIG. 3, the side edges 18, 18 are preferably formed of greater thickness then the major portion of the semicylindrical vertical support member 12 to enhance the strength of the side edges in securing the vertical support members to the second component used in the article display stand 10.
The vertical support members 12 are preferably molded of a polycarbonate thermoplastic material such as LEXAN. The polycarbonate thermoplastic material is preferably molded in a transparent form although a coloring material may be used to vary the overall look of the stand. Other equivalent polycarbonates may be used so long as they provide good dimensional stability and high impact strength as LEXAN polycarbonate.
The second component is the horizontal support member 22 with one member being used as a lower end 24 and a second member being used as an upper end 26. Each support member 22 includes a flat planar outer surface 28 and an inner surface 30 formed with spacer elements 32 and retainer elements 34 to position and support the vertical support members 12. Both the spacer elements 32 and the retainer elements 34 are preferably integrally molded with the inner surface 30 although the elements 32 and 34 could be separately formed and then joined to the inner surface 30 by the use of a suitable fastening means such as adhesive. It is preferred, however, that the horizontal support member 22 be molded in one piece of the same type of plastic material used for the vertical support members 12 although the horizontal support members will generally be opaque. As shown, the horizontal support members 22 are circular in shape although other shapes may be used to vary the design appearance.
The spacer elements 32 are preferably C-shaped although other shapes may be utilized to perform the same function, namely, to provide a curved segment against which the concave surface 14 of the vertical support member 12 can be placed to restrain movement of the vertical support member when a load is placed thereon. To attach the vertical support member 12 to the horizontal support member 22, the retainer elements 34 are provided in a U-shaped configuration having leg sections 36 and a bight section 38. An opening 40 is formed between leg sections 36 with the width of the opening 40 between leg sections 36 being slightly smaller than the thickness of the side edges 18 to thus provide a tight friction grasp of the vertical support members. As been best in FIG. 3, the spacer elements 32 and the retainer elements 34 are positioned on the inner surface 30 so that a space 42 is formed between the two vertical support members 12 when in position. This space not only permits a more rapid assembly of parts but the space adds to the aesthetic look of the assembled stand 10.
The parts are preferably shipped to the user in unassembled condition with a horizontal support member 12 placed within the concave portion of an adjacent member in stacked fashion so that only a small container need be used to ship a large number of stands 10. Assembly of an article display stand 10 is fairly obvious from the preceeding description. One of the horizontal support members 22 is selected and placed on a planar surface with the inner surface 30 facing upwardly. A first vertical support member 12 is placed about the spacer element 32 and the side edges 18 are press fitted into the openings 40 of two of the retainer elements 34 until the bottom edge 20 lies against the inner surface 30. In similar fashion, a second vertical support member 12 is attached thereto and a second horizontal support member is then placed in position on top of the vertical support members 12 and the side edges 18 are press fitted into the retainer elements 34 until the top edges 20 of the vertical support members 12 lie against the inner surface 30 of the horizontal support member. The large amount of bearing surface between the vertical support members and the horizontal support members insures that the assembled stand 10 is extremely stable and strong.
There has thus been provided an article display stand that can be quickly assembled and disassembled using just two different types of molded parts and which efficiently attains the objects set forth above. Since certain changes may be made in the above construction without departing from the scope of the invention, it is intended that all matters contained in the above description or as shown in the accompanying drawings shall be interpreted as illustrative and not in a limiting sense. | 1a
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The present application is in continuation of application Ser. No. 08/154,367, allowed and filed on Nov. 18, 1993, now U.S. Pat. No. 5,376,004.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to dental implants.
2. Description of the Related Art
Applicant believes that the closest reference corresponds to the implants sold by Stryker Dental Implants, Kalamazoo, Mich. 49001 and particularly, Stryker Fin Implant model nos. 260-135-008 and equivalents. However, this differ from the present invention because they fail to provide a termination having a multi-sided body (hexagonal portion) and a beveled portion adjacent thereto with the consequent compatible interface surface for engaging a prosthetic abutment free from debris traps. Also, the prior art fails to teach an anti-rotational mechanism for the abutment further, the prior art does not disclose a cylinder root form implant fixture with helical grooves or a screw type root form.
Another relevant reference is Duthie, Jr.'s patent wherein a dental implant that includes implant means 12 is disclosed with an abutment 44 that includes a frustoconical post member 40. Member 40 includes a distal and narrowest end 40 b that mates with tapered cavity 32 b. However, Duthie, Jr. fails to disclose a multi-face portion adjacent to an coaxially disposed with respect to the inwardly beveled portion. Also, Duthie, Jr. does not disclose an inwardly extending beveled portion. Duthie, Jr. also lacks a cylindrical portion since thread block section 26 is really part of the shaft. In fact, the purpose of the thread block section 26 is to permit bone to grow there. See column 4, line 18. This is not the purpose of cylindrical portion 60.
SUMMARY OF THE INVENTION
It is one of the primary objects of the present invention to provide an implant device that is free from debris traps or pockets where saliva, blood bacteria, soft tissue invagination or any other substances can be collected.
It is another object of the present invention to provide an implant device that includes a beveled portion for cooperative engagement with a cooperating abutment.
Still another object of the invention is to provide a versatile implant device to which different types of prosthetic abutments could be mounted.
Yet another object of this invention is to provide a hexagonal element that facilitates the application of the rotational force necessary to insert the implant in the bone and to prevent rotation of the abutment head on an individual or single tooth implant.
It is yet another object of this invention to provide such a device that is inexpensive to manufacture and maintain while retaining its effectiveness.
Further objects of the invention will be brought out in the following part of the specification, wherein detailed description is for the purpose of fully disclosing the invention without placing limitations thereon.
BRIEF DESCRIPTION OF THE DRAWINGS
With the above and other related objects in view, the invention consists in the details of construction and combination of parts as will be more fully understood from the following description, when read in conjunction with the accompanying drawings in which:
FIG. 1 represents a side elevational view of one of the preferred embodiments for a dental root form implant fixture of the threaded shaft type with an abutment having a smooth engagement tapered shaft.
FIG. 2 represents an alternate embodiment wherein the smooth engagement tapered shaft includes a threaded end, and the anchorage section is partially shown in cross-section taken along line 2 in FIG. 5.
FIG. 3 represents a side elevational view of a second alternate embodiment for a root form implant fixture of the fin type.
FIG. 4 is a partial representation of a third alternate embodiment for a cylinder form implant fixture of the helical groove type.
FIG. 5 is a top view of the second alternate embodiment.
FIG. 6 shows an elevational view of a fourth alternate embodiment, with partial cross-sections, having a removable abutment head.
FIG. 7 represents the components shown in FIG. 6 after being assembled.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring now to FIG. 1, where the preferred embodiment for the present invention is generally referred to with numeral 10, it can be observed that it basically includes root form implant fixture 20 and abutment member 100. Root form implant fixture 20 includes anchorage section 30 and engagement section (neck) 40.
Anchorage section 30 includes shaft 32 with threads 34 having sufficient separation of its threads to permit the bone in which it is inserted to occupy the space in between for best anchorage results. Shaft 32 can also be of the type known in the art as the fin type, as shown in FIG. 3, wherein several disks are rigidly positioned in a spaced apart parallel relationship with respect to each other, mounted to shaft 32. Another type of shaft 32 is the one shown in FIG. 4 and it corresponds to a cylinder with a helical groove.
As shown in FIG. 1, engagement section 40 is integrally built at one of the ends of shaft 32 and it includes cylindrical portion 60, beveled portion 70 and multi-face portion 80, all adjacent to each other in that order. Multi-face portion 80 has a hexagonal shape, in the preferred embodiment.
Central and longitudinally extending cavity 90 extends through the center of cylindrical, beveled and multi-face portions 70 and 80, as well as part of shaft 32, as best seen in FIG. 2. In the preferred as well as the alternate embodiment shown in FIG. 2, cavity 90 narrows down (tapers) as it extends toward anchorage section 30. At the end of cavity 90, in the alternate embodiment shown in FIG. 2, there is a threaded bottom part 92. It should be noted that for both, the preferred embodiment shown in FIG. 1 and the alternate embodiment of FIG. 2, the same cavity 90 is used even if the abutment's post 120 of the preferred embodiment lacks a mating thread.
Abutment member 100 has head 110 with elongated post 120 that is built in, as seen in FIG. 1. The angle of head 110 with respect to the longitudinal axis of member 100 varies depending on the correction for parallelism that may be necessary. In the figures applicant has shown abutments with 0 degrees of correction to facilitate the description of the invention. Lack of parallelism is undesirable and it arises when fixtures 20 are not positioned parallel to each other. Elongated post 120, in the preferred embodiment shown in FIG. 1, is smooth and bites against internal walls of central cavity 90 thereby locking it in place. The metal to metal biting engagement of post 120 and internal walls of cavity 90 provides a retention of abutment 100 and hermetic seal for any unoccupied space inside cavity 90 thereby preventing the collection of saliva, blood or any other decaying substance.
In FIG. 2, alternate abutment member 100' includes threaded pin 130' rigidly mounted at the distal end of post 120'. Threaded pin 130' cooperatively engages with threaded bottom part 92 of cavity 90.
The second and third alternate embodiments shown in FIGS. 3 and 4 for fixtures 20" and 20'" are basically similar to those shown in FIGS. 1 and 2 except that shafts 32" and 32'" of anchorage sections 30" and 30'" are of the fin and helical groove types, respectively.
A fourth alternate embodiment is shown in FIG. 6 and is generally referred to with numeral 10"". Root form implant fixture 20"" used with dental implant device 10"" is identical to the one used with devices 10 and 10'. Fixture 20"" can be of any type (threaded, fin or cylinder). Abutment head 110"" is removably mounted over fixture 20"" and in cooperative non-rotational engagement thereon. Inwardly chamfered rim 112"" matingly comes in complementary abutting contact with beveled portion 70"". This flat face to face engagement of rim 112"" and beveled portion 70"" will create a hermetic seal that will prevent the infiltration of saliva, bacteria, exudate or soft tissue invagination or any other foreign bodies. Internal multi-faced socket 114"" similarly matingly and cooperatively engages with multi-face portion 80"", thereby preventing rotation of abutment 110".
Post 120"" is coaxially inserted through central opening 111"" of abutment head 110"" and pin member 130"" at one end protrudes through rim 112"" to engage with cavity 90"" in fixture 20"". This engagement is accomplished in the same manner as described for the preferred and the first alternate embodiments. The only difference being that post 120"" is also provided with an internal socket 122"" to permit rotating it and causing sleeve 124"" to come in contact with counterbore surface 116"", thereby holding abutment head 110"" down.
Screw member 200"" is designed to hold the prosthesis (fixed or removable) to abutment head 110"", as best seen in FIG. 7.
The foregoing description conveys the best understanding of the objectives and advantages of the present invention. Different embodiments may be made of the inventive concept of this invention. It is to be understood that all matter disclosed herein is to be interpreted merely as illustrative, and not in a limiting sense. | 1a
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CROSSREFERENCE TO RELATED APPLICATIONS
This application is based on a Provisional Patent Application, Ser. No. 60/076,313 filed Feb. 27, 1998.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a general method for isolation and growth of nitrite-resistant bacteria with a high level of inducible nitrate reductase activity. In particular, the present invention relates to a method of isolation and growth of bacteria with a high level of inducible nitrate reductase activity using Chinese cabbage and celery extracts as a source of the bacteria and media.
The present invention also relates to a general method of inhibiting bacterial growth in foods by adding nitrate-rich vegetable extracts. More specifically, the present invention demonstrates an anti-bacterial effect of Chinese cabbage and celery extracts on beef during storage.
2. Description of Related Art
Sodium nitrate and nitrite are added to meat as preservatives to ward off bacteria. These compounds are also responsible for a bright-red color of cured meat (Committee on nitrite and alternative curing agents in food, national Academy of Sciences, Chapter 3, 1981). Vegetables such as celery, spinach, beets, turnip greens, radishes and lettuce have a high nitrate content (Committee on nitrite and alternative curing agents in food, national Academy of Sciences, Chapter 5, 1981). As a result, nitrate consumed by U.S. residents is primarily through vegetables. However, the main source of nitrite in the U.S. is cured meats (Committee on nitrite and alternative curing agents in food, national Academy of Sciences, Chapter 5, 1981; White, 1975).
In mammalian cells, nitric oxide synthase catalyzes formation of nitric oxide from L-arginine. Nitric oxide plays a significant role in signal transduction and cell to cell communication. Nitric oxide release can be assayed by measuring its stable degradation products, nitrite and nitrate (Schmidt, 1995).
The most commonly used method for analysis of nitrite is a colorimetric method using the Griess reaction (Committee on nitrite and alternative curing agents in food, national Academy of Sciences, Chapter 5, 1981; Schmidt, 1995). Nitrate is determined by measurement of nitrite by the Griess reaction after reduction of nitrate to nitrite (Committee on nitrite and alternative curing agents in food, national Academy of Sciences, Chapter 5, 1981; Schmidt, 1995). Nitrate is reduced to nitrite by passing the reaction mixture through a column packed with cadmium shavings or by adding granulated cadmium in the mixture (Committee on nitrite and alternative curing agents in food, national Academy of Sciences, Chapter 5, 1981; Vodovotz, 1996).
Recently, nitrate was enzymatically reduced to nitrite by incubation with nitrate reductase. Nitrate reductase has been studied in bacteria, fungus and plants. Thus far three different kinds of nitrate reductases have been found. Assimilatory nitrate reductase converts nitrate to ammonia, vianitrite, which is assimilated to nitrogen metabolism.
Ammonia, the end product of the pathway inhibits nitrate reductase activity and oxygen does not have any effect on the nitrate reductase activity (Kubo, et al., 1988; Hyde et al., 1990). A membrane-bound, respiratory (dissimilatory) nitrate reductase converts nitrate to nitrite (Carlson, et al. 1982) and then the formed nitrite is converted to nitric oxide and nitrous oxide by respiratory nitrite reductase (Smith, et al. 1992). This pathway, which produces ATP from ADP using nitrate in anaerobic condition, is insensitive with ammonia.
Recently, the third nitrate reductase, periplasmic nitrate reductase, has been found. Contrary to the other nitrate reductases, the periplasmic nitrate is not encoded on the chromosome, but by the megaplasmid and the gene products with a signal peptide are found in the periplasm (Bursakov, et al. 1997; Siddiqui, et al. 1993; Carter, et al. 1995). This nitrate reductase may be involved in cellular redox balance.
A few commercially available nitrate reductases are nitrate reductase which are obtained from E. coli (Worthington Biochemical Co. and Sigma Co, Aspergillus (Boehringer-Mannheim), and corn (The Nitrate Elimination Co.).
The significance of the presence of nitrite and nitrate in meat relates to health concerns. Adding nitrite and nitrate to meat became a health problem because sometimes nitrite reacts with the amines in meat. This reaction forms a chemical, nitrosamines, that is found to cause cancer in laboratory animals (Graham, 1980). To avoid the health problem caused by this nitrosamine formation, some meat products contain BHA and BHT, preservatives of another kind. However, neither of these preservatives are naturally occurring.
It would therefore be useful to develop a method for the isolation and growth of nitrite released in bacteria with high nitrate reductase activity. Additionally, it would be useful to develop a method for the retardation of bacterial growth in foods using plant extracts.
SUMMARY OF THE INVENTION
According to the present invention, there is provided a method for retarding bacterial growth in foods by adding plant extracts. Also provided is a bacterial growth inhibitor for foods containing a plant extract. A method for isolating nitrate-resistant bacteria with nitrate reductase activity by growing nitrate-resistant bacterial and nitrate rich media is also provided. Also provided is a method of measurement utilizing nitrate-resistant bacteria with high nitrate reductase activity.
DESCRIPTION OF THE DRAWINGS
Other advantages of the present invention will be readily appreciated as the same becomes better understood by reference to the following detailed description when considered in connection with the accompanying drawings wherein:
FIG. 1 illustrates comparison of visible absorption spectra of extracts obtained from beef patties cooked with and without adding Chinese cabbage extract;
FIG. 2 illustrates a standard curve for measurement of nitrite levels;
FIG. 3 illustrates nitrite formation in beef extracts stored with Chinese cabbage juice;
FIG. 4 A and FIG. 4B illustrates anti-bacterial activity of Chinese cabbage juice; and
FIG. 5 illustrates time-dependent increase of nitrite levels of nitrate-rich vegetable extracts.
DETAILED DESCRIPTION OF THE INVENTION
Generally, the present invention provides a method for the isolation and growth of nitrite-resistant bacteria with a high level of inducible nitrate reductase activity. The method includes the steps of growing nitrite-resistant bacteria in nitrate-rich media. In the preferred embodiment, Chinese cabbage and celery extracts were used as media to grow nitrite-resistant bacteria. However, the media can be any other nitrate-rich vegetable or plant extracts, or synthetic media with high nitrate and cofactors for suitable growth of nitrite-resistant bacteria with a high level of inducible nitrate reductase activity.
In a preferred embodiment, the nitrite-resistant bacteria were obtained from Chinese cabbage or celery extracts. The source of bacteria can be other vegetable or plant extracts, or another source which can harbor nitrite-resistant bacteria, e.g. dirt. In the preferred embodiment, nitrite-resistant bacteria which have a high level of inducible nitrate reductase activity were selected by growing bacteria in filter-sterilized Chinese cabbage extract followed by testing for nitrite formation. Almost all of the nitrite-resistant bacteria were white colony forming bacteria which had high nitrate reductase activity. Thus, the selection procedure can be eliminated. The white colony forming bacteria have unique morphology when they were grown in agar plates. Accordingly, the bacteria can be selected by morphology. The media can be pasteurized or heat-sterilized.
The nitrate-resistant bacteria can be selected from vegetable extracts without incubation, by their morphology or other unique characteristics. However, nitrate reductase activity of the bacteria has to be induced by incubation of the bacteria with nitrate-rich vegetable extracts or suitable nitrate-rich media. The bacteria harbor on the surface of the vegetables and do not show nitrate reductase activity, however when they are mixed with the vegetable extracts, the nitrate reductase activity of the bacteria is induced.
In the preferred embodiment, nitrate reductase activity of the nitrite-resistant bacteria was induced by incubation of the bacteria with Chinese cabbage or celery extracts. Media to induce nitrate reductase activity of the bacteria can be other nitrate-rich vegetable or plant extracts, or synthetic media with high nitrate and cofactors for suitable growth of nitrite-resistant bacteria.
In another embodiment of the present invention, the isolated nitrite-resistant bacteria with high nitrate reductase activity can be utilized to determine nitrate levels and nitric oxide synthase activity. Further, the nitrite-resistant bacteria can be utilized to obtain purified nitrate reductase. This purified nitrate reductase is useful as a measuring device for nitrate levels, determination of nitric oxide synthase activity, the conversion of nitrate to nitrite as part of the elimination procedure and for measuring antibody production. The tests used to measure the above items can be determined by one skilled in the art.
The present invention further relates to a general method for the retardation of bacterial growth in foods by the addition of nitrate-rich vegetable extracts. The method includes the steps of mixing foods with nitrite-rich vegetable extracts prior to storage. In the preferred embodiment, Chinese cabbage or celery extracts were the nitrite-rich vegetable extracts utilized. The vegetable extracts can be other nitrate-rich vegetable or plant extracts. The extracts can be pasteurized or filter- or heat-sterilized.
In the preferred embodiment, Chinese cabbage or celery extracts were added to beef The extracts can also be added to other meats or edible foods. The food can then be stored at room temperature, or refrigerated or frozen. This allows the food to be packaged or processed with heat.
The above discussion provides a factual basis for the use of vegetable extracts for both the isolation and growth of nitrite-resistant bacteria and the use of vegetable extracts for the retardation of bacterial growth in foods. The methods used with and the utility of the present invention can be shown by the following non-limiting examples and accompanying figures.
EXAMPLES
General Methods:
General methods in molecular biology: Standard molecular biology techniques known in the art and not specifically described were generally followed as in Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Springs Harbor Laboratory, New York (1989, 1992), and in Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Baltimore, Md. (1989).
Example 1
Methods and Materials:
Reagents. Ready-to-use agar plates (trypticase soy agar with 5% sheep blood) were obtained from Baxter Diagnostics Inc. (McGaw Park, Ill.). Color reagent, which contains sulfanilamide and N-(1-naphthyl)ethylenediamine, was obtained from The Nitrate Elimination Co. (Lake Linden, Mich.). Other reagents were purchased from Sigma Chemical Co. (St. Louis, Mo.).
Production of Beef Patties. Beef was divided into equal portions of 135 grams. Fifty ml of water, Chinese cabbage or celery extracts were added to beef, kept at 4° C. for three days and cooked.
Measurement of Absorption Spectra of Cooked Beef Extracts. A portion (three g) of cooked beef patties obtained with or without vegetable extract was crushed, and ten ml water and 0.2 ml 5N NaOH were added and kept at room temperature for an hour to dissolve proteins. The dissolved beef patties were spun for 30 seconds using a table top centrifuge and supernatants were taken. Absorption spectra of the supernatants were obtained in the range of 200 to 700 nm using a Shimadzu UV-Vis spectrophotometer (UV 1601).
Sample Dilution for Bacterial Culture on Agar Plates. For experiments to isolate nitrite-resistant bacteria, three g of beef, mixed with sterilized water or Chinese cabbage juice, were taken and mixed in 350 ml of water in a jar. A sample (0.5 ml) was taken from the jar and put into a 50 ml sterilized conical tube filled with 49.5 ml of water (35,000-fold dilution).
A sample (0.5 ml) was taken from the tube and put into the second 50 ml sterilized conical tube filled with 49.5 ml of water (3.5 million-fold dilution). A sample (0.5 ml) was taken from the first test tube and the second test tube, and placed in the ready-to-use agar plates.
The number of bacterial colonies on each plate was counted after incubation at room temperature for three days. The number of bacteria in three grams of beef sample was calculated by multiplying the number of bacteria on the plate with the dilution factor ×2 (0.5 ml of sample was put in the plate).
Bacterial Culture on Agar Plates. Aliquots of diluted samples were taken and placed on ready-to-use agar plates (trypticase soy agar with 5% sheep blood) (Baxter Diagnostics Inc., McGaw Park, Ill.). When the solution was absorbed by the agar, the plates were turned upside-down and kept at room temperature for three days. The number of bacterial colonies on each plate was compared.
A Standard Curve for Nitrite Levels. Nitrite levels were determined using the Griess reaction as previously described by Schmidt, 1995. Various concentrations (0 to 20 μg/ml) of potassium nitrite solutions were made. In a microtube, 100 μl of nitrite solution, 100 μl of 0.5 M phosphate buffer, pH 7.6, and 100 μl (8 mg/ml) of color reagent (The Nitrate Elimination Co., Lake Linden, Mich.) were added. In each tube, 700 μl of water was added and absorption spectra of the nitrite solutions were obtained using a spectrophotometer (Shimadzu Co.).
Optical density of each nitrite solution was measured at 540 nm, and a standard curve to measure nitrite levels was obtained.
Measurement of Nitrite Levels in Beef Mixed with Chinese Cabbage. Beef was divided into three portions of equal size for each group. Each portion was mixed with either water or Chinese cabbage juice and stored at 4° C. for nine days. Beef extract (100 μl), 100 μl of 0.5 M phosphate buffer, pH 7.6, 100 μl of color reagent, and 700 μl of water were mixed and the absorption spectra of the mixture were obtained. For the sample without the color reagent, 100 μl of water was added to the mixture in place of the color reagent.
Measurement of nitrate/nitrite levels in vegetable and fruit juices. Nitrate in juices is converted to nitrite by addition of nitrate reductase, and the formed nitrite reacts with a color reagent to produce pink azo dyes. Vegetable and fruit juices were spun in microtubes for three minutes using a microfuge. The supernatant (100 μl) was taken and added to a microtube.
Nitrate reductase purified from corn (The Nitrate Elimination Co.) was dissolved in 0.5 M phosphate buffer, pH 7.6, and 0.025 unit (100 μl) was added to the vegetable or fruit juice.
The mixture was incubated for 15 minutes at room temperature and 100 μl of color reagent was added. For the measurement of absorption spectra, 700 μl of water was added to each tube. Optical density at 540 nm of each sample was taken and, using a standard curve for nitrite, concentration of nitrite in the tube was obtained. The concentration of nitrate/nitrite in a juice was obtained by multiplying the value with a dilution factor of ten. Nitrite levels in extracts were obtained by addition of 100 μl of 0.5 M phosphate buffer, 100 μl of color reagent, and 700 μl of water to 100 μl of extracts.
Measurement of Time-Dependent Nitrite Formation in Nitrate-Rich Vegetable Juices. Chinese cabbage and celery were washed and wiped with clean paper towel. Chinese cabbage and celery extracts were obtained. Aliquots of extracts (200 μl) were taken for each time point up to 30 hours after extraction of juices. Three samples were taken for each time point. Color reagent (100 μl) was added to each tube at the designated time point and 700 μl of water was added. Optical density at 540 nm of each sample was taken. Mean and standard deviation of each time point were obtained using StatView 512+TM (BrainPower, Inc., Calabasas, Calif.).
Filter-Sterilization of Chinese Cabbage Juice. Chinese cabbage juice was filtered using Acrodisc LC PVDF disposable filter (0.2 μm, Gelman Co.) and stored in sterilized conical tubes or microtubes.
Results
Chinese cabbage and celery extracts were added to ground beef and stored at 4° C. for three days before cooking. Beef patties mixed with the vegetable extracts, not those with water, showed red color.
The red-colored substance of the cooked beef patties was extracted with an alkaline solution and the visible absorption spectra of extracts were compared (FIG. 1 ). Beef patty extracts stored with vegetable extracts showed exactly the same height of hemoglobin or myoglobin peak at 410 nm as those without addition of the vegetable extract. However, the beef extracts with Chinese cabbage extract which was red colored showed higher absorbance at 450 to 700 nm as compared with that of beef patties cooked without Chinese cabbage juice which showed brown color. (Red color absorbs 450 to 600 nm).
Beef patties cooked right after addition of the vegetable extracts did not develop the red color. Formation of red color in the beef patties was dose—(vegetable extract) and time—(days of storage) dependent. The addition of antibiotics to the beef patties stored with the vegetable extracts prevented red color formation of the cooked beef patties. These results suggest that bacteria changed nitrate in vegetable to nitrite which reacted with hemoglobin or myoglobin.
Optical density of each nitrite solution (the final concentration is 0 to 1.5 μg/ml) was measured at 540 nm and a standard curve to measure nitrite levels was obtained. Optical densities at 540 nm correlated with the concentrations of nitrite in the solutions (FIG. 2 ).
The beef was divided into three portions of equal size for each group. Each portion was mixed with either water or Chinese cabbage juice and stored at 4° C. for nine days. The addition of color reagent, which produces a pink azo dye by reaction with nitrite, increased optical density at 540 nm in extracts obtained from beef stored with Chinese cabbage juice (FIG. 3 ). The difference in optical density at 540 nm between the mixtures with and without addition of color reagent (the beef extracts were stored with Chinese cabbage juice) was 0.12, which correlates with 0.3 μg/ml of nitrite solution in the tube. When the value is multiplied by ten (a dilution factor), establishing a nitrite concentration of the beef extract was 3 μg/ml.
The beef was divided into three portions of equal size for each group. Each portion was mixed with either water or Chinese cabbage juice and stored at 4° C. At zero and six days of storage, beef patties were cooked to analyze red color formation (FIG. 4, Panel A), and 3 g of beef patty was diluted seven million-fold and plated on agar plates (FIG. 4 Panel B).
Cooked beef patty mixed with Chinese cabbage juice showed bright red color after six days of storage (FIG. 4, Panel A). This result showed that nitrate in Chinese cabbage juice was changed to nitrite by bacteria in the mixture. The number of bacteria in beef mixed with water dramatically increased after six days of storage, whereas that of beef mixed with Chinese cabbage juice was about the same (FIG. 4, Panel B). This result suggests that bacteria changed nitrate in Chinese cabbage to nitrite, and the formed nitrite inhibited bacterial growth in beef during storage.
Beef mixed with Chinese cabbage juice had ˜20 million colonies/3 g after storage at 4° C. for six days (FIG. 4, Panel B). The bacteria, which survived in high levels of nitrite in the mixture (>20 μg), formed white or yellow colonies. The majority of the colonies formed on agar plates were white.
Chinese cabbage or celery extracts (200 μl) were taken for each time point up to 30 hours. Each time point had three samples and samples were kept at room temperature. Color reagent (100 μl) was added to each tube at the designated time point and optical density at 540 nm of each sample was measured after 700 μl of water was added. Time-dependent increases in optical density at 540 nm for Chinese cabbage and celery extracts are shown in FIG. 5 . These results showed that nitrite was formed from nitrate in the vegetable extracts by bacteria which were harbored on the surface of the vegetables. The levels of nitrite dramatically increased at about ten hours after extraction of juice. The concentration of nitrite in the vegetable extracts was higher than 20 μg/ml after ˜15 hours incubation at room temperature.
Chinese cabbage or celery extract was stored at room temperature for 30 and 24 hours, respectively. Both vegetable extracts showed dark red color after addition of color reagent which measures nitrite levels. Nitrite concentrations of the extracts were higher than 20 μg/ml. The vegetable extracts were diluted seven million-fold and aliquots of the diluted samples were placed on agar plates. About ten colonies of white and yellow were formed on the agar plate after three days of incubation at room temperature. Majority of the colonies formed by the nitrite-resistant bacteria were white colored. The shapes and colors of the bacteria were same as those obtained from beef mixed with Chinese cabbage juice after storage at 4° C. for six days (FIG. 4, Panel B). The white and yellow colonies on the agar plate, which were obtained from Chinese cabbage juice after 30 hours incubation at room temperature, were taken, spread on a fresh agar plate, and incubated at room temperature for three days. Chinese cabbage juice was filter-sterilized using Acrodisc LC PVDF disposable filter (0.2 μm, Gelman Co.), and used as nitrate-rich media to grow bacteria. The white and yellow colonies were taken with a sterilized inoculation loop and put in microtubes containing the filter-sterilized Chinese cabbage juice (200 μl). The filtered Chinese cabbage juice stored at room temperature without inoculation of bacteria was clear after 24 hours of incubation at room temperature, whereas the tubes inoculated with white or yellow bacteria became turbid due to growth of bacteria. When a color reagent (100 μl) for the detection of nitrite was added, the juice inoculated with white colony turned red, whereas those of yellow colony didn't change.
In summary, the addition of Chinese cabbage juice to beef inhibited bacterial growth except for a few nitrite-resistant bacteria. High levels of nitrite were formed in nitrate-rich vegetable extracts during storage. The source of the nitrite-resistant bacteria was those harbored on the surface of vegetables. White colony-forming bacteria, which were nitrite-resistant, were isolated from Chinese cabbage juice and beef mixed with Chinese cabbage juice after storage, and their nitrate reductase activity was confirmed using filter-sterilized extracts of nitrate-rich vegetables. The nitrate reductase activity of the bacteria was induced by incubation of the bacteria with nitrate-rich vegetable extracts.
These results show that filter-sterilized nitrate-rich vegetable extracts are suitable growth media for culture of nitrite-resistant bacteria, and suggests that bacteria which formed white colonies, not those of yellow colonies, have nitrate reductase activity. The invention has been described in an illustrative manner, and it is to be understood that the terminology which has not been used is intended to be in the nature of words of description rather than of limitation.
Obviously, many modifications and variations of the present invention are possible in light of the above teachings. It is, therefore, to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described. | 1a
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BACKGROUND
The present invention relates to the field of food displays, and particularly to a shelving system for a point-of-purchase food display.
Point-of-purchase food displays commonly include a container having transparent side walls that facilitate viewing the food product by a customer. The container can be opened to facilitate insertion and removal of the food product. In general, racks or shelves are positioned within the container to further assist viewing of the food product. Such displays also commonly include a light for illuminating the food product, a heater for heating the air in the container, and a fan for circulating the heated air. These electrical components are typically positioned above the container and are covered by a hood for aesthetic reasons.
These food displays can also include adjustable racks or shelves that may be positioned in different positions within the container. For example, such shelves frequently are designed to be tilted so that the front of the shelf can be positioned lower than the rear of the shelf to facilitate improved viewing of the food product on the shelf.
SUMMARY
The present invention provides a food storage device comprising a housing defining a volume for storing a food product, a shelf positioned at least partially within the volume and adapted to support a food product, and a coupling assembly coupling the shelf to the housing and adjustable (e.g., infinitely) to position the shelf in one of a plurality of different angles relative to the housing. Preferably, the housing comprises a frame creating a surface coupled to the magnetic assembly, and a translucent panel coupled to the frame to facilitate viewing food product positioned in the housing.
In one embodiment, the coupling assembly comprises a magnetic assembly including a magnet secured to the shelf and magnetically coupled to the housing. Preferably, the magnetic assembly further comprises a magnet holder secured to the shelf, wherein the magnet is secured to (e.g., positioned in) the holder. In this embodiment, the magnet can be secured to the magnet holder by an intermediate material (e.g., a plastic) positioned between the magnet and the magnet holder.
The coupling assembly preferably includes a bracket that is positioned in an opening in the shelf. For example, the bracket can include an upper protrusion that engages an upper surface of the shelf and a lower protrusion that engages a lower surface of the shelf.
Other aspects of the invention will become apparent by consideration of the detailed description and accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of a food storage device embodying the present invention.
FIG. 2 is a perspective view of a shelf of the food storage device of FIG. 1 .
FIG. 3 is an enlarged partial side view of the shelf of FIG. 2 .
FIG. 4 is a perspective view of a magnetic assembly.
FIG. 5 is an exploded perspective view of the magnetic assembly of FIG. 4 .
FIG. 6 is an enlarged partial perspective view of the shelf of FIG. 1 with a food retaining device removed.
FIG. 7 is the same view as FIG. 6 with the food retaining device added.
FIG. 8 is a perspective view of the food retaining device.
DETAILED DESCRIPTION
Before any embodiments of the invention are explained in detail, it is to be understood that the invention is not limited in its application to the details of construction and the arrangement of components set forth in the following description or illustrated in the following drawings. The invention is capable of other embodiments and of being practiced or of being carried out in various ways. Also, it is to be understood that the phraseology and terminology used herein is for the purpose of description and should not be regarded as limiting. The use of “including,” “comprising,” or “having” and variations thereof herein is meant to encompass the items listed thereafter and equivalents thereof as well as additional items. Unless specified or limited otherwise, the terms “mounted,” “connected,” “supported,” and “coupled” and variations thereof are used broadly and encompass both direct and indirect mountings, connections, supports, and couplings. Further, “connected” and “coupled” are not restricted to physical or mechanical connections or couplings.
FIG. 1 shows a food storage device in the form of a heated food display 10 . The heated food display 10 includes a housing 14 , a shelf 18 positioned in the housing 14 , a magnetic assembly 22 that couples the shelf 18 to the housing 14 , and a food retaining device 26 coupled to the shelf 18 . The heated food display 10 is illustrated with two shelves 18 , although more than two shelves 18 or less than two shelves 18 can be used.
The housing 14 includes a frame 34 , a roof 38 , a floor 42 , and translucent panels 46 coupled to the frame 34 . The illustrated frame 34 is generally square-shaped and includes four vertical posts 50 at the corners that connect the roof 38 and the floor 42 . The four vertical posts 50 are constructed from a magnetically conductive material, such as steel. In other constructions, the posts 50 may be made of some other magnetically conductive material, a magnetic material, or may be coated with a protective finish or coating. In addition, other constructions may remove the roof 38 and the floor 42 . Furthermore, the frame 34 may include more than four posts 50 or less than four posts 50 .
The illustrated roof 38 includes lights (not shown) and a heating system (not shown). The lights may be turned on or off to better display a food product (not shown). The heating system circulates hot air through the heated food display 10 to maintain the temperature of the heated food product displayed on the shelves 18 . In other constructions, the heater may be in the floor 42 . In addition, the roof 38 may include a lighted sign or other display that indicates the contents of the heated food display 10 . The roof 38 is constructed of a molded plastic, although other constructions may use sheet metal or other materials. In still another construction, the food storage device is a cooled food display, wherein the roof 38 or floor 42 may contain a cooling unit to maintain a cool temperature within the housing 14 .
The illustrated floor 42 provides a base for the heated food display 10 and includes four feet (not shown) that the heated food display 10 rests on. One or more of the feet act as levelers to ensure the heated food display 10 is level and solidly positioned on a counter top (not shown) or other surface.
The illustrated translucent panels 46 are supported by the frame 34 and cooperate with the frame 34 , the floor 42 , and the roof 38 to define the inside of the heated food display 10 . One or more of the translucent panels 46 is movable (e.g., hinged) with respect to the frame 34 such that the translucent panel 46 provides access to the inside of the housing 14 . In other constructions, the housing 14 may include more than four translucent panels 46 or less than four translucent panels 46 . For example, one or more of the translucent panels 46 may be replaced with a mirror surface. In addition, the housing 14 may be different shapes and the proportions may be different than those illustrated.
Referring to FIG. 2 , the illustrated shelf 18 is constructed from welded metallic rods that are arranged to form a rectangular surface that supports food products inside the housing 14 . The plurality of metallic rods includes support members 54 and surface members 58 that are spaced a distance apart from each other to define spaces 62 such that air may circulate within the housing 14 through the shelves 18 . The shelf 18 defines a first side 66 , a second side 70 , a shelf front 74 , and a shelf back 78 . In other constructions, the shelves 18 may be formed as a single piece, or may be constructed from different materials, such as a plastic. In addition, the shelves 18 may be a different shape, have larger or smaller spaces 62 , or may be formed as a solid surface.
In the illustrated construction, four magnetic assemblies 22 are provided to support each shelf 18 . Referring to FIGS. 3-6 , each illustrated magnetic assembly 22 includes a bracket 82 and a magnet holder 86 . The bracket 82 includes an arm 90 and an upper portion 94 . The illustrated arm 90 and upper portion 94 are formed as a single piece and are oriented at 90 degrees with respect to each other. The 90 degree relation acts as a leveling mechanism for the shelf 18 such that the shelf 18 is level with respect to the first side 66 and the second side 70 .
As shown in FIG. 3 , the upper portion 94 includes two upper protrusions 98 that engage the top of the surface members 58 , and four lower protrusions 102 that engage the bottom of the surface members 58 such that the bracket 82 is secured between the surface members 58 . In other constructions, the magnetic assembly 22 may be formed as multiple pieces and may attach to the shelf 18 in different ways or may be formed as part of the shelf 18 . In addition, the magnet holder 86 and the bracket 82 may be formed as a single piece.
Turning now to FIG. 5 , the illustrated magnet holder 86 is attached to the arm 90 and secured with a first fastener 106 . A magnet 110 is held in the magnet holder 86 by an intermediate material 112 . In the illustrated construction, the intermediate material 112 is a plastic with thermal properties to match or exceed the maximum temperatures within the heated food display 10 . In other constructions the intermediate material 112 may be a glue, a rubber, an epoxy, or another material.
FIG. 5 illustrates the magnetic assembly 22 in an exploded state wherein the intermediate material 112 is visible that secures the magnet 110 in the magnet holder 86 . The magnet holder 86 includes a second fastener 114 such as a threaded stud which is inserted through an aperture 118 in the arm 90 and fastened with the first fastener 106 such as an acorn nut. In addition, the second fastener 114 and the first fastener 106 may be different fasteners as is known by those skilled in the art.
Each magnetic assembly 22 engages the surface members 58 to secure the magnetic assembly 22 to the shelf 18 . Each magnetic assembly 22 is operable to magnetically couple the shelf 18 to one of the posts 50 of the housing 14 , thereby positioning the shelf 18 with respect to the housing 14 . In this way, the shelf 18 may be positioned inside the housing 14 at a number of angles with respect to the floor 42 . In other constructions, more than four magnetic assemblies 22 or less than four magnetic assemblies 22 may be secured to each shelf 18 .
FIGS. 3 and 4 illustrate a distance d 1 that is defined as the vertical distance between a top surface 122 of the lower protrusion 102 and a bottom surface 126 of the upper protrusion 98 . The distance d 1 is slightly larger than the diameter of the surface members 58 such that when the surface members 58 are engaged with the bracket 82 the magnetic assembly 22 is secured to the shelf 18 and inadvertent disengagement is inhibited. In other constructions, the distance d 1 may be equal to the diameter of the surface members 58 or slightly less than the diameter of the surface members 58 .
Referring to FIG. 5 , a width d 2 of a stabilizing portion 130 is sized to fit between two adjacent surface members 58 (see FIG. 6 ). In the illustrated construction, the width d 2 is slightly smaller than the distance between the two adjacent surface members 58 . In other constructions, the width d 2 may be larger than the distance between the two adjacent surface members 58 or substantially equal to the distance between the two adjacent surface members 58 .
In operation of the illustrated construction, the magnetic assemblies 22 are secured to the shelves 18 by positioning the bracket 82 , while disengaged, below the shelf 18 between two adjacent surface members 58 at the midpoint of the space 62 defined by the adjacent surface members 58 and spaced from the sides 66 , 70 . The surface members 58 are then elastically deformed such that the space 62 is enlarged to the point where the upper portion 94 of the bracket 82 may be moved through the space 62 . When bracket 82 is positioned with the upper portion 94 positioned as shown in FIG. 6 , the surface members 58 are released and return to the original position wherein the upper protrusions 98 may not move through the space 62 and the upper protrusions 98 engage the top of the surface members 58 and the lower protrusions 102 engage the bottom of the surface members 58 such that the magnetic assembly 22 is secured to the shelf 18 .
When the magnetic assemblies 22 are secured to the shelf 18 and still spaced from the sides 66 , 70 , the shelf 18 can be positioned within the housing 14 . After the shelf 18 is satisfactorily placed, the magnetic assemblies 22 are slid toward the corresponding side 66 , 70 into the positions shown in FIGS. 2 and 6 . The magnetic assemblies 22 are positioned along the posts 50 to couple the shelf 18 to the posts 50 of the housing 14 and hold it in a position with respect to the floor 42 such that the shelf 18 and posts 50 are arranged as shown in FIG. 7 . This arrangement allows the positioning of the shelf at an infinitely variable range of angles while holding the shelf 18 level with respect to the first side 66 and the second side 70 .
Referring to FIGS. 2 and 8 , the illustrated food retaining device 26 is removably coupled to each shelf 18 . The illustrated food retaining device 26 is formed as a single piece and includes a front side 134 , a back side 138 , a bottom edge 142 , a first end 146 , a second end 150 , and two tabs 154 attached to each of the front side 134 and the back side 138 (see FIG. 8 ).
The first end 146 extends to the first side 66 of the shelf 18 and the second end 150 extends to the second side 70 of the shelf 18 such that the food retaining device 26 extends substantially between the first side 66 and the second side 70 . The food retaining device 26 inhibits food products from inadvertently falling off the shelf 18 . The food retaining device 26 may be removed from the shelf 18 by flexing the food retaining device 26 so the tabs 154 disengage the surface members 58 . In some situations, it is conceivable that removing the food retaining device 26 may be desirable. The food retaining device 26 may be formed from multiple pieces or may be constructed from a screen like material.
As is best seen in FIG. 3 , the food retaining device 26 is positioned near the shelf front 74 and is secured to the shelf 18 by positioning the tabs 154 to engage the surface members 58 of the shelf 18 while the bottom edge 142 of the back side 138 is positioned on the support members 54 of the shelf 18 . The food retaining device 26 also defines cutouts 158 on the front side 134 that extend from the first end 146 to the tab 134 closest to the first end 146 , and from the second end 150 to the tab 134 closest to the second end 150 . The cutouts 158 are sized to provide clearance for the magnetic assemblies 22 . In other constructions, the cutouts 158 may be different sizes or shapes.
Once the magnetic assemblies 22 are positioned as shown in FIG. 2 , the food retaining device 26 can be engaged with the shelf 18 . The food retaining device 26 is elastically deformed such that the tabs 154 fit in the space 62 defined between the surface members 58 . When in the position shown in FIGS. 2 and 3 , the food retaining device 26 is released and returns to the original state and the tabs 154 engage the surface members 58 to attach the food retaining device 26 to the shelf 18 . Only one food retaining device 26 is preferred as the shelf 18 is substantially level with respect to the first side 66 and the second side 70 such that food product is inhibited from rolling side to side and falling from the shelf 18 off either the first side 66 or the second side 70 . In other constructions, the food retaining device 26 may be placed at different positions between the shelf front 74 and the shelf back 78 . In addition, more than one food retaining device 26 is conceivable.
Various features and advantages of the invention are set forth in the following claims. | 1a
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BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates generally to folding beds. More particularly, the invention relates to a folding bed with an attached folding bench.
[0003] 2. Description of the Prior Art
[0004] Wall beds and similar folding beds, often referred to as Murphy beds, have been in use for many years. Folding beds are moveable between a substantially vertical storage position to a substantially horizontal position, and visa versa. When in the lowered position, a folding bed may appear to be similar to a normal bed, sometimes with a headboard such as the retractable headboard disclosed in U.S. Pat. No. 5,446,932 to Bue, and assigned to SICO, Inc. When in the raised position, the folding bed is typically confined folded into a wall or storage cabinet in the wall, where it is concealed. These beds provided greater utility of the space, saving space over conventional beds and allowing multiple wide ranging uses of the room with quick and easy conversion between a sleeping room and another use. This cabinet may include shelves or a desk such as the folding beds disclosed in U.S. Pat. Nos. 6,212,710B1 and 4,793,011.
[0005] A folding bed cabinet may include a built-in seat or bench that is usable only when the bed is in the upright position. U.S. Pat. No. 5,652,978 discloses such a folding bed with a seating bench that automatically extends upward into a seating position as the bed folds into an upright position. A drawback to this type of seating bench and folding bed combination is that the bench does not have the option of being folded up, down or otherwise out of the way when the bed is in the upright position. Consequently, the folded bed takes up more floor space and is not as versatile for purposes of compact storage of the bed.
[0006] A folding bed may further include storage space within or adjacent to the storage space allocated for the folding bed. U.S. Pat. No. 6,212,710B1 illustrates cupboards included in a folding bed cabinet. U.S. Pat. No. 5,522,102 discloses an enclosure unit partially surrounding and removable from the lower portion of an upright bed frame. These designs have various constraints including, for example, size, permanency, easy of access, and manufacturability.
[0007] It can be seen then that a new and improved folding bed is needed that overcomes the problems with the prior art. An improved folding bed should provide a more versatile folding seat that requires less overall floor space when the bed is in the upright storage position. An improved folding bed should also provide an adjacent storage space with advantages over the prior art. The present invention addresses these as well as other problems associated with folding beds.
SUMMARY OF THE INVENTION
[0008] The present invention is directed to a folding bed, and in particular to a folding bed having a folding bed assembly and an independently actuated folding seat assembly. The bed assembly and seat assembly are supported on a frame that may be utilized with a storage compartment or locker and incorporated into a cabinet or a recess in the wall or may be self-standing and supported on casters, providing for easily moving the bed between various locations.
[0009] The bed assembly includes a mattress mounted to a bed frame and retained with a strap. Folding legs extend outward from the extended edge of the bed frame and provide support in unfolded position. The bed assembly folds along one of its sides between an unfolded use position wherein the mattress and bed frame are substantially horizontal for sleeping, and a folded storage position, wherein the mattress and bed frame are substantially vertical. The bed assembly includes a linkage having a link connecting the support frame to the folding legs. The bed frame pivots near a center portion at each end of the bed frame on the support frame. The bed linkage automatically retracts and extends the folding legs as the bed is folded and unfolded. A counterweight and/or one or more gas springs may be utilized to balance the bed so that the folding may be easily accomplished with minimal effort.
[0010] The bed assembly also includes a lock with a handle mounted in the bed frame and flush with an outer surface of the bed frame in a non-actuated position. The lock is depressible to actuate a shaft extending through the bed frame to the inner side of the bed to engage one of two brackets, each configured for receiving the extended shaft, A first bracket receives the shaft in the unfolded use position and a second bracket receives the shaft in the folded stored position.
[0011] The seat assembly includes a seat back mounted to an underside of the bed frame and a seat bottom extending outward from a strut extending outward from an underside of the bed frame transverse to the plane of the bed frame. The seat bottom folds between a position substantially flush against the seat back and an extended use position. Folding legs mount to a seat frame near an outer edge to provide sufficient load capacity to support several persons on the seat. The seat linkage includes a link connecting the legs to the support frame so that the legs automatically retract in the storage position and extend in the use position. A lock mounts to one of the folding legs for the seat and includes a spring-loaded actuator handle and an engagement pin. The engagement pin extends through the leg to engage the bed frame when the seat is in the folded stored position. The lock prevents accidental folding of the seat assembly.
[0012] The present invention may also include a cabinet covering the mechanisms as well as the bed assembly and seat assembly. It can be appreciated that the present invention provides full access for cleaning the floor and minimal extension outward with side folding and a balanced folding mechanism mounting from an upright portion of the wide base of the support frame.
[0013] These features of novelty and various other advantages that characterize the invention are pointed out with particularity in the claims annexed hereto and forming a part hereof. However, for a better understanding of the invention, its advantages, and the objects obtained by its use, reference should be made to the drawings which form a further part hereof, and to the accompanying descriptive matter, in which there is illustrated and described a preferred embodiment of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] Referring now to the drawings, wherein like reference numerals and letters indicate corresponding structure throughout the several views:
[0015] [0015]FIG. 1 shows a perspective view of a first embodiment of a folding bed with the bed unfolded according to the principles of the present invention;
[0016] [0016]FIG. 2 shows a perspective view of the bed of FIG. 1 with the bed assembly folded and the seat assembly folded;
[0017] [0017]FIG. 3 shows a front elevational view of the bed of FIG. 1 with the bed assembly folded up and the seat assembly unfolded;
[0018] [0018]FIG. 4 shows a right end elevational view of the bed of FIG. 1 in an unfolded position;
[0019] [0019]FIG. 5 shows a right end elevational view of the bed of FIG. 1 in a partially folded position;
[0020] [0020]FIG. 6 shows a right end elevational view of the bed of FIG. 1 in a folded storage position;
[0021] [0021]FIG. 7 shows a right end elevational view of the bed of FIG. 1 with the seat unfolded;
[0022] [0022]FIG. 8 details shows a detail view of a first lock receiver bracket for the folding bed of FIG. 1;
[0023] [0023]FIG. 9 details shows a detail view of a second lock receiver bracket for the folding bed of FIG. 1;
[0024] [0024]FIG. 10 shows a perspective view of a second embodiment of a folding bed having a cover cabinet according to the principles of the present invention; and
[0025] [0025]FIG. 11 shows a perspective view of a third embodiment of a folding bed having a cover cabinet and end storage compartments and mounted to a wall according to the principles of the present invention.
DETAILED DESCRIPTION
[0026] Referring now to the drawings, particularly FIG. 1, there is shown a folding bed, generally designated 20 . The folding bed 20 includes a folding bed assembly 22 and a folding seat assembly 24 that are actuatable independently of one another. The bed 20 is supported by support frame 26 having a wide base with a vertical portion extending upward there from. The bed 20 also may include a storage compartment or locker 90 situated behind the bed and against which the bed assembly 22 folds when in the storage position. The storage compartment 90 may have sliding doors to provide easy access with room to keep bed linens, pillows and other accessories at a convenient location. Although the present invention is freestanding on the support frame 26 , it could also be mounted into a wall and pulled outward from there. If freestanding, the bed 20 typically includes a cabinet 92 receiving the bed assembly 22 , the seat assembly 24 , and the storage compartment 90 . The bed assembly 22 folds between the use position shown in FIG. 1 and the storage position shown in FIG. 2. Unlike typical prior art wall beds, which fold from one of their ends, the bed 20 has the bed assembly 22 fold along one of its sides. The seat assembly folds between a storage position shown in FIGS. 1 and 2 and a use position shown in FIG. 3.
[0027] The bed assembly 22 includes a mattress 30 supported on a substantially horizontal bed frame 34 . A strap 32 extends around the mattress 30 and maintains it in position against the bed frame 34 when folded and unfolded. The configuration of the bed assembly 22 is such that the mattress 30 is never folded, unlike the typical sleeper couch. When unfolded, two legs 36 support the bed frame 34 , one at each of the comers at the extended edge of the bed frame 34 .
[0028] As most clearly shown in FIGS. 4 - 6 , the bed assembly includes a folding linkage 40 which facilitates folding of the bed assembly 22 from an unfolded use position, as shown in FIG. 4, through an intermediate position, shown in FIG. 5, to a folded storage position, shown in FIG. 6, and back. The bed assembly 22 folds so that the bed frame 34 is substantially horizontal in the unfolded use position shown in FIG. 4, and substantially vertical in the folded storage position, shown in FIG. 6. The folding linkage 40 mounts on the support frame 26 with a tab 46 extending horizontally from the rectangular portion 28 , acting as a linkage support. A main pivot 44 of the bed assembly 22 is positioned just above and at an outer end of the linkage support portion 28 of the frame 26 . A first link 42 pivotally mounts to the tab 46 on one end and to a folding leg 36 at the extended end. Each of the legs 36 also pivotally mounts to a side of the bed frame 34 near an outer edge of the bed frame. As shown in FIG. 5, as the bed assembly 22 is unfolded, the linkage 40 rotates the legs 36 outward from a position beside an end of the bed frame 34 . To facilitate folding, in a preferred embodiment, the bed frame 34 includes a counterweight in the frame to provide balance about the pivot 44 . A gas spring 62 mounts between the support frame 26 and the bed frame 34 . Although one gas spring 62 is shown mounted at one end of the bed 20 , various gas springs of various sizes and having various damping characteristics, or combinations of two or more gas springs 62 may be utilized in the present invention at one or both ends of the bed 20 . As shown in FIG. 6, when the bed 20 is positioned with the bed assembly 22 in the folded storage position, the bed linkage 40 automatically positions the bed frame 34 at a substantially vertical position. In addition, the folding legs 36 of the bed assembly 22 are also retracted to a position extending outward from and collinear with an edge of the bed frame 34 .
[0029] As shown in FIG. 6, further unfolding moves the bed assembly legs 36 to a substantially vertical position transverse to the bed frame 34 . Moving the bed assembly 22 from an unfolded position to a folded position moves the bed assembly legs 36 back to their substantially vertical stored position, retracted against the bed frame 34 . When fitted with casters 38 , at the folded position, the bed 20 is free to me moved and may be easily rolled from location to location.
[0030] Referring again to FIG. 1, there is shown an actuator handle 52 for a lock assembly for a bed lock assembly 50 . Lock handle 52 connects to a shaft 56 that inserts into a first bracket and a second bracket, one bracket associated with each position of the bed assembly 22 to lock the bed assembly 22 at the fully folded position or the fully unfolded position. A spring 54 pivots the lock handle 52 back to its home position from the release position, indicated by an arrow in FIG. 1. The shaft 56 inserts into a hole in a first receiver bracket 58 mounted to the rear of the riser portion, as shown in FIG. 8. Depressing the lock handle 52 retracts the shaft 56 from engagement with the first receiver bracket 58 and allows the bed assembly 22 to be released from the unfolded position, shown in FIG. 1. In the normal release position, the shaft 56 is inserted into the orifice in the first receiver bracket 58 and prevents accidental folding of the bed assembly 22 . The locking capability provides for a more secure sleeping environment for users.
[0031] In addition, as shown in FIG. 9, the shaft 56 inserts into an orifice in a second receiver bracket 60 , positioned at the base of the support frame 26 . When the shaft 56 is inserted into the orifice of the second bracket 60 , the bed assembly 22 cannot be moved from the storage position, shown in FIGS. 2 and 6. This prevents accidental unfolding of the bed assembly 22 and provides for a safer secure folding bed. In either position, the lock assembly 50 is easily released by depressing lock handle 52 that is flush with an outer portion of bed frame 34 . This configuration minimizes accidental release of the lock assembly 50 and also eliminates an extended element, which may pose a safety hazard.
[0032] Referring now to FIGS. 6 and 7, the seat assembly 24 includes a seat back 70 and a seat bottom 72 that folds between a use position and a storage position. Seat back 70 is mounted substantially flush against the underside of the bed frame 34 . The seat back 70 and seat bottom 72 may be cushioned but may also be hard surfaces. In addition, the cushions may be removable from the seat assembly 24 . It will be appreciated that in the unfolded position, the seat assembly 24 provides comfortable seating and support for the backs of several seated users. Moreover, the seat assembly 24 includes folding seat legs 74 positioned near the extended edge of a seat frame 76 from the seat bottom 72 so that rigid support is provided. With the legs 72 and the support frame 26 , substantial load capacity is provided to accommodate seating of several persons on seat assembly 24 .
[0033] The seat frame 76 pivotally mounts on a seat linkage support strut 82 extending transversely from an underside of the bed frame 34 . The seat legs 74 pivotally mount to the seat bottom frame 76 at an extended end. A link 84 mounts to a tab extending forward from the linkage support 28 of the support frame 26 and bends slightly to pivotally mount to the seat legs 74 . The seat linkage 78 facilitates folding between the storage position shown in FIG. 6 and the unfolded use position shown in FIG. 7. Moreover, the linkage 78 allows for folding of the seat assembly 24 with the bed assembly 22 as shown in FIGS. 4 - 6 . The various elements of the seat linkage 78 remain in the substantially same alignment and do not pivot relative to one another when the bed assembly 22 folds, with the exception of the link 84 that folds from a substantially vertical upward extending position shown in FIG. 6, to the outward horizontally extending position shown in FIG. 7.
[0034] Referring again to FIG. 2, the seat assembly 24 includes a lock 88 . An engagement pin of the lock 88 extends from one of the seat legs 74 through the bed frame 34 to prevent movement of the seat assembly 24 relative to the bed frame 34 . A spring-loaded actuator handle 80 is depressible to release the seat assembly 24 and allow folding of the seat assembly 24 . The actuator handle is simply pivotally mounted to seat leg 74 and biased toward an engaged position. Pivoting of the actuator handle 80 retracts the pin of the lock 88 and allows unfolding of the seat assembly 24 .
[0035] Referring now to FIG. 10, there is shown a second embodiment of a folding bed, generally designated 100 . The folding bed 100 is similar to folding bed 20 , but includes a further housing 102 extending over the bed assembly and seat assembly so that a cabinet-type appearance is presented. The cover 102 may take on various configurations including a roll top-type configuration sliding on tracks, a folding cover with one or more panels pivotally mounted, or other well know cover arrangements. The cover 102 moves between a position covering the seat assembly 24 and bed assembly 22 and is removed or retracted for easy access and use.
[0036] Referring to FIG. 11, there is shown a third embodiment of a folding bed, generally designated 200 . The folding bed 200 is similar to folding bed 100 , with a housing 202 extending over the bed assembly and seat assembly so that a cabinet-type appearance is presented. As with bed 100 , the cover 202 may take on various configurations including a roll top-type configuration sliding on tracks, as shown. Folding bed 200 also includes end storage compartments 204 at either end of the bed 200 . The compartments 204 include front access doors 206 providing easy direct access for storage of pillows, bed linens and other accessories. The compartments 204 may also include top access rather than front access and a single compartment at one end of the bed, rather than a pair of compartments my be utilized, depending on needs and available space. The end compartments 204 may also be used with the rear storage compartment shown in the first embodiment. The bed 200 is shown permanently mounted directly to a wall. It can be appreciated that the first two embodiments of the folding bed, 20 and 100 , may also be incorporated into a wall. In addition, the bed 200 may be configured as a stand-alone unit.
[0037] Although the present invention has been shown with both a bed assembly 22 and a seat assembly 24 , it can be appreciated that the folding bed assembly may be utilized without the folding seat assembly 24 . The present invention provides a sturdy economical folding bed that folds along its side rather than an end. Moreover, the folding bed may be incorporated into rooms and permanently inserted into a wall of the room or it may be utilized as a mobile unit. The support frame 26 may be fitted with casters that provide easy movement of the folding bed 20 . With the bed 20 having three positions, it provides great versatility to any room that incorporates the folding bed in its design. In a first position with the bed assembly 22 folded and the seat assembly 24 folded, the folding bed 20 provides maximum floor space. With the bed assembly 22 folded and the seat assembly 24 unfolded, the folding bed 20 provides bench type seating for several persons, requiring minimal floor space. In a third position with the bed assembly 22 unfolded, the folding be 20 provides a bed in the same space.
[0038] It is to be understood, however, that even though numerous characteristics and advantages of the present invention have been set forth in the foregoing description, together with details of the structure and function of the invention, the disclosure is illustrative only, and changes may be made in detail, especially in matters of shape, size and arrangement of parts within the principles of the invention to the full extent indicated by the broad general meaning of the terms in which the appended claims are expressed. | 1a
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This application claims the benefit of Provisional Application No. 60/176,626, filed Jan. 19, 2000 and No. 60/186,328 filed Mar. 2, 2000, the entire content of which is hereby incorporated by reference in this application
This application is a continuation-in-part of application Ser. No. 09/761,639, filed Jan. 18, 2001, now U.S. Pat. No. 6,334,369 the entire content of which is hereby incorporated by reference in this application.
The present invention relates to an improved therapeutic method for the treatment of chronic uremic patients undergoing periodical dialysis.
BACKGROUND OF THE INVENTION
It is well known that patients affected by chronic uraemia, undergoing periodic dialysis, frequently develop a clinical picture characterized by marked muscular asthenia and a sensation of torpor, particularly evident immediately following dialysis and which may often last even for several hours making difficult, if not impossible, to resume working activity until these conditions subside. Clinical experts recognize this problem as “post-dialytic syndrome”.
These conditions have been sometimes attributed to the loss of carnitine during dialysis.
A method for treating the post-dialytic syndrome by compensating for the loss of carnitine occurring during the dialysis session is disclosed in U.S. Pat. No. 4,272,549. This patent describes a method for alleviating asthenia and muscle weakness in a chronic uremic patient under regular dialysis treatment by administering to the patient a polysaline dialytic solution which contains a quantity of carnitine (this refers to L-carnitine throughout the present specification), or a pharmaceutically acceptable salt of it, sufficient to adjust the molar concentration of carnitine in the dialysis solution at least equal to the molar concentration of carnitine in the patient's plasma. Preferably, the concentration of carnitine in the dialytic solution is substantially equimolar to the concentration of carnitine in the patient's plasma, but a certain excess of carnitine is also provided, for example between 50 and 100 μmole per liter of solution. A specific illustration includes administration of from 3 to 6 grams of carnitine or an equivalent amount of a pharmaceutically acceptable salt thereof. The carnitine may be administered orally, preferably on days between haemodialysis in amounts ranging from 3 to 6 grams of carnitine per day.
This oral treatment is coupled with a rather complex treatment regimen with carnitine during the dialytic session, in which carnitine is administered by slow infusion. On the days of dialysis, carnitine may also be administered partly by the oral route and partly by slow infusion. In this case, the overall quantity of carnitine administered shall not exceed approximately 10 g per day. “Slow infusion” means an infusion in which the solution containing carnitine, or any of its pharmaceutically acceptable salts, is administered at the rate of 20 to 40 drops per minute. Particularly favourable therapeutic results are said to be achieved by orally administering carnitine to the patient receiving dialysis treatment only on those days during which the patient does not receive dialysis, while during the actual dialytic session, a dialyzing liquid containing carnitine is used.
A preferred regimen for treating chronic uremic patients undergoing haemodialysis, includes the following steps:
1) on the days between one haemodialytic session and the next, oral administration to these patients of 3 to 6 g per day of carnitine or any of its pharmaceutically acceptable salts;
2) on the days of haemodialytic session, dialyzing these patients using, as dialyzing liquid, a solution containing a quantity of carnitine or of any of its pharmaceutically acceptable salts, sufficient to adjust the molar concentration of carnitine in the dialysis solution at least equal to the molar concentration of the plasma carnitine of the patient receiving dialytic treatment.
Using this procedure, it is possible to avoid the loss of plasma carnitine which otherwise takes place during a haemodialytic session; that is, the concentration of plasma carnitine remains practically unchanged during the dialytic session. In this manner, it is possible to avoid tissue carnitine depletion, which is the long-term consequence of repeated losses of carnitine the patient undergoes during successive dialytic sessions over a prolonged period of time, for example a month or longer.
Although the desired objective is achieved using a hemodialysis solution equimolar in carnitine with respect to the patient's blood, it is preferred to operate with a slightly more concentrated solution. In practice, the haemodialysis solution contains 50 to 100, preferably 60-80 μmoles/liter of carnitine or of any of its pharmaceutically acceptable salts. On the days of haemodialysis, carnitine may also be administered partly by the oral route and partly by slow infusion. In this case, the overall quantity of carnitine administered shall not exceed approximately 10 g per day.
The procedures in U.S. Pat. No. 4,272,549 are effective in treating “post-dialysis syndrome”, but present a cumbersome schedule of treatment. This fact leads to problems. Patient compliance, whose quality of life is already heavily affected, is a concern as patients are apt to overlook the oral self-administration of a prescribed dosage of carnitine between the dialytic sessions. There is also the problem of carnitine bioavailability through the oral route, which is subject to saturation mechanism and to some restrictions as to the absorption sites (Harper at al. Eur. J. Clin. Pharmacol. 1988; 35(5):555-62 and Matsuda et al. Biol. Pharm. Bull July, 1998, 21 (7):752-5). Also, oral administration of carnitine to a chronic uremic patient may give rise to the accumulation of toxic metabolites.
A recent article by Sloan et al. (Am. J. Kidney Dis. August, 1998, 32(2):265-72) demonstrated that oral supplementation of carnitine is effective in improving the quality of life of patients in the early stage of treatment, but the perceived effect was not sustained through long term treatment (six months).
Other than the fact that carnitine deficiency may be connected with post-dialytic syndrome, this deficiency is a disturbance of the homeostasis of such an important inborn substance, that the medical community recognizes the necessity to treat carnitine deficiency per se.
SUMMARY OF THE INVENTION
Disclosed is a method for treating chronic uremic patients undergoing periodical dialysis. This method prevents and treats carnitine deficiency in patients with end stage renal disease who are undergoing dialysis. The method comprises administering to the dialysis patient an effective dose of carnitine intravenously into the venous return line at the conclusion of each dialysis session. Dialysis session as used herein means both haemodialysis and peritoneal dialysis.
The method of the present invention provides a surprising improvement over the procedures described in U.S. Pat. No. 4,272,549 and eliminates the need for oral treatment, without affecting the maintenance or correction of carnitine deficiency obtained by the administration of carnitine through intravenous route.
Ahmad S. et al (Kidney International, Vol. 36, Suppl. 27 (1989), S-243-S-246) report a study on the administration of L-carnitine in hemodialysis patients investigating the effect on fatty acid abnormalities in the patients' serum. Carnitine was given intravenously for the first six months at the dosage of 20 mg/kg and subsequently was reduced to 10 mg/kg. The administration was performed via the blood line after each dialysis session during the rinse back cycle. Patients treated with carnitine had a partial correction of the abnormal fatty acid profile noted in untreated dialysis patients. The authors found difficult to explain the persistence of some abnormalities in lipid profiles and made no effort to correlate plasma levels with possible clinical manifestations of fatty acid deficiency. This study is not related to the general picture of carnitine deficiency.
In two subsequent articles, Ahmad, Golper et al. (Kidney International, Vol. 38 (1990), 904-911 and 912-918) report a multicenter trial of carnitine in maintenance hemodialysis patients. The administration of carnitine was performed as described in the 1989 article, but, as a clinically significant study, the carnitine dose was kept constant at 20 mg/kg. In the first paper, the authors still investigate on the effect of carnitine on serum lipid profile, concluding that carnitine does not seem to have a great lipid-lowering potential. In the second paper, carnitine appears to be associated with a decrease in dialytic symptoms, an improvement in exercise capability, sense of well being. The skilled reader will observe that in the clinical trial no reduction of carnitine dosage was attempted or devised.
As it will be apparent from the detailed description below, the best mode of carrying out this invention provides an advantageous treatment wherein, after a starting dose of carnitine, which may also be intended as attack does, a lower maintenance dose is given.
The invention shall be disclosed in detail, with reference to Figures and Examples.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 illustrates a treatment schedule, where the letters A-F denote the heart effluent sampling times for the measurement of metabolites;
FIG. 2A shows the effect of carnitine on creatine phosphate and ATP;
FIG. 2B shows the effect of carnitine fumarate on creatine phosphate and ATP;
FIG. 3A shows lactate released by the heart, as measured in the effluent;
FIG. 3B shows succinate released by the heart, as measured in the effluent;
FIG. 4 illustrates the release of malate;
FIG. 5 illustrates the release of LDH; and
FIG. 6 illustrates the production of lactate.
DETAILED DISCLOSURE OF THE INVENTION
Disclosed are methods of preventing or treating carnitine deficiency in chronic uremic patients undergoing periodic dialysis by administering to the patient at the conclusion of dialysis an effective amount of L-carnitine, either as inner salt or a pharmaceutically acceptable salt thereof, preferably the salt is L-carnitine fumarate. Administration is by the intravenous route or by peritoneal route. Preferably from about 10 to about 20 mg/kg body weight of carnitine, calculated as L-carnitine, is administered into a venous return line at the conclusion of each dialysis session.
Also disclosed are methods of preventing carnitine deficiency in end stage uremic patients undergoing periodic dialysis over an extended period of time by administering to these patients at the conclusion of each dialysis session an effective amount of L-carnitine, either as inner salt or a pharmaceutically acceptable salt thereof.
The preferred starting dose is 10-20 mg/kg dry body weight administered as a slow 2-3 minute bolus injection into the venous return line after each dialysis session.
Initiation of the therapy may be prompted by through (pre-dialysis) plasma carnitine concentrations that are below normal (40-50 μmol/L). Dose adjustments should be guided by through (pre-dialysis) carnitine concentrations, and downward dose adjustments (for example to 5 mg/kg after dialysis) may be made as early as the third or fourth week of therapy.
Carnitine can be administered as inner salt or in any pharmaceutically acceptable salts thereof.
Examples of pharmaceutically acceptable salts are disclosed in U.S. Pat. Nos. 6,124,360, 6,130,249, 6,080,786 4,602,039 application No. WO98/44918, and an exemplary list is given in WO00/06134.
The procedures described in U.S. Pat. No. 4,272,549 discussed above are not specific to any particular carnitine salt. In the present invention for treating chronic uremic patients undergoing periodical dialysis, any of the pharmaceutically acceptable salts of carnitine are acceptable. However, at times the skilled clinician may encounter problems with some patients. During the dialytic session, some patients are affected by hypervolemic heart, and this can give a severe outcome as heart failure. Moreover, a number of patients undergoing hemodialysis are affected by diabetes.
In a particular embodiment of the present invention, it has been found that fumarate of L-carnitine exerts a surprising beneficial effect on heart. Moreover, due to its physiologic role, fumarate may have beneficial effects in diabetic patients. Accordingly, a particular embodiment of the present invention relates to the method above disclosed, wherein fumarate is the pharmaceutically acceptable salt of L-carnitine.
Suitable formulations of carnitine, or a pharmaceutically acceptable salt thereof, are in the form of injectable compositions, for example comprising an equivalent amount of carnitine of 200 mg per 1 mL. A 2.5 or a 5 mL single dose ampoule may be convenient. When a pharmaceutically acceptable salt of L-carnitine is used, such as fumarate L-carnitine, the amount of active ingredient will be calculated so as to provide an equivalent amount of L-carnitine as above specified.
While the invention has been described in connection with what is presently considered to be the most practical and preferred embodiment, it is to be understood that the invention is not to be limited to the disclosed embodiment, but on the contrary, is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Patients showing a pre-dialysis carnitine level equal or lower than 40-50 μM were treated by the procedures of the present invention with a 10-20 mg/kg dose of carnitine at the conclusion of the 4-hours dialytic session. According to a standard dialytic schedule, the treatment was repeated twice a week every 44 hours, then after 68 hours. This treatment was continued for 3-4 weeks, monitoring pre-dialytic levels of carnitine. As a further embodiment of the present invention, a maintenance dosage is provided, administering, as a preferred example, a dose of 5 mg/kg of carnitine. The maintenance dosage may be practised with the same schedule detailed above and is preferably administered after at least one first cycle with the dose of 10-20 mg/kg (3-4 weeks).
The following table explains the preferred method for a 3-weeks treatment:
Carnitine
day of the week
Dialysis
administration
Monday
X
X
Tuesday
Wednesday
X
X
Thursday
Friday
X
X
Saturday
Sunday
Monday
X
X
Tuesday
Wednesday
X
X
Thursday
Friday
X
X
Saturday
Sunday
Monday
X
X
Tuesday
Wednesday
X
X
Thursday
Friday
X
X
Saturday
Sunday
Wherein X shows a 4-hours dialytic session and the carnitine intravenous administration according to the present invention at the end of the session. 44 hours occur between two subsequent carnitine administrations from Monday to Friday and 68 hours occur between two subsequent carnitine administrations from Friday to Monday.
The maintenance dosage of 5 mg/kg is particularly advantageous, since the patient does not need to continue to receive the attack high dose of 10-20 mg/kg, thus avoiding the always undesirable possible accumulation effect.
The particular embodiment of L-carnitine fumarate is illustrated in the following examples.
EXAMPLE 1
Effect of the Administration of L-carnitine Fumarate on the Perfused Heart
In this example, the low-pressure or low-flow ischaemia model was used, which is a model recognised as valid for cardiac ischaemia (Bolukoglu, H. et al. Am. J. Physiol. 1996: 270; H817-26).
The treatment schedule is illustrated in FIG. 1, in which the letters A-F denote the heart effluent sampling times for the measurement of metabolites. The hearts are removed from the animals and mounted on a Langerdorff appliance. The perfusion medium replacing the blood was a Krebs-Heinsleit standard bicarbonate buffer containing glucose 12 mM as energy source for cardiac metabolism.
After 30 minute perfusion at a pressure of 100 cm of water, ischaemia was induced by reducing the perfusion pressure of the heart to 25 cm of water, thus reducing coronary flow from approximately 2 ml/min to approximately 0.3 ml/min. Reduction of the perfusion pressure gives rise to ischaemia, since the heart will pump the fluid in the low-perfusion area rather than via the coronary bloodstream, supplying the flow to the heart.
This control model was compared with hearts perfused with L-carnitine 10 mM or L-carnitine fumarate 10 mM.
Cardiac function was tested in three different ways.
In the first, the NRM 31 P signal was monitored in real time.
This signal provides the best indication of the energy status of the heart.
In the second, the haemodynamics of the heart was measured by means of a pressure transducer mounted to measure the perfusion pressure. The haemodynamic measurements include heart rate, relative dP/dt (measurement of the contraction force of the heart) and the cardiac contraction amplitude. Coronary flow was also measured as an indicator of the heart's ability to provide oxygen and energy for its own metabolism.
In the third type of test, the metabolites and the enzyme LDH released by the heart were analysed in the effluent. The release of LDH indicates damage to cardiac tissue. The release of metabolites by the heart was tested by means of mass spectrometry coupled with gas chromatography.
The results of the experiments show that the hearts treated with carnitine fumarate have reduced release of LDH; the reserves of high-energy phosphate after 45 minutes of ischaemia are greater in treated hearts, as indicated by the increase in creatine phosphate observed at NMR and the profile of the metabolites released indicates that the treated heart generates less lactate, but more malate. A high lactate level indicates intense anaerobic metabolism and acidosis. The increase in malate indicates that fumarate is metabolised by the heart to yield a system of intermediates of the citric acid cycle favourable to the heart. Haemodynamic function, as indicated by the post-ischemic cardiac contraction amplitude and by coronary flow, is greater in hearts treated with carnitine fumarate.
EXAMPLE 2
The procedures of example 1 were substantially repeated, with the addition of a treatment with carnitine alone as a further control.
The results are given in FIGS. 2-6, where:
FIG. 2 illustrates the effect of carnitine (A) and carnitine fumarate (B) on creatine phosphate and ATP. The data were evaluated after 40 minutes of ischaemia. CP indicates creatine phosphate and α, β and γ denote the phosphate peaks of ATP; as can be seen in part (A) of the figure, the ATP peaks are lacking in the absence of fumarate.
FIG. 3 shows the comparison between lactate (A) and succinate (B) released by the heart, as measured in the effluent. The lactate reduction indicates the favourable effect of carnitine fumarate. The low amount of succinate as compared to lactate indicates that the generation of ATP as a result of the reduction of fumarate to succinate is not the main source of anaerobic ATP.
FIG. 4 illustrates the release of malate. The greater malate levels in the treated heart indicate that fumarate enters the cardiac mitochondrion and is metabolised in the TCA cycle.
FIG. 5 illustrates the release of LDH. The greater LDH levels is in controls indicate that carnitine fumarate affords protection against ischemic damage.
FIG. 6 illustrates lactate production. | 1a
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BACKGROUND OF THE INVENTION
The invention concerns a holder for an electronic detection element adapted to be attached by means of a band around the neck or around a different part of the body of an animal to be detected.
It is necessary for electronic identification that the object to be identified is provided with a detection element, sometimes referred to as responder. Such an element is disclosed e.g. in Dutch patent application No. 77,11891 of applicants, or their corresponding British patent No. 1,577,920.
It is conventional to embed such a detection element in a synthetic plastics holder, which is attached to a collar the two ends of which are subsequently buckled together. It is necessary now that the holder with the detection element always hangs in approximately the same place, preferably at the bottom of the neck of the animal, so that when the animal approaches the detection antenna, it will always bring the detection element at a predictable distance, at least within the range of the transceiver, in order to be identified with certainty. In practice, the holder with the detection element should have a given weight in order to be kept through gravity at the bottom of the neck of the animal. The weight of the holder with the detection element competes with the weight of the buckle often present at the top of the neck of the animal. In order to remain at the bottom of the neck, the holder with detection element should therefore have so much weight that the loosely fitting collar will not turn around the neck of the animal. This has resulted in rather heavy and voluminous holders, which, due to their volume, reached the required weight for compensating the counterweight of the buckle, but which became at the same time unnecessarily sensitive, due to their dimensions, to external damage caused by congeners of the animal or due to their being caught behind obstacles with which the animal comes into contact unconsciously or precisely very consciously in order to get rid of itching.
The miniaturization of the identification systems has meanwhile progressed to the extent that the last generation of detection elements have dimensions and weights that are a fraction of the versions hitherto conventional. It may then be considered to attach such a detection element in a different place in or on the body of the animal. Most of the animals to be identified, however, will keep their collars, even if such a different attachment place is possible, since one will wish to recognize the animal electronically but also visually, which is possible by applying a name and/or number on or about the collar.
If therefore, even though it is technically possible to install the detection element elsewhere, perhaps with a different, more expensive method, the animals will yet continue to wear collars in large numbers, it is advantageous to use said collar to install the miniaturized detection elements in a simple manner.
If the dimensions of the detection element are reduced from e.g. about 150×60×25 mm to about 60×35×12 mm or less in the near future, the problem of maintaining the detection element at the bottom of the neck of the animal will be felt more strongly, since the competing weight of the buckle on top of the neck will not or not appreciably decrease, while precisely the total weight of the detection element with the associated holder will strongly decrease.
SUMMARY OF THE INVENTION
It is an object of the invention to eliminate the above problems, to which effect a holder of the above-described type is characterized in that the holder is fitted with a cavity for receiving the detection element and with at least one clamping member for adjustably clamping a band end.
According to a further embodiment of the inventive idea, furthermore the integrated holder/buckle unit according to the invention may be fitted with a maximum band pull protection. This is necessary with many animals, since an animal, when being seized with the collar behind an obstacle, will try to break free. When the collar is made of a solid, wear-resistant material, substantial forces on the neck may be produced, with all detrimental effects thereof. To prevent this, the buckle can be constructed in such a manner that in exceeding a predetermined maximum band pull, it releases the band. In addition to being adapted to be embedded in the holder, the detection element according to the invention will also be embedded in a loose block and be replaceably installed in the holder/buckle. In case of damage to the holder/buckle, the relative expensive detection element, may then be transferred into another. It is also possible that the holder/buckle has a different form and/or colour for different dealers; the detection element may then always keep the same form and be effectively manufactured in large series.
BRIEF DESCRIPTION OF THE DRAWINGS
Some embodiments of the construction of the invention will now be described by way of example, with reference to the accompanying drawings, in which:
FIG. 1 is a longitudinal section of a first embodiment of a holder according to the invention;
FIG. 2 is a bottom view of the holder shown in FIG. 1 without flap and collar;
FIG. 3 is a longitudinal section of the second embodiment of a holder according to the invention;
FIG. 4 is a longitudinal section of a third embodiment of a holder according to the invention;
FIG. 5 shows a detail of FIG. 4;
FIG. 6 shows a variant of FIG. 4;
FIG. 7 shows a detail of FIG. 6; and
FIGS. 8 and 9 show two other embodiments of a holder according to the invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
FIG. 1 is a longitudinal section of a preferably synthetic plastics holder 1, wherein a detection element 2 diagrammatically shown is embedded. At the bottom of the holder there is pivotally provided a flap 3 at one end at 4, which flap serves for clamping one of the ends of a band 6. In the closed position of the flap 3 shown, this is secured by lugs 5 (see also FIG. 2). For the purpose of clamping the free end of the band 6, the flap 3 is fitted adjacent the pivoted end with a boss 7 which, in the closed position of the flap 3, extends to adjacent a rib 8 of the holder 1 opposite to boss 7.
In the opened position of the flap 3, the band end can be passed freely between the boss 7 and the rib 8 and be pulled underneath the responder 2 and again be conducted at the other end of the responder through a slot 9 in the holder in outward direction. In closing the flap, the band is fixedly clamped between the boss 7 and the rib 8. The other end of the band (at the right-hand side in the drawing) has a looped form and is passed around a pin 10 installed in the holder, said pin being preferably designed as a shear pin.
The embodiment shown in FIG. 3 deviates from the embodiment shown in FIG. 2 in that the flap 3 is fitted with a cavity for receiving the responder 2. The responder may again be embedded in the cavity of the flap 3 and consequently be integral with the flap, but, as shown in FIG. 3, may also be provided with retaining lugs 11, which are adapted to detachably retain through snap action a loose responder block. The free band end in this embodiment is conducted along the top of the responder 2.
In the embodiment shown in FIGS. 4 and 5, the responder 2 is embedded in a cavity of the holder 1 or detachably installed therein as a responder block. Both ends of the band 6 with associated flaps 40, 41, which again are adapted for coaction with corresponding lugs 42, 43, can be fastened. To this effect, both band ends are inserted via slots 44, 45 in the holder, while said ends come to lie on the responder or the responder block. Above the slots 44 and 45, being provided at the opposite ends of the holder, there are provided transverse ribs 46, 47 of the holder, which are hollow at the bottom. In said cavities fit correspondingly curved half-round end edges 48 of the otherwise flat flaps, as shown in FIG. 5. The flaps, as shown by arrows 49, can be swivelled upwardly with their flat ends, while the curved end edges turn in the cavities of the ribs. The band ends, in the upwardly turned position of the flaps, are inserted in the holder and subsequently clamped with the free edge of the curved end edges of the flaps against the lower edge of the slots 44 and 45 by bringing the flaps in the position shown.
In order to increase the clamping effect, the free edges of the curved end edges of the flaps may be fitted with teeth 50, as shown in FIG. 5.
When in this embodiment a loose responder block is employed, the first portions of the flaps are so long that in the closed position they partly lie on the responder block, as shown in FIG. 4.
The maximum band pull force that can be exerted without loosening the band, is determined by the strength of the half-round end edges 48.
FIGS. 6 and 7 show a variant of FIGS. 4 and 5, in which the rotary flaps have been replaced by substantially flat slides 60, each having an end edge 61 bent at an angle slightly more than 90°. The ribs 62 of the holder corresponding to the ribs 46, 47 are now flat at the bottom and, together with the opposite lower edges of the slots 44, form a slightly wedge-shaped space accommodating the slides. The bent edge 61 of each slide is adapted for coaction with an ascending portion 63 of the lower edges of the slots 44 for clamping the band ends. To this effect, the bent edges 61 may again be fitted with teeth 64, as shown in FIG. 7.
When the band pull force exceeds a given value, the slide passes the ascending portion 63.
FIG. 8 shows a variant, in which instead of a slide 60, as shown in FIG. 7, there is employed a wedge 80 fitted at the bottom with teeth. The maximum band pull force is now determined by the ribs 62 designed as shear pins. In this embodiment, furthermore the responder block 2 is detachably retained in the appropriate cavity in the holder by retaining lugs 81, which are comparable with the retaining lugs 11 of FIG. 3.
FIG. 9 finally shows a variant in which the band ends are each provided between and about three ribs 90, 91 and 92 integral with the holder and designed as shear pins.
It is observed that after the foregoing, various modifications are obvious to one skilled in the art. For instance, the responder could be placed e.g. in a different position in the holder. Such modifications are deemed not to depart from the scope of the invention. | 1a
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RELATED APPLICATIONS
This application is a continuation-in-part of U.S. application Ser. No. 09/893,967 filed Jun. 29, 2001, now U.S. Pat. No. 6,557,482, the entire contents of which is incorporated herein by reference.
TECHNICAL FIELD
The present invention relates to devices for discouraging the entry of birds into spaces where their presence is undesirable, and more particularly, to a rotating device for scaring birds away from an area in which their presence is undesirable and to methods of making this device.
BACKGROUND OF THE INVENTION
In coastal regions of the United States and other countries, marine craft, docks, aids to navigation and other marine structures suffer considerable damage and soilage from the droppings of sea gulls, tems, pelicans, cormorants and other birds. Similarly, communities near garbage dumps and land fills, which often attract large numbers of birds, may sustain similar soilage and damages, such as “white washed” rooftops.
Many devices, such as flags, plastic owls, snakes and other animals, noisemakers, deck sweepers and the like, have been tried in the past to deter birds from alighting on such structures. These prior art devices have had only limited success, at least in part because birds seem to become adapted to the presence of the device and then to ignore it.
SUMMARY OF THE INVENTION
A bird repeller made in accordance with the present invention repels birds through a combination of sound, vibration and/or visual effects, which annoy the birds enough to prevent them from landing within 10-15 feet of the repeller. Furthermore, the almost constant variations in these effects prevent the birds from getting so use to the repeller that they come to ignore it over a period of time. Prototype testing suggests th at one repeller would be effective to keep free of bird droppings an area of 300 square feet or more, and that, over an extended period of time, birds will stay as far away from the repller as they did on the first day of installation. It is believed that birds do not get accustomed to the sound, vibration and visual effects of the device because these effects are constantly changing with the rotational speed of the rotor member, which varies with the changes in the driving wind velocity.
The bird repeller comprises a revolving hollow rotor that has laterally projecting fins adjacent to vents in a barrel section of the rotor. The barrel section has a chamber surrounded by a wall made of a cuttable and deformable material. The fins ar e shaped by the way in which they are cut out of the barrel section, and then they are pivoted radially outward around a hinge portion and arranged to catch even the slightest breeze to create a wind turbine effect that spins the rotor on a vertical axis. As air currents of the wind pass across the fins and through the vents, they create a whirring sound that varies with the slightest change in the wind velocity. In addition to the whirring sound, a drum section of the rotor connects the barrel section to a neck of the rotor that rubs and beats against a vertical pole on which a head section of the rotor is rotatably mounted. This rubbing and beating causes the rotor to vibrate and generates a clacking noise having a constantly changing rhythm or reverberation cycle. Optionally, bells, clappers or other shakable noisemakers may be attached to an intermediate section of the pole, which also vibrates and shakes in response to the rubbing and beating action of the rotor neck against the pole. The resulting noise and vibratory sounds also change constantly with the velocity of the wind. Another option is to mount an electrical, solar powered sound device on the rotor body to provide the sound of a bird of prey or other bird predator.
In addition, the movement of the large projecting fins in the light of daytime is believed to cause a visual disturbance to the birds. This visual disturbance may be enhanced by the addition of holographic eyes or other designs on the fins, the designs being located preferably on the side of the fins in the direction of their rotation. The fin designs may also include a sparkling material capable of reflecting light in a flashing manner as the rotor rotates. The combination of the whirring and vibratory sounds with the visual effects of the spinning fins has the consequence of making birds sufficiently uneasy that they give a wide berth to the repeller.
Another advantage to the repeller of the invention is the simplicity of its construction and method of manufacture. The rotor, which is preferably made of plastic, is mounted on a cap adhered to the top of a head portion of the vertical mounting pole and is secured to the head cap by a stainless steel screw via a nylon spacer that serves as a rotor bearing. This rotary mounting connection allows the rotor to rotate freely around the head portion of the pole. A proximate end portion of the mounting pole is held stationery by securely fastening it to any support structure, such as by clamped metal bands, bolts, or by simply slipping the base of the pole into a fishing rod holder on a boat, dock or other support structure.
By way of example, the rotor may be fashioned from a large inverted plastic juice bottle by cutting through a barrel section of the bottle material along a cut line for forming three free edges of each fin and then bending the fin radially outward along the remaining proximate edge of the fin that forms a deformable hinge by which the fin remains attached to the barrel section at the angle to which it is bent. A vent corresponding to each fin is formed when the cutout for the fin is bent outward. The bottle from which the rotor may be made preferably has an upper tapered portion leading to the bottle neck, and this tapered portion forms an acoustic section of the rotor that enhances the vibratory sounds caused by the neck rubbing against the pole. In other words, the wall of the acoustic section resonates in response to vibrations caused by the rubbing action between the rotor neck and the pole.
The number and size of the fins and vents may vary widely, although 4 to 8 fins and vents are preferred, more preferably 6 or less for the rotor size described below. Although rectangular and oval-like fins and vents are shown in the drawings by way of example, these elements may have other shapes and the fins and vents on the same rotor may have different sizes and shapes. A preferred rotor size is between 8 and 12 inches long and between 4 and 6 inches in diameter at the barrel so that the rotor is compact and can be easily stored in a small space, such as a storage cabinet on a boat, when it is not deployed in its active position on the mounting pole. The neck opening, which slips over the mounting pole, is preferably between about 1.25 and about 1.5 inches in diameter where the adjacent diameter of the mounting pole is about 1 inch. This gives a clearance of about 0.125 to about 0.25 inch between the neck and opposite sides of the mounting pole, which provides a preferred frequency of bird repelling vibrations. Where the overall length of the rotor is about 12 inches, the preferred lengths of the head, barrel, acoustic section and neck are respectively about 0.5 inch, about 6.5 inches, about 3.75 inches and about 1.25 inches. For a barrel of about 6.5 inches long and about 5.0 inches in diameter, the fins and vents are preferably about 2.75 inches long and about 1.75 inches wide, and the optimum number of fins and vents is 6.
Although the preferred material of the rotor is plastic, other materials may be used, such as steel, aluminum and other metals. Instead of nylon, the bearing washer may be made of Teflon or stainless steel. The mounting pole may be made of hollow or solid plastic, wood or metal. The plastic may be PVC, the wood may be pine or oak, and the metal may be steel or aluminum.
The need for a bearing washer may be avoided by the rotary mounting structure employed in a second embodiment of the invention. In this embodiment, a lag-bolt type structure passes through and is secured to the head section of the rotor, with the shaft of the bolt projecting into the rotor along its rotational axis. The distal end of the bolt shaft rests freely in and rotates within a socket formed by a small metal or plastic cup that is mounted on the cap secured to the head of the vertical mounting pole. This second embodiment of the invention may have greater rotational wobble than the first embodiment, and thereby may produce a more effective vibratory sound by the rubbing action between the neck of the rotor and the mounting pole. The rotary connection may also have a longer wear life than the mounting screw and washer bearing of the first embodiment. However, the first embodiment may be mounted either upright, as shown in the drawings, or upside down with the proximate end of the mounting pole secured to an overhead mounting structure, whereas the second embodiment can only be mounted in an upright position.
A third embodiment illustrates a method of making all of the embodiments, and emphasizes a fin structure that is lighter than the two embodiments described above.
The above features and benefits and the proven effectiveness of a prototype, combined with simplicity and low cost of making the device, make the bird repeller of the present invention significantly superior to any previously known repeller of the prior art.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention, both as to its structure and operation, may be further understood by reference to the detailed description below, taken in conjunction with the accompanying drawings in which:
FIG. 1 is a prospective view illustrating installation of the invention on a dock to repel sea birds;
FIG. 2 is a plan view of the invention of FIG. 1;
FIG. 3 is a fragmentary cross-sectional view of the invention in elevation taken along lines 3 — 3 of FIG. 2;
FIG. 4 is a cross-sectional view taken along lines 4 — 4 of FIG. 3;
FIG. 5 is a fragmentary cross-sectional view in elevation of another embodiment of the invention;
FIG. 6 is an elevational view illustrating a method of making the repeller body of a third embodiment of the invention;
FIG. 7 is a cross-sectional view of the repeller body taken along lines 7 — 7 of FIG. 6;
FIG. 8 is partial cross-sectional view in elevation of an optional modification of the third embodiment of the invention; and,
FIG. 9 is partial cross-sectional plan view taken along lines 9 — 9 of FIG. 8 .
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
Referring to FIG. 1, there is shown a bird repeller assembly, generally designated 10 , comprising a body 11 , rotationally mounted on a pole or standard 12 secured by a pair of metal or plastic bands 14 , 14 to the piling 15 of a dock 16 . As may be seen best in FIGS. 2-4, body 11 comprises a barrel section 18 having a plurality of fins 20 each adjacent to a corresponding vent opening 22 .
Each fin 20 is attached to the barrel 18 by an elongated hinge segment 24 and preferably has a pressed out cup-like portion or indent 26 for enhancing the catching of a wind current or other air flow produced by the prevailing wind as represented by arrow W. The vents 22 are preferably formed by stamping or otherwise cutting out the fins 20 from the wall of barrel 18 . The wind provides an airflow over the fins 20 which causes the body 11 to rotate in the adirection of arrow R (FIG. 2) due to the concave curvature of the fin surface 27 , and the convex curvature of the fin surface 25 . This rotation is enhanced by the cupping action of the fin indent 26 , which projects from the convex fin surface 25 in the rotational direction R and has a concave surface 29 and a convex surface 31 (FIG. 4 ).
A head section 28 above barrel 18 is rotatably secured to the top or distal end of pole 12 by a screw 30 that passes through a bearing washer 32 and is threaded into a cap 34 adhered to the distal end of the pole. Below the barrel 18 is an acoustic section 36 formed integrally with a neck 38 having accordion-like convolutions 40 . The inner surface of the convolutions 40 form ridges 42 that rub and beat against the pole 12 as the rotor body 11 rotates relative thereto. This rubbing and beating action causes vibratory noise and clacking reverberations that are amplified by the acoustic section 36 . As an optional feature, one or more shakable noisemakers, such as a plurality of bells 39 , may be attached to the pole 12 , which vibrates and thereby shakes the noisemakers to produce additional bird repelling noise in response to the rubbing action of the rotor neck against the pole.
The wind currents, which produce rotation of the rotor by impacting against the fins, also pass over the fins and through the vents 22 thereby generating a whirring noise. In other words, wind currents pass through the upwind vent openings oriented toward the wind arrow W and into the inner chamber 44 of the rotor 11 , and then pass out of the chamber 44 through the downwind vent openings oriented away from the wind arrow W. This wind current air flow, in combination with rotation of the repeller body 11 , is believed to be the source of the whirring noise observed during prototype testing. In addition, the rubbing and beating action of the neck against the pole generates a clacking noise having a constantly changing rhythm or reverberation cycle.
Referring now to FIG. 5, there is shown a second embodiment of the invention wherein the same numeral part designations have been used to indicate structural elements identical with those shown in FIGS. 1-4. In the modified or second embodiment shown in FIG. 5, the rotary connection between the rotor body 11 and the top of the pole 12 is significantly different from that shown in FIG. 3 .
In the second embodiment, a lag-bolt, generally designated 50 , has a head 51 engaging the outer surface of head section 28 , and a threaded shaft 54 that passes through the head section 28 and is secured thereto by a pair of anchor arms 52 - 52 . The lag-bolt 50 is of conventional design wherein thc arms 52 - 52 are initially folded so as to pass through an aperture 53 in the center of the head section 28 , and then the arms 52 - 52 are expanded against the underside of the head section 28 , as shown in FIG. 5, by rotation of the lag-bolt shaft 54 in response to rotation of its head 51 by a screwdriver, wrench or other conventional tool. After the lag-bolt is secured in the position shown, the neck 40 of the rotor is slipped over the top of the mounting pole and the rotor is lowered until the distal end of the bolt shaft 54 rests within and against the bottom of a cup 58 secured to a pole cap 60 , such as by an adhesive 62 where the pole cap 60 is made of plastic, or by soldering or welding where the pole cap 60 is made of metal. As an alternative, the cup 58 and the pole cap 60 may be made of the same material and formed as a single-piece, integral structure.
When assembled as shown in FIG. 5, the distal end of lag-bolt shaft 24 rests on the bottom of cup 58 and the shaft rotates within the cup 58 and supports the rotor body 11 for rotation in response to the wind. The fins, vents, neck and remaining structure of the second embodiment function in the same manner as those of the first embodiment as described above. However, since the distal end of shaft 54 rests freely within the cup 58 , the second embodiment may be operated only in an upright position such as that shown in FIG. 5, whereas the first embodiment may be operated either in an upright position, such as shown in FIG. 1, or in an inverted position, such as where the opposite or proximate end of pole 12 is secured to an overhead structure, e.g., a roof beam of a dock shelter, porch roof or the like.
The bird disturbing visual effects provided by the spinning fins may be enhanced by placing designs, such as the holographic eyes 46 shown in FIG. 5, on one or both sides of one or more of the fins. The designs may include a light reflective material, such as sparkling particles 48 , that reflect light in a flashing manner during rotation of the rotor in the presence of light. The reflective material also may be used without a design, as shown in FIG. 2, on one or both sides of one or more of the fins.
Example of an Assembly Method
As shown in FIGS. 6-8, another embodiment of the bird repeller in the invention may be made from a one-half gallon round plastic container or bottle having a body 11 ′ with six (6) cup-like protrusions or bosses 77 projecting radially outward from its side, these projecting bosses or cup-like portions having been formed as an integral part of the body 11 ′ by molding, stamping, pressing out or the like. The body 11 ′ also includes a barrel section 18 ′, an acoustic section 36 ′, a neck section 38 ′, and a neck mouth opening 79 which is approximately 1 ¼ inch in diameter. The following additional supplies may be used in making this embodiment of the bird repeller: a #10, ¾ inch stainless steel Phillips head screw 30 ; a washer 32 having an aperture for receiving screw 30 ; a section of ¾ inch PVC pipe 12 preferably at least three feet in length; a PVC rounded end cap 34 for the ¾ inch PVC pipe 12 ; and decal stickers 45 depicting eycs 46 and glitter 48 . The following tools may be used to assemble the foregoing supplies: a sharp knife 65 , a drill (not shown), {fraction (3/16)} inch and {fraction (7/64)} inch drill bits (not shown), and a Phillips head screw driver (not shown). The embodiment of FIGS. 6-8 may then be made in accordance with the following steps:
1. Using the sharp knife 65 , cut shapes corresponding to the desired fins 20 ′ out of the bosses 77 at six (6) substantially equally spaced positions around the side wall of the container body 11 ′ by cutting along a cut line 67 that represents the base where the boss 77 transitions into the cylindrical wall of the barrel 18 ′ (this differs from the embodiments of FIGS. 1-5, wherein the fin 20 includes a small portion of the cylindrical barrel wall, and produces a lighter weight fin 20 ′). Before cutting, make marks 68 and 69 on the barrel wall and cut along line 67 from mark 68 to mark 69 , leaving thc fin 20 ′ attached to the barrel 18 ′ by a deformable hinge portion 24 ′. In FIG. 7, boss 89 is uncut, boss 91 is being cut by knife 65 , and boss 93 has been cut to form a shape corresponding to that of fin 20 ′. Then, bend each fin outward until it extends from the wall of barrel 18 ′ so that a tangent T to the hinge portion and to the distal inner edge of the fin makes an angle F in the range of about 20′ to about 90°, preferably about 30° to about 60°, more preferably about 40° to about 50°, most preferably about 45°, relative to a radial line L from the spin axis represented by the axis of screw 30 as shown in FIG. 7 . The tangent T touches the innermost surface of the hinge portion 24 ′ and the outermost inner edge of the fin at its distal end 33 ′.
2. Drill a hole in the top center of the bottom 72 of the bottle using the {fraction (3/16)} inch drill bit.
3. Drill a hole in the top center of the PVC cap 34 using the {fraction (7/64)}inch drill bit.
4. Insert a top portion of the ¾ inch PVC pole 12 through the mouth opening 79 of the bottle neck 38 ′ and push the top portion of the pole through one of the fin openings 22 ′.
5. Push the PVC cap 34 onto the projecting top end of the ¾ inch PVC pole 12 using hand pressure until it is tightly secured by a friction fit or by a PVC adhesive.
6. Retract the top portion of the pole back into the bottle and align the PVC cap hole with the hole in the bottom 72 of the bottle.
7. Secure the bottom 72 to the cap 34 with the #10, ¾ inch stainless steel Phillips head screw 30 passing through the aperture of washer 32 , being careful not to over tighten and making sure that each fin 20 ′ extends substantially along the tangent T as described in step 1.
8. Test the resulting bird repeller body 11 ′ by spinning it, and adjust the screw 30 as needed to make sure the body 11 ′ spins freely.
9. Optionally, stickers 45 with eyes 46 and/or glitter 48 may be secured to one or both sides of the fins 20 ′ on the body 11 ′.
10. A number of different methods may be used to attach the bottom of the pole to a dock piling 15 or other fixed structure so that the pole is fixed in a substantially vertical position. The attaching methods include the straps 14 shown in FIG. 1, or alternatively by first attaching to piling 15 with straps 14 , or with screws and/or nails, a section of 1 inch PVC pipe that will accept the bottom of the ¾ inch pole, in the same manner that a fishing rod holder supports the rod on a boat.
Referring now to FIGS. 8 and 9, on the exterior surface of the bottom wall of the inverted bottle, which is the top wall 72 of the head section 28 ′ of the repeller body 11 ′, there may optionally be mounted a housing 71 enclosing from the weather a noise device that mimics the sound of a bird of prey or other predator. This noise device may comprise a solar cell 73 , a rechargeable battery 74 , a sound chip 75 , and a speaker 76 that emits the sound of the predator to scare birds away form the area to be protected. Solar cell 73 is electrically connected to battery 74 by wires 84 and 85 , battery 74 is electrically connected to chip 75 by wires 80 and 81 , and chip 75 is electrically connected to speaker 76 by a wire 83 . Wire 83 passes through an aperture 87 in the top wall 72 because the speaker 76 is preferably mounted within the hollow chamber of body 11 ′ so that the sound emitted by the speaker passes freely (loudly and clearly) through the vents 22 ′.
While specific bird repeller assemblies and methods for their manufacture have been described and illustrated in detail, it will be apparent to those skilled in the art that many modifications and variations are possible without deviating from the broad scope of the present invention. For example, other types of rotary connections may be used to mount the head of the rotor on the distal end of the pole. In addition, the rotor and the pole may be made of a variety of materials, and the neck, acoustic section, barrel, head section, fins and vents may have a wide variety of shapes and sizes. Thus, the specific embodiment described herein is for the purpose of illustrating the present invention, and persons skilled in the art will recognize variations thereof that fall within the scope of this invention, which is limited only by the claims appended hereto, and the equivalence of the features described therein. | 1a
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FIELD OF THE INVENTION
[0001] The present invention relates to compositions useful in cancer treatment. Particularly, the invention relates to compositions prepared from herbs commonly available for practicing Traditional Chinese Medicine and to methods of treating or improving cancerous conditions using the herbal compositions.
BACKGROUND OF THE INVENTION
[0002] Tumor cell invasion and secondary spread through the blood and lymphatic system, also known as metastasis, is the hallmark of malignant disease and the greatest challenge to cancer treatment. Tumor metastasis requires two important processes, namely, angiogenesis and tumor cell invasion of the basement membrane (BM) and the extracellular matrix (ECM). Circulating tumor cells arrested in the capillary beds of different organs must invade the endothelial cell lining and degrade its underlying basement membrane (BM) in order to escape into the extravascular tissue(s) where they establish metastasis (Liotta L. A. et al. (1983) Tumor invasion and the extracellular matrix, Lab. Invest., 49:639-649).
[0003] Major components of the BM and the ECM are glycosaminoglycans, mainly heparan sulphate proteoglycan (HSPG). The basic HSPG structure includes a protein core and several linear heparan sulphate (HS) chains that covalently attached to the protein core. Several cellular enzymes (e.g., collagenase IV, plasminogen activator, cathepsin B, elastase) are thought to be involved in degradation of the BM (Liotta L. A. et al. (1983) Tumor invasion and the extracellular matrix, Lab. Invest., 49:639-649). Among these enzymes is an endo-beta-D-glucuronidase (heparanase) that cleaves HS at specific intrachain sites, i.e., between GlcUA and GlcNAc sites (Vlodavsky I. et al. (1992) Expression of heparanase by platelets and circulating cells of the immune system: Possible involvement in diapedesis and extravasation, Invasion & Metastasis, 12:112-127; Nakajima M. et al. (1988) Heparanase and tumor metastasis J. Cell. Biochem., 36:1 57-167; Vlodavsky I. et al. (1983) Lymphoma cell mediated degradation of sulphated proteoglycans in the subendothelial extracellular matrix: Relationship to tumor cell metastasis, Cancer Res., 43:2704-2711; Vlodavsky I. et al. (1988) Involvement of heparanase in tumor metastasis and angiogenesis, Is. J. Med., 24:464-470). Expression of an HS degrading heparanase was found to correlate with the metastatic potential at mouse lymphoma (Vlodavsky I. et al. (1983) Lymphoma cell mediated degradation of sulphated proteoglycans in the subendothelial extracellular matrix: Relationship to tumor cell metastasis, Cancer Res., 43:2704-2711), fibrosarcoma and melanoma cells (Nakajima M. et al. (1988) Heparanase and tumor metastasis, J. Cell. Biochem., 36:1 57-167). The same is true for human breast, bladder and prostate carcinoma cells (see U.S. Pat. No. 6,190,875). Moreover, elevated levels of heparanase were detected in sera (Nakajima M. et al. (1988) Heparanase and tumor metastasis, J. Cell. Biochem., 36:157-167) and urine (U.S. Pat. No. 6,190,875) of metastatic tumor bearing animals and cancer patients and in tumor biopsies (Vlodavsky I. et al. (1988) Involvement of heparanase in tumor metastasis and angiogenesis, Is. J. Med., 24:464-470). Heparanase has also been implicated in T cell-mediated delayed type hypersensitivity, experimental autoimmune encephalomyelities and adjuvant arthritis, suggesting that heparanase plays a role in cell diapedesis and extravasation associated with inflammation and autoimmune diseases.
[0004] Therefore, inhibitors of heparanase are useful for treating various cancers in human and other mammal subjects. An inhibitory effect on heparanase is a valuable biomarker in screening for substances as medicament in cancer treatment, which remains a serious challenges for the medical world.
SUMMARY OF THE INVENTION
[0005] The present invention provides novel compositions with inhibitory effects on heparanase, which are made from herbs commonly used in Traditional Chinese Medicine. The composition of the present invention are suitable for treating or improving pathological conditions involving elevated heparanase activities, such as tumor cell metastasis in various cancer patients.
[0006] In one aspect, the present invention provides an herbal composition comprising an effective amount of Rhizoma Curcumae Kwangsiensis (Ezhu), Herba Dendrobium candidum (Shihu), Rhizoma Pinelliae preparatum (Fabanxia), and Rhizoma Typhonii (Baifuzi). This composition may further comprise an effective amount of Radix Sophora tonkinensis (Shandougen), Radix Arnebia euchroma (Zicaogen), Frutus lycium barbarum (Gouqizi), Radix Astagalus membranaceus (Huangqi), Herba Oldenlandia diffusa (Baihuasheshecao), Rhizoma polygonati (Huangjing) and Radix Glycyrrhizae (Gancao). This herb mixture composition is processed according to the procedures known to people skilled in practicing herbal medicine, particularly, the Traditional Chinese Medicine. The processed composition may take any form as suitable, such as tea-like drinks (decoctions), pills, capsules, liquid alcoholic extracts, dried extracts, etc.
[0007] In another aspect, the present invention provides a composition comprising an effective amount of each extract of Rhizoma Curcumae Kwangsiensis (Ezhu), Herba Dendrobium candidum (Shihu), Rhizoma Pinelliae preparatum (Fabanxia), and Rhizoma Typhonii (Baifuzi). This extract mixture may further comprise an effective amount of each extract of Radix Sophora tonkinensis (Shandougen), Radix Arnebia euchroma (Zicaogen), Frutus lycium barbarum (Gouqizi), Radix Astagalus membranaceus (Huangqi), Herba Oldenlandia diffusa (Baihuasheshecao), Rhizoma polygonati (Huangjing) and Radix Glycyrrhizae (Gancao). In this aspect, the extract of each herbal ingredient is prepared separately and then mixed with the extracts of other herbs in a pre-prescribed ratio.
[0008] While each individual herb used in the present invention are commonly available and known among practitioners of Traditional Chinese Medicine, to the knowledge of the applicants, the composition with the particular ingredients disclosed herewith is unknown, much less its anticancer effects. Another aspect of the invention is that certain ingredients of the composition complementarily exert their medicinal effects with each other, creating synergy between them. For instance, synergistic effects for heparanase inhibition were obtained between Rhizoma Curcumae kwangsiensis (Ezhu) and Radix Sophora tonkinensis (Shandougen), between Rhizoma Pinelliae preparatum (Fabanxia) and Radix Sophora tonkinensis (Shandougen), and between Rhizoma Curcumae kwangsiensis (Ezhu) and Rhizoma Pinelliae preparatum (Fabanxia).
[0009] A better understanding of the present invention may be obtained in light of the following examples which are claimed to illustrate, but are not to be construed to limit the present invention.
BRIEF DESCRIPTION OF THE INVENTION
[0010] FIG. 1 shows the synergistic effect of heparanase inhibition between ingredients of the composition of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0011] All the herbs used in the present invention are commercially available. After ascertaining the authenticity of the individual herbs, traditional methods may be used to process the composition of the present invention into a form suitable for administering to human subjects. Those conventional methods are known to people skilled in the art, described in books and commonly used by practitioners of herbal medicine. By way of example, not limitation, a suitable administering form can be tinctures, decoctions, or dry extracts. Extracts may be further process into pills, tablets, capsules or injections.
[0012] A tincture is prepared by suspending herbs in a solution of alcohol, such as, wine or liquor. After a period time of suspension, the liquid (the alcohol solution) may been administered two or three times a day, one teaspoon each time. A decoction is the most common form of herbal preparations. It is traditionally prepared in a clay pot, but nowadays it can also be prepared in glass, enamel or stainless steel containers. The herbs should be soaked for a period of time in a proper amount of water and then quickly brought to a boil and simmered until the amount of water is reduced by half.
[0013] An extract is a concentrated preparation of the essential constituents of the medicinal herb. Typically, the essential constituents are extracted from the herbs by suspending the herbs in an appropriate choice of solvent, typically, water, ethanol/water mixture, methanol, butanol, iso-butanol, acetone, hexane, petroleum ether or other organic solvents. The extracting process may be further facilitated by means of maceration, percolation, repercolation, counter-current extraction, turbo-extraction, or by carbon-dioxide hypercritical (temperature/pressure) extraction. After filtration to rid of herb debris, the extracting solution may be further evaporated and thus concentrated to yield a soft extract (extractum spissum) and/or eventually a dried extract, extracum siccum, by means of spray drying, vacuum oven drying, fluid-bed drying or freeze-drying. The soft extract or dried extract may be further dissolved in a suitable liquid to a desired concentration for administering or processed into a form such as pills, capsules, injections, etc.
[0014] As a particular embodiment of the present invention, a polysaccharide-enriched extract is prepared for each herbal ingredient. The extraction process is described below in detail.
[0015] Ten grams of an herb was cut into pieces and boiled 2 times sequentially with 5 volumes of water, 30 minutes each time. The soluble fraction (˜50 ml) was filtered by filter paper and the filtrate was the total extract of the herb. Polysaccharide-enriched and non-polysaccharide-enriched extracts were prepared by the following protocol: Fifty milliliters (˜50 ml) of the total extract were added to 3 volumes of 100% ethanol. The mixture was incubated at 4° C. overnight, and centrifuged at 3,000×g at 4° C. for 10 minutes. The supernatant was filtered and the filtered supernatant became the non-polysaccharide-enriched extract, whereas the pellet was the polysaccharide-enriched extract. All three extracts were concentrated by a Rotary evaporator Rotavapor® (Brinkmann, Westbury, N.Y.) and were dried to powder form with freeze-dryer. Appropriate concentration of each extract was obtained by dissolving the powder with an amount of water suitable for the heparanase activity assay.
[0016] The polysaccharide-enriched extracts were then tested for their abilities to inhibit heparanase. In order to determine anti-heparanase activity by the extract, a heparanase activity assay was carried out to determine the activity of a heparanase in the presence of the extract. The heparanase activity can be compared to a control, e.g., the activity of the same heparanase determined by the same activity assay but with the absence of the extract. In general, any suitable heparanase activity assay would allow determination of inhibitory effect on heparanase by an extract. There are many known assay protocols for determine heparanase activity. Although such assays are not part of the present invention, the following information is provided for easy reference.
[0017] A typical heparanase catalytic activity assay involves radiolabelling a substrate (either in vitro or metabolically) and analyzing the degraded products due to heparanase catalytic activity (Vlodavsky I. et al., (1992) Expression of heparanase by platelets and circulating cells of the immune system: Possible involvement in diapedesis and extravasation, Invasion & Metastasis, 12:112-127; Bartlett M. R. Underwood P. A. et al., (1995) Comparative analysis of the ability of leukocytes, endothelial cells and platelets to degrade the subendothelial basement membrane: evidence for cytokine dependence and detection of a novel sulfatase, Immunol. Cell Biol., 73:113-124).
[0018] As part of the effort of searching effective herbal formulations for cancer treatment, a large number of herbs used in Traditional Chinese Medicine are studied for their anti-heparanase effect. For each herb, three types of preparations, namely, total extract (TE), polsaccharide-enriched extract (PER), non-polysaccharide-enriched extract (NPER), were made according to the process described in the foregoing. Table 1 summarizes the research data on 150 medicinal herbs.
TABLE 1 Effects of 150 Medicinal Herbs On Heparanase Effects on Heparanase Heparanase-293T Heparanase-placenta Chinese Medicinal Herbs TE PER NPER TE PER NPER 1 Rhizoma Curcumae kwangsiensis (Ezhu) +++ −* −* +++ + + 2 Herba Oldenlandia diffusa (Baihuasheshecao) − − − −* −* −* 3 Rhizoma Paris polyphylla (Chonglou) + + + +++ +++ −* 4 Radix Salvia miltiorrhizae (Danshen) − −* − + −* − 5 Rhizoma Sparganium stoloniferum (Sanleng) + + + + − − 6 Rhizoma Pinellia ternate (Banxia) − − − + − −* 7 Rhizoma Pinelliae preparatum (Fabanxia) + + + ++ + − 8 Herba Scutellariae barbatae (Banhilian) −* −* −* − − − 9 Pseudobulbus Cremastra appendiculata −* −* −* −* −* −* (Shancigu) 10 Lasiosphaera fenzlii/Calvatia gigantea (Mabo) −* −* −* −* − − 11 Ganoderma lucidum/G. sinense (Lingzhi) −* −* −* −* − − 12 Radix Angelicae sinensis (Danggui) −* −* −* −* ++ ++ 14 Danggui Buxue Tang −* −* −* − − − 15 Cordyceps sinensis (Dongchongxiacao) − −* −* − − − 16 Radix Astagalus membranaceus (Huangqi) − − − −* − −* 17 Radix Angelica pubescens (Duhuo) − −* − − − −* 18 Rhizoma Notopterygium incisum (Qianghuo) − − − − − − 19 Radix Angeliica dahurica (Baizhi) −* −* + −* −* −* 20 Rhizoma Ligusticam chuanxiong (Chuanxiong) −* −* − −* −* 21 Peucedanum praeruptorum (Qianhu) +++ −* +++ − − −* 22 Radix Sophora tonkinensis (Shandougen) + ++ − +++ +++ − 23 Fructus Thichsanthes kirilowii (Gualou) − −* − − − − 24 Herba Taraxacum mongolicum (Pugongying) − − − − − − 25 Radix Sophora flavescens (Kushen) + ++ ++ +++ +++ − 26 Radix Arnebia euchroma (Zicaogen) − − ++ ++ + + 27 Semen Impatientis (Jixingzi) + + ++ +++ +++ +++ 28 Rhizoma Anemasshena asphodeloides Bge. − − − − − − (Zhimu) 29 Rhizoma Atractylodes lancea (Sangzhu) − − − − − + 30 Flemingia philippinensis (Qianjinba) −* −* −* − −* +++ 31 Caulis Polygoni multiflori (Shouwuteng) −* −* −* +++ −* +++ 32 Radix Curcuma wenyujin (Yujin) − −* − −* −* −* 33 Radix Ilex asprella (Gangmeigen) −* −* − +++ − −* 34 Polyporus umbellatus Fries (Zhuling) −* −* −* + −* −* 35 Poria cocos (Fuling) − − −* − − −* 36 Semen Arecae catechu L (Binglang) ++ + − − − −* 37 Furctus Rosa laevigata Michx (Jinyingzi) − − − − − −* 38 Rhizoma Cyperus rotundus (Xiangfu) − − − −* − −* 39 Fructus Chaenomeles sinensis (Nanmugua) ++ − − −* −* −* 40 Fructus Aurantii (Zhishi) − ++ − − − + 41 Rhizoma Arisaematis (Tiannanxing) ++ ++ + −* − −* 42 Bombyx mori Linnaeus (Cansha) −* ++ − −* − −* 43 Fructus Forsyththia suspense (Lianqiao) − − −* + − − 44 Radix Aconiti kusnezoffii (Caowu) − − − +++ − − 45 Herba Dianthus superbus (Qumai) − − − −* −* −* 46 Rhizoma Dryopteris crassirhizoma (Guanzhong) − −* ++ − + −* 47 Flos Lonicerae (Jinyinhua) − − −* − − −* 48 Flos Serratum chinensis (Mumian) − − − + − −* 49 Herba Polycapaea corymbesa (Baiguding) − − +++ − − + 50 Herba Gerbera piloselloides (Maodading) ++ ++ + + + +++ 51 Rhizoma Belamcanda chinensis (Shengan) +++ + − ++ +++ +++ 52 Caulis Psychotria serpens ++ − + ++ +++ + 53 Rhizoma Cynanchum stauntonii (Baiqian) +++ − ++ +++ − −* 54 Rhizoma Costus speciosus (Biqiaojiang) −* −* −* +++ − −* 55 Radix Aristolochia westlandi (Guangfangji) −* −* − −* −* −* 56 Radix Isatidis indigotica (Banlangen) − − − −* − − 57 Rhizoma Typhonii (Baifuzi) + −* + ++ −* − 58 Radix Aconiti lateralis preparata (Chuanwu) −* −* − − − − 59 Flolium isatidis indigotica (Daqingye) ++ ++ ++ + − − 60 Herba Lycopus lucidus (Zelan) − ++ ++ + ++ −* 61 Herba Pistia stratiotes (Daipiao) − ++ ++ − −* − 62 Semen Caesalpinia minax (Huijiayunshi) ++ − ++ +++ − + 63 Ficus pumila (Xueli) − −* + − +++ +++ 64 Folium Podocarpus Macrophylla −* −* −* +++ −* − (Xiaoluohansong) 65 Caulis Oldenlandia hedytidea (Niubaiteng) +++ +++ +++ ++ −* + 66 Rhizoma Bombyx mori Linnaeus (Sutiejue) −* −* −* + − − 67 Herba Asarum Maxinum (Dahuaxixin) −* +++ +++ − − − 68 Rhizoma Coptis Chinensis (Huanglian) −* − −* −* − −* 69 Fructus Evodia rutaecarpa (Wuzhuyu) −* −* −* ++ − − 70 Herba Dendrobium candidum (Shihu) − − − ++ − + 71 Frutus lycium barbarum (Gouqizi) − −* − ++ − − 72 Herba Nerrilia, Nervilia fordii (Qingtiankui) + −* + − − −* 73 Rhizoma Cordydalis yanhusuo (Yanhusuo) + + ++ + − ++ 74 Herba Dendrobii nobile Lindl. (Shihu) +++ ++ + +++ ++ + 75 Radix Cordonpsis pilosulae (Dangshen) ++ ++ ++ + − + 76 Bulbus Fritillaria puqiensis (Beimu) + + +++ ++ ++ ++ 77 Bulus Fritilaria anhuiengis (Beimu) + − ++ − − + 78 Syngnathus (Hujiao) + − − ++ + − 79 Synagnathus hardwickii (Hailong) ++ − − −* + − 80 Radix Panacis quinquefolii (Xiyangshen) − − − − − − 81 Hippocampus kuda (Dahaima) − − − − + − 82 Radix Ramax ginseng (Renshen) − − − −* − − 83 Panax Quinquefolium (Huaqishen) − − − + − − 84 Fritillaria ussunensis (Pingbeimu) − − − − −* − 85 Fritillaria taipaiensis (Taibaibeimu) − −* −* − − − 86 Fritillaria thanbergii (Zhebeimu) − −* −* − − − 87 Semen Ziziphi Spinosae (Suanzaoren) − ++ − −* −* −* 88 Semen Alpiniae katsumada (Caodoukou) − + + − − − 89 Rhizoma Curcumae longae (Jianghuang) − − + − − − 90 Radix et Rhizoma rhei (Dahuang) + + ++ − − ++ 91 Flos Magnoliae officinalis (Houpu) −* − − −* + + 92 Semen Nelumbo nucifera (Lianzixin) ++ +++ +++ +++ +++ +++ 93 Radix Solena amplexicaulis (Maogua) − +++ +++ −* +++ ++ 94 Herba Leonurus heterophyllus (Yimucao) − − − + + − 95 Pheretimea aspergillum (Dilong) − − − − − − 96 Semen Euphorbia lathyris (Qianjinzi) − + + − − − 97 Radix Euphorbia kansui (Gansui) − − − − − − 98 Hirude nipponica (Shuizhi) − − − −* −* −* 99 Semen Croton tiglium (Badou) − − −* ++ +++ −* 100 Semen Strychnos nux-vomica (Muqianzi) −* −* −* −* − −* 101 Radix Morinda officinalis (Bajitian) − + − −* − −* 102 Radix Aconitum brachypodum −* −* − −* −* − (Xueshangyizhihao) 103 Flos Datula metel (Yangjinhua) − ++ + − + + 104 Mylabris (Banmao) − − − − − − 105 Semen Dioscorea bulbifera (Huangyaozi) −* − + + +++ + 106 Flos Carthamus tinctorius (Honghua) −* −* + −* −* ++ 107 Flos Prunella vulgaris (Xiakucao) − − − − ++ + 108 Eupolyphaga seu Steleophaga (Tubiechong) −* −* −* −* − −* 109 Rhizoma Paris polyphylla (Zaoxiu) − + +++ + −* + 110 Semen Ligustrum Lucidum (Nuzhenzi) + − + −* −* −* 111 Radix Notoginseng (Sanqi) − − − −* − − 112 Semen Coix lacryma-jobi (Yiyiren) − − − − − − 113 Radix Stemona sessilifolia (Baibu) + + ++ − − − 114 Semen Prunus humilis (Yuliren) − − ++ − − − 115 Pollen Typha angustifolia (Puhuang) +++ − − − − − 116 Schelfflera octophylla (Yajiaomu) ++ − − − − − 117 Rhizoma Anemones raddeana Regel −* − − − − − (Liangmianzhen) 118 Flos chrysanthemi (Juhua) − − − −* − −* 119 Rhizoma polygonati (Huangjing) − − − +++ − − 120 Radix rehmanniae (Dihuang) − − + − − − 121 Rhizoma Polygonati odorati (Yuzhu) + + − − − − 122 Semen nelumbinis (Lianzi) − − − − − − 123 Radix paeoniae alba (Baishao) − − − − − −* 124 Radix paeoniae rubra (Chishao) − − + − − −* 125 Caulis polygoni multiflori (Heshouwu) − − + − − − 126 Herba epimedii (Yinyanghuo) − − − − − −* 127 Rhizoma Pseudodrynaria coronans (Gusuibu) − − − − − −* 128 Rhizoma cimicifugae (Shengma) −* − − − − − 129 Caulis Sargentodoxa cuneata (Daxueteng) − − − − − − 130 Piper kadsura (Haifengteng) − −* − − − 131 Luffae Fructus Retunervus (Guangzhousigua) −* − − +++ ++ − 132 Flos Magolia coco (Yehehuan) −* − −* − − − 133 Herba Gentiana Loureiri (Huananlongdan) −* − − − +++ − 134 Torilis japonica (Yaoyi) − − − −* +++ − 135 Herba Anisomeles indica (Fangfengcao) −* − − −* −* − 136 Herba Thalspi arvense (Xinming) − − − − − − 137 Flos Anisopappus chinensis (Shanhuangju) ++ + ++ ++ − − 138 Flos Artemisia lactiflora (Sijicai) −* −* + −* −* − 139 Herba Eupatoium fortunei (Peilan) − + − − ++ − 140 Herba Equisetum debile (Weiguancao) − + −* − − −* 141 Rhizoma Alocasia macrorrhiza (Haiyu) −* ++ − − + − 142 Rhizoma Clematis chinensis (Jinmaogouji) −* −* −* −* −* −* 143 Sargassum fusiforme (Haizao) − − − − − − 144 Thallus eckloniae (Kunbu) − − − − − − 145 Radix Scutellariae barcalensis (Huangqi) − + − + − − 146 Radix Rehmamnia glutinosa (Shengdi) − − − − − − 147 Desmodium Styracifolium (Jinqiancao) − − − − − − 148 Cortex moutan (Danpi) − − − − − − 149 Flos Inula japonica (Xuanfuhua) − − − − − − 150 Radix Clematis chinensis (Weilingxian) −* −* −* −* −* −* Notes: 1. TE: total extract; PER: polysaccharide-enriched extract; NPER: non-polysaccharide enriched extract 2. “−”: 1-25% inhibition, “+”: 26-50% inhibiton, “++”: 51-75% inhibition, “+++”: 76-100% inhibition, “−*”: activation
[0019] In addition to the above study on individual herbs, synergistic effects between two individual herbs when used in combination were also examined. As shown in FIG. 1 , the ingredients of the composition of the present invention demonstrate a synergic effect in terms of their inhibitory action on heparanase. For example, the sum of heparanase inhibition by Rhizoma Curcumae kwangsiensis (Ezhu) and Radix Sophora tonkinensis (Shandougen) acting individually was about 32.5% while it was 44.5% when used in combination. For Rhizoma Pinelliae preparatum (Fabanxia) and Radix Sophora tonkinensis (Shandougen), it was 21% verses 38.5%. For Rhizoma Curcumae kwangsiensis (Ezhu) and Rhizoma Pinelliae preparatum (Fabanxia), it was 28.5% verses 40.5%. The synergy was significant. In FIG. 1 , the Chinese characters indicate the each herb's name in Chinese.
[0020] As a particular embodiment of the present invention, an anti-cancer herbal composition is provided herewith as an example. This composition contains the following ingredients: Rhizoma Curcumae kwangsiensis (Ezhu), Herba Dendrobii nobile Lindl. (Shihu), Rhizoma Pinelliae preparatum (Fabanxia), Rhizoma Typhonii (Baifuzi), Radix Sophora tonkinensis (Shandougen), Radix Arnebia euchroma (Zicaogen), Frutus lycium barbarum (Gouqizi), Radix Astagalus membranaceus (Huangqi), Herba Oldenlandia diffusa (Baihuasheshecao), Rhizoma polygonati (Huangjing) and Radix Glycyrrhizae (Gancao).
[0021] Among them, Rhizoma Curcumae kwangsiensis (Ezhu), Herba Dendrobii nobile Lindl. (Shihu), Rhizoma Pinelliae preparatum (Fabanxia), Rhizoma Typhonii (Baifuzi) are essential ingredients and must be included in the composition, while the remaining listed herbs are optional, one or more of which may be omitted from the composition. An effective amount of each herb is used in the composition. The term “effective amount” means the amount of herbal ingredient will contribute towards the overall composition's ability to provide the intended effect. The effective amount of each herb can be determined by people skilled in the art. The following dosage ranges (for a single dose) are provided for easy reference or guidance. Dosages outside the described ranges may also be effective and provide satisfactory results.
[0022] Rhizoma Curcumae kwangsiensis (Ezhu): 5-50 grams, preferably about 15 grams;
[0023] Herba Dendrobii nobile Lindl. (Shihu): 5-50 grams, preferably about 10 grams;
[0024] Rhizoma Pinelliae preparatum (Fabanxia): 5-20 grams, preferably about 10 grams;
[0025] Rhizoma Typhonii (Baifuzi): 5-20 grams, preferably about 10 grams;
[0026] Radix Sophora tonkinensis (Shandougen): 5-20 grams, preferably about 10 grams;
[0027] Radix Arnebia euchroma (Zicaogen): 5-30 grams, preferably about 10 grams;
[0028] Frutus lycium barbarum (Gouqizi): 10-30 grams, preferably about 10 grams;
[0029] Radix Astagalus membranaceus (Huangqi): 10-30 grams, preferably about 15 grams;
[0030] Herba Oldenlandia diffuse (Baihuasheshecao): 20-40 grams, preferably about 30 grams;
[0031] Rhizoma polygonati (Huangjing): 20-50 grams, preferably about 30 grams;
[0032] Radix Glycyrrhizae (Gancao): 5-20 grams, preferably about 5 grams;
[0033] As discussed in the above, by conventional or known methods to people skilled in the art, the herbal composition is further processed into one of the suitable forms for human consumption as a measure of treatment or prevention of cancers. The herbal ingredients of the composition may be mixed before being further processed. Or, each ingredient is processed individually first and then the resulting processed ingredients, such as, for example, total extracts or polysaccharide-enriched extracts of each herb, are mixed according to the specified relative amounts. For example, if the amount of the total extract made from 5-50 grams of Rhizoma Curcumae kwangsiensis (Ezhu) is used in the composition, the amount of the total extract made from 5-20 grams of Rhizoma Pinelliae preparatum (Fabanxia) should be used to keep their relative amounts consistent with the above prescribed ranges.
[0034] Another particular embodiment of the present invention is defined by the relative amounts of its ingredients. It contains Rhizoma Curcumae kwangsiensis (Ezhu), Herba Dendrobii nobile Lindl. (Shihu), Rhizoma Pinelliae preparatum (Fabanxia), Rhizoma Typhonii (Baifuzi), where the ratio between Curcumae kwangsiensis (Ezhu) and Herba Dendrobii nobile Lindl. (Shihu) is from 0.1 to 10 by weight; the ratio between Curcumae kwangsiensis (Ezhu) and Rhizoma Pinelliae preparatum (Fabanxia) is from 0.25 to 10 by weight; the ratio between Curcumae kwangsiensis (Ezhu) and Rhizoma Typhonii (Baifuzi) is from 0.25 to 10 by weight. Preferably, the above ratios are 0.5-5, 1.0-5.0, and 1.0-5.0, respectively. More preferably, the above ratios are 1.5, 1.5, and 1.5, respectively. The ratio of weight is determined before the herbs are processed.
[0035] The above composition may optionally further comprise one or more herbs selected from the group consisting Radix Sophora tonkinensis (Shandougen), Radix Arnebia euchroma (Zicaogen), Frutus lycium barbarum (Gouqizi), Radix Astagalus membranaceus (Huangqi), Herba Oldenlandia diffusa (Baihuasheshecao), Rhizoma polygonati (Huangjing) and Radix Glycyrrhizae (Gancao). When one or more optional herbs are present in the composition, the ratios (by weight) between Curcumae kwangsiensis (Ezhu) and the optional herbs are 0.25-10, 0.16-10, 0.16-5.0, 0.16-5.0, 0.125-2.5, 0.1-2.5, and 0.25-10, respectively. Preferably, the ratios are 0.5-5, 0.3-5, 0.3-2.5, 0.3-2.5, 0.25-1, 0.2-1 and 0.5-5, respectively. More preferably, the ratios are 1.5, 1.5, 1.5, 1, 0.5, 0.5, and 3 respectively. The ratio of weight is determined before the herbs are processed.
[0036] While there have been described and pointed out fundamental novel features of the invention as applied to a preferred embodiment thereof, it will be understood that various omissions and substitutions and changes, in the form and details of the packages and methods illustrated, may be made by those skilled in the art without departing from the spirit of the invention. For example, it is expressly intended that all combinations of those elements and/or method steps which perform substantially the same function in substantially the same way to achieve the same results are within the scope of the invention.
[0037] The invention is not limited by the embodiments described above which are presented as examples only but can be modified in various ways within the scope of protection defined by the appended patent claims. | 1a
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention pertains to the art of dishwashers and, more particularly, to a system for preventing wash liquid from leaking about a door opening of a dishwasher.
2. Discussion of the Prior Art
In a typical dishwasher, washing fluid is pumped from a sump into upper and lower wash arms such that kitchenware retained on vertically spaced racks within a tub of the dishwasher will be sprayed with the washing fluid for cleaning purposes. The washing fluid is heated, filtered and recirculated. Prior to recirculating the washing fluid, the fluid is directed through one or more filters to remove soil from the fluid, with the soil being collected in a chamber. Periodically, the system will be purged in order to drain the collection chamber of the soil.
Typically, a dishwasher will be provided with a seal mounted around a door opening, wherein the seal is compressed when the dishwasher door is closed in order to prevent liquid from leaking from the tub based on a washing operation. Since the seal is compressed, it usually takes the shape of a portion of the door, such as a door spike, that is pushing into the seal. Unfortunately, repeated compression of the seal can cause the seal to deform. Over time, this deformation can cause the seal to leak.
To address this problem, the assignee of the present application has previously modified the flange structure provided about a door opening of a dishwasher tub in an attempt to direct leaking liquid back into the tub. To this end, it has been proposed to form each side flange with a laterally outermost ridge which angles inwardly and terminates at a position spaced from a lowermost portion of the door opening. With this structure, water or other washing liquid which leaks past the seal can be caused to flow along the ridge and be directed back towards the tub.
Regardless of this proposed solution to this leakage problem, it has been found that the prior ridge arrangement exhibited only limited success in preventing leakage. For instance, given the structure and configuration of the ridge, the liquid was accorded the opportunity of being re-directed laterally outwardly below the ridge or the liquid could flow over the ridge if relatively high flow rates were experienced. Based on the above, there exists a need in the art for an improved arrangement to prevent liquid from leaking about a door opening of a dishwasher door.
SUMMARY OF THE INVENTION
The present invention is directed to preventing the leakage of liquid from around a door opening of a dishwasher door, even if a seal provided about the opening is deformed due to being repetitively compressed. In accordance with the present invention, a flange is provided about a door opening of a dishwasher tub laterally outwardly of a seal which is caused to be compressed upon closing of the door. At lower lateral portions of the flange, a bead, including various segments, is formed to re-direct any liquid leaking past the seal back into the tub.
The bead in accordance with the preferred embodiment of the invention includes a first, elongated and substantially vertically extending portion, a second downwardly and laterally inwardly extending portion, another vertically extending portion, and a lowermost, inwardly angled portion. The second vertically extending portion is spaced laterally inwardly of the first vertically extending portion and extends adjacent an inwardly directed wall portion of the tub, near the seal, in order to define an elongated guide trough. In addition, in accordance with the most preferred embodiment of the invention, the flange has a reduced dimension along both the second vertically extending portion and the lowermost angled portion, with the lowermost angled portion making a smooth transition into the washing chamber.
With this overall arrangement, any liquid leaking past the seal, whether by the splashing of liquid in the tub or through condensation, is initially directed down along the first vertically extending portion. The liquid is then directed laterally inwardly to the point at which the guide trough starts. Thereafter, the liquid is further directed along the second vertically extending portion directly adjacent the interior of the tub. Finally, if the liquid reaches the end of the bead, it reaches the lowermost angled portion which directs the liquid to flow back into the tub.
Additional objects, features and advantages of the present invention will become more readily apparent from the following detailed description of a preferred embodiment when taken in conjunction with the drawings wherein like reference numerals refer to corresponding parts in the several views.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is an upper right perspective view of a dishwasher constructed in accordance with the present invention, with a door of the dishwasher being open to illustrate internal tub structure;
FIG. 2 is an enlarged perspective view of a lower corner portion of the tub of FIG. 1; and
FIG. 3 is another perspective view of the lower corner portion of the tub of FIG. 1 .
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
With initial reference to FIG. 1, a dishwasher constructed in accordance with the present invention as generally indicated at 2 . As shown, dishwasher 2 includes a tub 5 which is preferably injection molded of plastic so as to include integral bottom, side, rear and top walls 8 - 12 respectively. Within the confines of walls 8 - 12 , tub 5 defines a washing chamber 14 within which soiled kitchenware is adapted to be placed upon shiftable upper and lower racks (not shown), with the kitchenware being cleaned during a washing operation in a manner widely known in the art. Tub 5 has attached thereto a frontal frame 16 which pivotally supports a door 20 used to seal chamber 14 during a washing operation. In connection with the washing operation, door 20 is preferably provided with a detergent tray assembly 23 within which a is consumer can place liquid or particulate washing detergent for dispensing at predetermined portions of the washing operation. Of course, dispensing detergent in this fashion is known in the art such that this arrangement is only being described for the sake of completeness.
Disposed within tub 5 and, more specifically, mounted within a central opening formed in bottom wall 8 of tub 5 , is a pump and filter assembly 30 . Extending about a substantial portion of pump and filter assembly 30 , at a position raised above bottom wall 8 , is a heating element 44 . In a manner known in the art, heating element 44 preferably takes the form of a sheath, electric resistance-type heating element.
In general, pump and filter assembly 30 is adapted to direct washing fluid to a lower wash arm 47 and an upper wash arm (not shown). Dishwasher 2 has associated therewith a drain hose 85 including at least one corrugated or otherwise curved portion 89 that extends about an arcuate hanger 92 provided on an outside surface of side wall 10 . Drain hose 85 is also preferably secured to tub 5 through various clips, such as that indicated at 94 . In any event, in this manner, an upper loop is maintained in drain hose 85 to assure proper drainage in a manner known in the art. Actually, a detailed description of the exact structure and operation of pump and filter assembly 30 of dishwasher 2 does not form part of the present invention, but is rather set forth in pending U.S. application Ser. No. 10/186,739 entitled “Dishwasher Pump and Filtration System” filed Jul. 2, 2002, incorporated herein by reference.
Instead, the present invention is directed to the inclusion of liquid containment structure, generally indicated at 95 , provided along each of side walls 9 and 10 for preventing the leakage of wash liquid from around dishwasher door 20 . More specifically, frontal frame 16 actually extends along an outwardly projecting front flange 100 formed integral with both side walls 9 , 10 and top wall 12 . A front surface 101 (see FIGS. 2 and 3) leads to an in-turned wall portion 102 of side wall 9 which, in turn, leads to a flat wall strip 103 . Wall strip 103 carries an elongated gasket or seal 105 , between in-turned wall portion 102 and an extension 108 of side wall 9 , against which door 20 seats in order to seal off washing chamber 14 during operation of dishwasher 2 . That is, seal 105 is caused to be compressed upon closing of door 20 to prevent washing liquid, whether water or a combination of water and detergent, from flowing outside of dishwasher 2 .
FIGS. 2 and 3 best show the arrangement of front flange 100 and containment structure 95 . Here it should be noted that seal 105 is only shown in part for the sake of clarity. As depicted, front flange 100 is formed with an outermost, forwardly projecting ridge or bead generally indicated at 110 which functions to re-direct any wash liquid leaking past seal 105 back into tub 5 . More specifically, bead 110 includes various segments, i.e., a first, elongated and substantially vertically extending portion 125 leading to a downwardly and laterally inwardly extending portion 130 , followed by another vertically extending portion 135 , and terminating in a lowermost, inwardly angled portion 140 . With this arrangement, containment structure 95 is raised to a plane offset from a plane of front surface 101 , with bead portion 130 essentially defining a generally triangular-shaped plateau.
At this point, it should be recognized that front flange 100 , through to and including bead portions 125 and 130 , has heretofore been utilized by the assignee of the present invention for the purpose of diverting any leakage past seal 105 back into tub 5 . However, in accordance with the present invention, front flange 100 has been modified from this prior arrangement and bead portions 135 and 140 have been effectively added. More particularly, front flange 100 in accordance with the invention has been provided with a cut-out 150 so as to define a reduced dimensional portion of front flange 100 along which bead portions 135 and 140 extend. The presence of cut-out 150 advantageously enables a compact hinge arrangement (not shown) for door 20 to be employed. As shown, second vertically extending portion 135 is spaced laterally inwardly of the first vertically extending portion 125 and is spaced from in-turned wall portion 102 by an elongated guide trough 160 . As indicated above, second vertically extending portion 125 leads to inwardly angled portion 140 which, in turn, tapers to a corner juncture 170 between guide trough 160 of front flange 100 and in-turned wall portion 102 of tub 5 .
During operation of dishwasher 2 , any liquid leaking past seal 105 , whether from the spraying of washing liquid or, particularly, condensation, is initially directed down along first vertically extending portion 125 . The liquid is then directed laterally inwardly, due to the presence of bead portion 130 , to the point at which guide trough 160 starts. Thereafter, the liquid is further directed within guide trough 160 along second vertically extending portion 135 . Finally, if the liquid reaches the end of containment structure 95 , it comes upon lowermost angled portion 140 which smoothly transitions the liquid to flow back into tub 5 . Therefore, with this arrangement, even if seal 105 becomes deformed by repeatedly being compressed upon the closing of door 20 , any resulting liquid flow along front flange 100 will be contained within tub 5 instead of leaking to the surrounding environment.
Although described with reference to a preferred embodiment of the invention, it should be readily understood that various changes and/or modifications can be made to the invention without departing from the spirit thereof. For instance, although seal 105 is typically mounted to tub 5 , seal 105 could actually be carried by door 20 , while seating against tub 5 . In addition, bead 110 is preferably formed integral with tub 5 , but could be constituted by one or more separate elements mounted to tub 5 to perform the liquid containment function. Surprisingly, it has been found that containment structure 95 , in combination with the generally serpentine flow path from washing chamber 14 outwardly to front flange 100 , prevents leakage from washing chamber 14 of dishwasher 2 even when seal 105 is removed or severely damaged. In any case, the invention is only intended to be limited by the scope of the following claims. | 1a
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BACKGROUND OF THE INVENTION
[0001] The present invention relates to an endoscope system adapted to manage data of a plurality of endoscopes.
[0002] There are endoscopes provided with a solid state imaging device for capturing images inside human body. Such endoscopes, so called electronic endoscopes, are normally connected to a processor that transforms the output signals from the solid state imaging device into image signals so that output devices such as monitors and video printers can display or print the image captured by the solid state imaging device.
[0003] The endoscope is connected detachably to the processor so that the endoscope can be changed to a suitable type in accordance with the location of the human body to be inspected or treated with the endoscope. That is, the endoscope and the processor can be used in various combinations.
[0004] The endoscope is usually provided with a memory, such as an EEPROM, into which various kinds of data related to the endoscope are stored. Data stored into the memory includes, for example, type and serial number of the endoscope, and calibration data for adjusting the white balance of the image captured by the solid state imaging device. The calibration data for adjusting the white balance includes the amount of brightness increase/decrease of red and blue colors, which will be referred hereinafter as to “wb(r)” and “wb(b)”, respectively.
[0005] The endoscope type and serial number are read by the processor as the endoscope is connected to it to display them on, for example, the monitor. The calibration data for white balance, wb(r) and wb(b), are also read by the processor to adjust the white balance of the image generated in the processor based on the output signals from the solid state imaging device.
[0006] The white balance adjusting ability, however, are slightly different between each processor. Therefore, the processor often fails to achieve proper white balance by adjusting the colors merely in accordance with the calibration data obtained from the endoscope. In such case, proper white balance is achieved by performing manually a fine adjustment.
[0007] Recently, processors have been developed that are provided with a memory for storing the calibration data obtained as a result of the fine adjustment mentioned above. The calibration data is stored in the memory in association with data intrinsic to the endoscope such as serial number as a dataset like a database so that the processor can utilize the calibration data if the endoscope is connected and used again in the future. In this way, the processor eliminates the necessity of repetitive manual fine adjustment of the white balance.
[0008] The number of endoscopes, however, of which data can be registered to the memory of the processor is restricted because of the finite available memory space thereof. Thus, if there is not available memory space for storing data of a new endoscope, unimportant data such as that of old or seldom used endoscopes should be deleted manually to free up memory space. Such manual operation is a cumbersome task and may cause deletion of important data such as that of new or frequently used endoscopes for lack of proper care.
[0009] For example, there are endoscopes purchased and endoscopes leased for a certain term. The leased endoscopes, in particular, endoscopes leased for a short term tends to quickly increase the number of registered endoscopes until the memory is filled. The data of such leased endoscopes remain in the memory even after the leased term is over and prevent the registration of a new purchased endoscope of which data registration should take precedence to the that of leased endoscope's data.
[0010] Further, if the data filling the memory includes both data of purchased and leased endoscopes, the manual operation for registering new endoscope data may cause deletion of purchased endoscope data instead of data of the endoscope leased in the past and already returned.
SUMMARY OF THE INVENTION
[0011] The present invention provides the advantage in that, in an endoscope system, new endoscope data is automatically registered in a database of endoscopes' data without requiring cumbersome manual operation even if the database is full.
[0012] An endoscope system according to an aspect of the invention includes a processor connectable to various endoscopes to process signals generated by the endoscope being connected via a connector. The processor includes a database, a data selector and a data register. The database is configured to be registered a plurality of pieces of endoscope data, each of which being related to different one of the endoscopes connectable to the connector. Each piece of the endoscope data includes priority information indicating the priority of deleting the piece of endoscope data. The data selector selects one piece of the endoscope data based on the priority information. The data register registers a new endoscope with the database by replacing the selected piece of endoscope data with the piece of endoscope data of the new endoscope.
[0013] Thus, even if there isn't any available storage space in the database, the endoscope system can register a new endoscope with the database without deleting data of relatively important endoscopes.
[0014] Optionally, the priority information includes the date of when the piece of endoscope data is registered with the database. In this case, the priority information may include the date of when the endoscope is connected to the processor for the first time as the date of when the piece of endoscope data is registered with the database.
[0015] Optionally, the priority information includes the date of when the endoscope is used for the last time. In this case, the priority information may include the date of when the endoscope is connected to the processor for the last time as the date of when the endoscope is used for the last time.
[0016] In the above two optional cases, the data selector may select the piece of endoscope data related to the priority information including the oldest date, since such data may be related to old endoscopes or endoscopes seldom used.
[0017] According to another aspect of the invention, an endoscope system is provided which has an endoscope and a processor to be connected to the endoscope to process signals generated by the endoscope. The processor includes, a storage device, a data receiver, a database selector, and a data register. The storage device includes a plurality of databases. The data receiver receives first and second data related to the endoscope, the second data includes information on the property of said endoscope. The database selector selects one of the databases in the storage device based on the second data. The data register registers the endoscope with the selected database by storing at least the first data into the selected database so that the endoscope is registered with the database corresponding to the property of the endoscope.
[0018] Each of said plurality of databases may be defined in a different data file, or in a different single continuous storage area of said storage device.
[0019] Optionally, the data register is adapted to store priority information of the endoscope into the selected database in association with the first data. In case the selected database does not have available storage space for storing the first and second data, the data register selects one of the first and second data previously stored in the database based on the priority information to replace it with the first and second data received by the data receiver.
[0020] The priority information may include the date of when the endoscope data is stored into the selected database. For example, the priority information includes the date of when the endoscope is connected to the processor for the first time as the date of when the endoscope data is stored into the selected database.
[0021] Alternatively, the priority information may include the date of when the endoscope is used for the last time. For example, the priority information includes the date of when the endoscope is connected to the processor as said date of when the endoscope is used for the last time, which is updated when the endoscope is connected to the processor.
[0022] In the case the priority information includes the date described above, the data register may select the endoscope data related to the priority information including the oldest date.
[0023] Optionally, the processor further includes a text information generator for displaying text information on an monitor connected to the processor. The text information generator generates the text information on the property of the endoscope based on the second data. The text information generator displays the text information on the monitor when the endoscope is in use. Therefore, the operator using the endoscope can confirm the property of the endoscope on the monitor.
[0024] The data register may store the second data into the selected database in association with the first data, so that the text information generator can obtain the second data from the selected database when the endoscope is in use and display the text information.
[0025] The processor may include a video signal generator which generates video signal from output signals of an imaging device provided to the endoscope. The video signal generator may generate that video signal as the endoscope is connected to the processor to display an image captured by the imaging device on the monitor at the same time the text information is displayed. The endoscope information may be superimposed on the image captured by the imaging device.
[0026] The data receiver may receive the first and second data from a memory provided to the endoscope.
[0027] Alternatively, the data receiver may receive the first data from a memory provided to the endoscope while the second data from an input unit which can be manually operated by an operator.
[0028] Optionally, the second data includes information on the ownership of the endoscope. For example, the second data includes information on whether or not the endoscope is purchased. Alternatively, the second data includes information on whether or not the endoscope is leased. In the later case, the second data may include information on whether or not the endoscope is leased for a term longer than a predetermined term.
[0029] The first data may include information for adjusting white balance of an image captured by an imaging device provided to the endoscope.
BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS
[0030] [0030]FIG. 1 schematically shows the configuration of an electronic endoscope system according to an embodiment of the invention;
[0031] [0031]FIG. 2 shows an exemplary format of the data in a memory provided to an electronic endoscope of the endoscope system of FIG. 1;
[0032] [0032]FIG. 3 shows an example of the content of the data stored in the memory of the electronic endoscope in FIG. 1;
[0033] [0033]FIG. 4 shows an exemplary structure of a database established in a memory of a processor shown in FIG. 1;
[0034] [0034]FIG. 5 is a flow chart showing the main routine related to the operation of the processor according to first embodiment of the invention;
[0035] [0035]FIG. 6 is a flow chart showing a subroutine DISPLAY SCOPE NAME called in the main routine shown in FIG. 5;
[0036] [0036]FIG. 7 is a flow chart showing a subroutine FILE OPEN called in the main routine shown in FIG. 5;
[0037] [0037]FIG. 8 is a flow chart showing a subroutine ENDOSCOPE REGISTRATION called in the main routine in FIG. 5;
[0038] [0038]FIG. 9 is a flow chart showing a subroutine DISPLAY DATE & TIME in the main routine shown in FIG. 5;
[0039] [0039]FIG. 10 is a flow chart showing a subroutine ADJUSTMENT in the main routine shown in FIG. 5;
[0040] [0040]FIG. 11 shows a modification of the flow chart shown in FIG. 8;
[0041] [0041]FIG. 12 schematically shows an address map of the memory 208 in which two areas are defined for storing endoscope data as second embodiment of the invention;
[0042] [0042]FIG. 13 shows a modification of the flow chart shown in FIG. 7:
[0043] [0043]FIG. 14 shows a modification of the flow chart shown in FIG. 8.
DETAILED DESCRIPTION OF THE EMBODIMENTS
[0044] Hereinafter, an embodiment of the invention will be described with reference to the accompanying drawings.
[0045] [0045]FIG. 1 schematically shows the configuration of an electronic endoscope system 1 according to an embodiment of the invention.
[0046] The electronic endoscope system 1 includes an electronic endoscope 100 , and a processor 200 for processing signals from the electronic endoscope 100 .
[0047] The electronic endoscope 100 includes an flexible inserting tube 110 to be inserted into a human body and an operation portion 120 connected to the proximal end of the inserting tube 110 . The electronic endoscope 100 further includes a connector 130 which is detachably connected to the processor 200 .
[0048] A solid state imaging device such as a CCD 104 and an objective optical system 101 for forming an optical image on a light receiving surface of the CCD 104 are provided to the distal end portion of the inserting tube 110 .
[0049] Further, One or more operation buttons 107 are provided to the operation portion 120 for controlling the operation of the processor 200 .
[0050] Further, a memory such as an EEPROM 102 is provided to the electronic endoscope 100 for storing data related to the endoscope 100 , in particular, data intrinsic to each endoscope. In the present embodiment, the EEPROM 102 is located in the connector 130 .
[0051] The processor 200 includes a CPU 201 which is connected to the operation buttons 107 and the EEPROM 102 via an signal cable 108 of the endoscope 100 . The CPU 201 controls the operation of the processor 200 in accordance with the signals from the operation buttons 107 . The CPU 201 also accesses to the EEPROM 102 to retrieve data stored therein.
[0052] The CPU 201 is further connected to an input unit, such as a keyboard 400 , via an interface 212 , to control the operation of the processor 200 in accordance with the commands inputted through the keyboard 400 .
[0053] An operation panel 207 is provided to the processor 200 . A plurality of operation buttons (not shown) are arranged on the operation panel 207 at the portion exposed to outside of the case of the processor 200 . such that an operator of the endoscope system 1 can press each button. Each button outputs a signal to the CPU 201 , as being pressed, to control the operation of the processor 200 .
[0054] The processor includes a light source 203 optically connected to the end of a light guide 103 that is arranged throughout the electronic endoscope 100 from the connector 130 to the tip end of the inserting tube 110 . The light emitted from the light source 203 is transmitted through the light guide 103 to illuminate the area in front of the tip end of the inserting tube 110 .
[0055] An diaphragm 210 is provided on the light path of the light emitted from the light source 203 to restrict the amount of light introduced into the light guide 103 . An diaphragm controller 211 controls the opening size of the diaphragm 210 , or the amount of light introduced into the light guide 103 , in accordance with signals from the CPU 201 . The operator can freely control the opening size of the diaphragm 210 by operating the keyboard 400 or the operation panel 207 .
[0056] First and second signal processors 204 and 205 are provided to the processor 200 to display images captured by the CCD 104 on a monitor 300 . The first signal processor 204 receives the signal from the CCD 104 via a CCD signal cable 109 and transforms it into RGB digital image data represented in 256 levels of gray scale. The first signal processor 204 outputs the digital image data to the second signal processor 205 which generates video signal, such as NTSC, from the digital image data. The second signal processor 205 also adjusts the white balance of the video signal based on calibration data wr(r) and wr(b) received from the CPU 201 as will be described later. The second signal processor 205 outputs the video signal to the monitor 300 so that the monitor 300 displays the image captured by the CCD 104 .
[0057] Note that the output device to which the second signal processor 205 may be connected is not limited to the monitor 300 , however, the second signal processor 205 may also be connected to other kinds of output devices such as video printer, for example.
[0058] A CRT controller 206 is provided to the processor to superimpose text information on the image displayed on the monitor 300 . The CRT controller 206 generates video signals representing the text information, the patient information and so on, requested by the CPU 201 and output the video signals to the monitor 300 in synchronization with the video signal from the second signal processor 205 . In this way, the processor 200 superimposes arbitrary text information obtained from the CPU 201 on the image captured by the CCD 104 . The text information may include information obtained from the EEPROM 102 .
[0059] The processor 200 is also provided with a Real Time Clock (RTC) 209 and a memory 208 . The RTC 209 provides information on current date & time to the CPU 201 . The memory 208 is adapted to include one or more databases of data related to endoscopes, as will be described later.
[0060] [0060]FIG. 2 shows an exemplary format of the data in the EEPROM 102 , and FIG. 3 shows an example of the content of the data stored in the EEPROM 102 .
[0061] In the present embodiment, the storage capacity of the EEPROM 102 is 16 bytes. The following information are stored in the EEPROM 102 in the following order.
[0062] 1) “serial no.” (three bytes): the serial number of the electronic endoscope 100 which is unique for each endoscope. The “serial no.” may be set to one of values from 1 through 16777215 (0×1 through 0×ffffff hexadecimal digit).
[0063] 2) “scope name” (six bytes): six alphanumeric characters representing the type of the electronic endoscope 100 .
[0064] 3) “wb(r)” (one byte) a calibration value of the red color brightness for adjusting white balance of the image captured by the CCD 104 .
[0065] 4) “wb(b)” (one byte): a calibration value of the blue color brightness for adjusting white balance of the image captured by the CCD 104 . Both “wb(r)” and “wb(b)” can take a value between −128 and 127. As shown in FIG. 3, “wb(r)” and “wb(b)” are respectively set to −4 and 10 (0×7c and 0×8a in hexadecimal digit) in the present embodiment. This indicates that the brightness of red color should be decreased by four levels in gray scale, while the brightness of blue should be increased by ten levels.
[0066] 5) “ownership” (one byte): a variable representing whether the endoscope is purchased or leased. “ownership”=0, 1 and 2 (0×0, 0×1, and 0×2 in hexadecimal digit) respectively represents the endoscope is purchased, leased for a long term (a term not less than 30 days, for example), and leased for a short term (term less than 30 days, for example).
[0067] 6) “spec” (one byte): a variable representing the specification of the electronic endoscope 100 . If the electronic endoscope 100 is a standard type, then “speck” is set to 0. If the electronic endoscope is a custom made endoscope, then “spec” is set to a value corresponding to the particular specification. In the present embodiment, “spec” is set to 1 which indicates the optical system 101 includes a lens applied with special coatings.
[0068] 7) “expiration” (three bytes): the expiration date of the lease of the electronic endoscope 100 . The first one byte of “expiration” indicates the year, the next one the month, and the last one the day. In the example shown in FIG. 3, value 040331 is assigned to “expiration” which indicates the expiration of the lease is Mar. 31, 2004. If the electronic endoscope 100 is a purchased one, then 000000 is assigned to “expiration”.
[0069] Among the items recited above, the “serial no.”, “scope name”, “ownership”, and “expiration”are examples of information for managing endoscopes, while “wb(r)”, “wb(b)”, and “spec” are examples of information representing the characteristics of endoscopes.
[0070] The data of EEPROM 102 are copied to the memory 208 of the processor 200 as the electronic endoscope 100 is connected to the processor 200 for the first time to register the endoscope to one of the database.
[0071] [0071]FIG. 4 shows an exemplary structure of the database established in the memory 208 of the processor 200 . The memory 208 -is operated by the CPU 201 such that it includes at least two data aggregates each of which being defined to correspond to a specific condition of the endoscopes. In the present embodiment, two data files of CSV format, for example, are established in the memory 208 as two data aggregates. One of the data file, “file-0”, is defined to register data related to purchased endoscopes, or endoscopes of which “ownership” is set to 0, while the other data file, “file-1”, is defined to register data related to leased endoscope, or endoscopes of which “ownership” is set to 1 or 2.
[0072] It should be noted, however, that the memory 208 may also include three data files, and utilize the first one for registering data related to purchased endoscopes, the second one for registering data related to endoscopes leased for long term (“ownership”=1), and the third one for registering data related to endoscopes leased for short term (“ownership”=2).
[0073] Each data file includes 39 records and each record is defined for storing data related to one specific endoscope. Thus, data of 39 endoscopes can be stored in each of the data files.
[0074] Each record includes the following items in the following order,
[0075] 1) “register no.”,
[0076] 2) “scope name”
[0077] 3) “serial no.”,
[0078] 4) “wb(r)”,
[0079] 5) “wb(b)”,
[0080] 6) “ownership
[0081] 7) “spec”,
[0082] 8) “expiration”,
[0083] 9) “registered date & time”,
[0084] 10) “used date & time”,
[0085] 11) “count”.
[0086] “register no.” is utilized for identifying the record. In the present embodiment, a serial number from 1 to 39 is assigned to the records.
[0087] “scope name”, “serial no.”, “wb(r)” and “wb(b)”, “ownership”, “spec”, and “expiration”, are items same as that in the EEPROM 102 .
[0088] “registered date & time” is the date and time when the electronic endoscope 100 is connected to the processor 200 for the first time. “registered date & time” includes six figures date information and four figures time information. If “registered date” is set to “001015.1424”, for example, then it represents Oct. 15, 2000, 2:24 p.m.
[0089] “used date & time” is the date and time when the electronic endoscope 100 was connected to the processor 200 , or used, for the last time. The format of “used date & time” is same as that of “registered date & time”
[0090] “count” is the number of times the electronic endoscope 100 is connected to the processor 200 , or used. This variable may be used as an indication of the frequency in use of the endoscope.
[0091] [0091]FIG. 5 is a flow chart showing the main routine related to the operation of the processor 200 according to first embodiment of the invention.
[0092] At first, the CPU 201 of the processor 200 initializes a variable “current_scope” to 0 (S 100 ). The variable “current 13 scope” is for storing the “register no.” of the record in which the data of the endoscope currently connected to the processor 200 are stored. If 0 is assigned to “current_scope”, it represents that no endoscope is currently connected to the processor 200 .
[0093] After the initialization of “current_scope”, the CPU 201 waits until the electronic endoscope 100 is connected to the processor 200 if there isn't any (S 102 ).
[0094] If the electronic endoscope 100 is connected to the processor 200 (S 102 : Yes), the CPU 201 accesses to the EEPROM 102 of the electronic endoscope 100 and obtains the data stored therein (S 104 ). Next, the first and second signal processors transform the output signal from the CCD 104 into video signal to display the image captured by the CCD (S 106 ).
[0095] Then, the CPU 201 displays the “scope name” of the currently connected electronic endoscope 100 on the monitor 300 (S 108 ). Further, the CPU 201 opens one of the data files in the memory 208 (S 11 O), and then stores the data obtained from the EEPROM 102 therein (S 112 ).
[0096] Next, the white balance of the image captured by the CCD 104 of the electronic endoscope 100 is adjusted using the calibration value (“wb(r)”, “wb(b)”) obtained form the EEPROM 102 (S 114 ). That is, the CPU 201 sends the calibration value of “wb(r)” and “wb(b)” to the second signal processor 205 so that the second signal processor 205 adjusts the color balance of the image signals generated there.
[0097] After S 114 , the processor watches whether the endoscope 100 is still connected, and as long as the electronic endoscope 100 is still connected to the processor 200 (S 116 :Yes), the processor 200 displays the current date and time on the monitor 300 (S 118 ), and also performs various kinds of adjustments in accordance with manual operation by the operator (S 120 ).
[0098] If the electronic endoscope 100 is disconnected from the processor 200 , the CPU 201 closes the file opened in S 110 (S 122 ). After S 122 , the operation of the processor 200 goes back to S 100 .
[0099] [0099]FIG. 6 is a flow chart showing a subroutine DISPLAY SCOPE NAME called in S 108 of the main routine shown in FIG. 5.
[0100] In scope name displaying routine, the CPU 201 first decides whether the currently connected endoscope is a purchased one or a leased one. This is done by checking the value of “ownership” obtained from the EEPROM 102 (S 152 ).
[0101] If “ownership” indicates the endoscope is purchased, i.e., “ownership”=0, then CPU 201 sends the alphanumeric characters of the “scope name” obtained from the EEPROM 102 to the CRT controller 206 to superimpose the type of the electronic endoscope 100 on the image captured by the CCD 102 and displayed on the monitor 205 (S 154 ).
[0102] If “ownership” indicates the endoscope is leased, i.e., “ownership”=1 or 2, then the CPU 201 sends the characters indicated by “scope name” together with characters “leased” to the CRT controller to superimpose those characters on the image displayed on the monitor 300 (S 156 ). After the execution of S 154 or S 156 , the operation of the processor 200 returns to the main flow shown in FIG. 5.
[0103] [0103]FIG. 7 is a flow chart showing a subroutine FILE OPEN called in S 110 of the main routine shown in FIG. 5. In this routine, the CPU 201 selects the data file, or database, for storing the data of the electronic endoscope 100 in accordance with the ownership of the electronic endoscope 100 .
[0104] That is, the CPU 201 checks the state of “ownership” obtained from the EEPROM 102 (S 172 ). IF “ownership” is 0, indicating the endoscope is purchased, then the CPU 201 select the data file “file-0” by substituting the file name into a character string “file name” (S 174 ). If “ownership” is 1 or 2, indicating the endoscope is leased, then the CPU 201 selects the data file “file-1” (S 176 ). After the selection of the data file, the CPU 201 accesses the memory 208 and opens the data file specified by “file name”.
[0105] It should be noted that the data file to be opened may also be determined based on information of “scope name”, “spec” and/or “expirations” of the endoscopes. Further, the data file to be opened may be determined based on information manually Inputted through input units such as the keyboard 400 , instead of the data obtained from the EEPROM 102 .
[0106] [0106]FIG. 8 is a flow chart showing a subroutine ENDOSCOPE REGISTRATION called in S 112 of the main routine of FIG. 5.
[0107] In this routine, the CPU 201 decides whether or not the data related to the currently connected endoscope is already registered with the memory 208 (S 202 ). This is achieved by searching within the data file opened in S 110 for a record including data that matches the “scope name” and “serial no.” obtained from the EEPROM 102 .
[0108] If there is a record including the above mentioned data (S 202 :Yes), it means the data of the electronic endoscope 100 currently connected is already registered with the memory 208 . In this case, the “register no.” of the record found is set to “current_scope” (S 204 ) and the operation of the processor 200 proceeds to S 220 which will be described latter.
[0109] If a record including the above mentioned data is not found, it means the electronic endoscope 100 is not yet registered (S 202 :No). In this case, the CPU 201 checks whether there is still any available memory space, or open records, in which the data except for the “register no.” are empty, within the data file to register the data obtain from the EEPROM 102 (S 206 ).
[0110] In the case where there is still an open record (S 206 :Yes), the “register no.” of the open record is set to “current scope” (S 208 ). If there are more than one open records, the smallest “register no.” is preferably selected and set to the “current scope”. After execution of S 208 , the operation of the processor 200 proceeds to S 216 which will be described later.
[0111] In the case where no open record is found (S 206 :No), then the “register no.” of the record including the oldest “registered date & time” is specified (S 210 ), and the data of the record identified by the specified “register no.” is deleted, except for the “register no”, to free up the record (S 212 ). Further, the specified “register no.” is set to “current_scope” (S 214 ).
[0112] After the execution of S 208 or S 214 , the CPU 201 stores the data obtained from EEPROM 102 , or the data of currently connected electronic endoscope 100 , into the record identified by the register number in “current_scope” (S 216 ).
[0113] Specifically, the CPU 201 stores “serial no.”, “scope name”, “wb(r)”, “wb(b)”, “ownership”, “spec”, and “expiration” obtained from the EEPROM 102 into the record. In this manner, the data of the new endoscope is automatically registered with the database.
[0114] Next, the CPU 201 obtains the current date and time information from the RTC 209 and stores it in “registered date & time” of the record specified by “register no.” (S 218 ). This is to make a record of the date and time of registration of the new electronic endoscope 100 ,
[0115] After the execution of S 218 or S 204 , “used date & time” and “count” of the record specified by “current scope” are updated. That is, the current time information obtained from the RTC 209 is overwritten to “used date & time” (S 220 ), and “count” is incremented by one (S 222 ). After S 222 , the operation of the processor 200 returns to the main flow shown in FIG. 5.
[0116] [0116]FIG. 9 is a flow chart showing a subroutine DISPLAY DATE & TIME in S 118 of the main routine shown in FIG. 5.
[0117] In this routine, the CPU 201 checks whether or not the date and time information of a variable “date & time” indicates the exact time by comparing “date & time” with the date and time information from the RTC 209 (S 242 ).
[0118] If the difference between the two pieces of the date and time information is less than a second, then the CPU 201 decides the two pieces of the date and time information are same (S 242 :Yes). In this case, the operation of the processor 200 immediately returns to the main flow of in FIG. 5 without updating the “date & time”.
[0119] If the difference between the two date and time information is not less that one second (S 242 :No), then the date and time information from the RTC 209 , or the current date and time, is set to “date & time” (S 244 ). Then, the CPU 201 generates text information indicating the date and time stored in “date & time” such as “May 21, 2002, 15:20:31”, for example, and sends it to the CRT controller 206 to superimpose the current date and time on the image displayed by the monitor 300 (S 246 ). In this manner, time information displayed is updated every second.
[0120] After the execution of S 246 , the operation of the processor 200 returns to the main flow shown in FIG. 5.
[0121] [0121]FIG. 10 is a flow chart showing a subroutine ADJUSTMENT in S 120 of the main routine shown in FIG. 5. This routine is for allowing the operator to manually adjust the white balance of the image captured by the CCD 104 , and the opening size of the diaphragm 210 .
[0122] In this routine, the CPU 201 decides whether or not the adjustment of white balance is requested by checking the signals from the keyboard 400 , the operation panel 207 , and the operation buttons 107 (S 262 ). If there is a request (S 262 :Yes), then the CPU 201 rewrites the value of the “wb(r)”, “wb(b)” in the record specified by “current scope” in accordance with the signal from the keyboard 400 , the operation panel 207 , or the operation buttons 107 (S 264 ). Further, the CPU 201 sends the value of latest “wb(r)” and “wb(b)” to the second signal processor 205 so that the second signal processor 205 re-adjusts the white balance of the image generated there (S 266 ).
[0123] After the execution of S 266 or in the case there isn't any request for white balance adjustment (S 262 :No), the CPU 201 checks again the output signals from the keyboard 400 , the operation panel 207 , and the operation buttons 107 to decide whether or not the adjustment of diaphragm is requested (S 268 ).
[0124] If there is a request (S 268 :Yes), then the CPU 201 opens/closes the diaphragm 210 , via the diaphragm controller 211 , in accordance with the request from the keyboard 400 , the operation panel 207 , or the operation buttons 107 to control the amount of light introduced into the light guide 103 (S 270 ).
[0125] If there isn't any request (S 268 :No), the operation of the processor returns to the main flow of FIG. 5.
[0126] It should be noted that the operation of processor 200 described in FIG. 5 through FIG. 10 may be modified in many ways within the scope of the invention.
[0127] For example, S 210 in the subroutine ENDOSCOPE REGISTRATION shown in FIG. 8 may be replaced with a step that specifies the “register no.” of the record including the oldest “used date & time” as shown in FIG. 11 (see S 210 *). If S 210 is replaced with S 210 *, the data related to the endoscope not used recently, and may have the lowest possibility to be used again in the future, is deleted to free up memory space for registering data of the new endoscope. Further, S 212 in FIG. 8 may also be canceled if data is overwritten in S 214 through S 216 .
[0128] The manner of managing the data in the memory 208 may also be modified in many ways. For example, a plurality of areas may be defined within one data file of the memory 208 , and data of the electronic endoscope 100 may be registered in the area corresponding to the feature of the electronic endoscope 100 indicated by “ownership”, “spec”, and/or “expiration”, or any data inputted manually into the keyboard 400 .
[0129] [0129]FIG. 12 schematically shows an address map of the memory 208 in which two data areas are defined in one data file as second embodiment of the invention. As shown in FIG. 12, the memory 208 includes a data file 216 , and first and second data areas 220 a and 220 b are defined within the data file 216 . The first data area 220 a extends from address 0 to 1499 (in decimal system), and the second data area 220 b from address 1500 to 2999 (in decimal system). Each of first and second data areas 220 a and 220 b includes 39 records having same format as that shown in FIG. 4. The first and second data areas 220 a and 220 b are for registering data related to purchased endoscopes and leased endoscopes, respectively.
[0130] If the memory 208 is managed as shown in FIG. 12, S 110 and S 112 of FIG. 5 should be modified as shown in FIG. 13 and 14 .
[0131] That is, in the subroutine FILE OPEN (S 110 ), the CPU 201 opens the data file 216 (S 302 ). Next, the CPU 201 checks the state of “ownership” obtained from EEPROM 102 (S 304 ). If “ownership” is 0 (S 304 :Yes), indicating the endoscope is purchased, then the CPU 201 sets a variable “offset” to 0 (S 306 ). “Offset” is used later as an address start to reading the memory 208 . If “ownership” is 1 or 2, indicating the endoscope is leased, then the CPU 201 sets “offset” to 1500. After the execution of S 306 or S 308 , the operation of the processor 200 returns to the main flow shown in FIG. 5 to execute the subroutine ENDOSCOPE REGISTRATION (S 112 ).
[0132] In the subroutine ENDOSCOPE REGISTRATION (S 112 ) shown in FIG. 14, S 202 , S 206 , S 208 , and S 210 are replaced with S 202 *, S 206 *, S 208 *, and S 210 *, respectively. Other steps are same as that in FIG. 8.
[0133] The contents of S 202 *, 206 *, S 208 *, and S 220 * are same as that of the replaced steps except that the memory area that the CPU 201 can treat is limited to the address “offset” through “offset”+1499. That is, if “offset” is set to 0 in the subroutine FILE OPEN (S 110 ), then the CPU 201 can read, write, and delete data only within the first data area 220 a of the memory 208 , and if “offset” is 1500, then the CPU 201 can handle the data only in the second data area 220 b . Accordingly, if a new leased endoscope, for example, is connected to the processor 200 , the CPU 201 never accesses to the first data area 220 a , and thus never deletes data of purchased endoscopes, which may be more important than data of leased endoscopes, in order to register leased endoscopes' data.
[0134] The present disclosure relates to the subject matters contained in Japanese Patent Application No. P2001-200209, filed on Jun. 29, 2001, and Japanese Patent Application No. P2001-323463, filed on Oct. 22, 2001, which are expressly incorporated herein by reference in their entireties. | 1a
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FIELD OF THE INVENTION
The herein disclosed invention finds applicability in the field of therapeutic devices used to free-up stiff muscles and stiff joints. In particular, the invention is directed to relieving the effects of carpal tunnel syndrome.
BACKGROUND OF THE INVENTION
A moderately active individual makes thousands of different hand movements in a single day. Such activity may lead to repetitive strain injuries, such as carpal tunnel syndrome (CTS), in which the tendons and ligaments in the carpal tunnel swell and compress nerves, resulting in hand numbness.
The increase of computer keyboards in offices and homes has created a dramatic increase in the number of repetitive strain injuries such as carpal tunnel syndrome. Carpal tunnel syndrome (CTS) is believed to be caused by compression of the median nerve resulting from a swelling of tendons and sheaths. Swelling of the tendons in the carpal tunnel reduces circulation to the hands causing numbness and pain. It is well known that a person who performs repetitive motions with his hands might develop a repetitive stress injury such as carpal tunnel syndrome.
Individuals who spend extended periods of time with their wrist in a flexed condition may develop CTS. A major cause of CTS is the continuous flexing of the wrist which is particularly common amongst individuals who spend long periods of time at keyboards, whether such keyboards be associated with computers per se, or with cash registers or other such devices. Such flexing is generally accompanied by pronation of the hand, i.e., holding the palm in a downward facing position, which further strains the connective tissue and nerves running through the carpal tunnel. Musicians are also subject to CTS, CTS itself is caused by compression of the median nerve, which runs through the wrist and branches into the palm, thumb and first three fingers. The median nerve runs through a bony structure which is identified as the carpal tunnel. The flexor tendons and the carpal ligament in the carpal tunnel may swell due to repetitive hand movements, pinching the medial nerve and producing the condition known as CTS. CTS generally results in an inability effectively to grip with the hands, and is usually accompanied by a tingling and numbness in the fingers.
The herein disclosed invention is designed to provide a therapy device for relieving the effect of carpal tunnel syndrome; and to bring flexibility to the hand and wrist as soon as possible.
BRIEF SUMMARY OF THE INVENTION
The Dynasplint™ carpal tunnel therapy device of this invention is a mechanical device for applying pressure at three points by means of a graded tensioning mechanism to create an “opening” or spread of the carpal tunnel, thereby, relieving stress and compression of the median nerve. Pressure is applied for relatively prolonged periods of time with a graded increase of pressure to allow for the relief of pressure on the median nerve which is being impinged, producing symptoms associated with carpal tunnel syndrome. The carpal tunnel therapy device is unique in being able to adjust for the degree of tension to be applied to the hand to relieve pressure on the nerve.
The Dynasplint Carpal Tunnel Syndrome (CTS) System is designed to treat, a disorder marked by compression of the carpal tunnel region in the wrist. CTS is a disabling wrist/hand condition usually involving tightening of the transverse carpal ligament causing compression of the median nerve, artery and vein. Signs and symptoms of numbness, tingling, burning and muscle weakness can occur.
CTS can be very disabling often resulting in partial loss of the use of the hand. Treatment frequently consists of surgical release of the transverse carpal ligament with weeks of recovery needed. Often times physical therapy is employed both pre- and post operatively.
The success rate for treatment of CTS has varied greatly. Even with surgery, many patients are left with continued weakness and/or paresthesias. Occupations involving hand use, ranging anywhere from secretarial duties such as typing and writing to the carpenter's need to use a screwdriver can cause CTS and be difficult for the patient to resume normal activity once this disabling condition develops. CTS has an etiology associated with repetitive trauma syndrome (RTS), which occurs when relatively minor traumas occur many times over a period of weeks or months. The cumulative stress then causes the tissue around the carpal tunnel to shrink and tighten (forming a contracture) which in turn compresses the enveloped tissues (median nerve, vein and artery). This compression then “cuts off” the vitally important nerve conductivity and blood flow which in turn results in the disabling muscle weakness of the thumb, index and middle fingers and causes paresthesias of the same digits plus the radial side of the 4 th digit.
The purpose of the Dynasplint CTS system is to restore the normal length of the transverse carpal ligament and other associated surrounding tissues so that the median nerve, vein and artery have less compression which then allows freer blood flow and improved nerve conductivity. This compressive relief can then lead to abatement of paresthesias, improved muscle strength and overall improved hand function thereby allowing return to work and other activities.
The CTS System is designed to be used for 30-60-minute sessions, 1-3 times per day with low tension progressing as tolerated to higher levels of tension. Total duration of wear may be up to three months or longer but frequently less time of wear will be curative.
Prior Art Patents
Taylor (U.S. Pat. No. 6,010,431) teaches an exercise device for relieving carpal tunnel syndrome by pushing down of the hand to urge apart opposite sides of the palm to thereby relieve compression on the blood vessels and nerves.
Anliker (U.S. Pat. No. 5,613,923) teaches a device for treating repetitive strain injury which employs a glove, a resilient member and an anchor mechanism, wherein the user's fingers and thumb are extended. In actual use the user's fingers and wrist are extended; and the user's fingers and thumb are abducted. The user encounters resistance, exercising the extensor muscles of the fingers, hand, wrist and elbow, thereby relieving carpal tunnel syndrome.
Washburn (U.S. Pat. No. 5,551,933) teaches a hand-held device with a bead on a series of loops serving as a track for the bead. The bead is moved along the track by wrist-motion. This wrist motion exercises the wrist, thereby relieving carpal tunnel syndrome.
Gibney (U.S. Pat. No. 5,492,525) and (U.S. Pat. No. 5,366,436) teaches an exercise device to treating symptoms related to carpal tunnel syndrome. The thumb fingers are inserted into the device; and the thumb and fingers are stretched away from each other. This exercise is designed to relieve carpal tunnel syndrome.
Charles (U.S. Pat. No. 5,514,052) teaches a finger exerciser to relieve carpal tunnel syndrome. The device can retain the fingers and can apply tension to the fingers by means of tension stays which apply tension to elastic cords. By stretching the fingers and strengthening extensor muscles of the wrist, hand and fingers, the ill-effects of carpal tunnel syndrome are alleviated.
None of the prior art cited shows a graded tensioning mechanical device such as described by this invention for treating carpal tunnel syndrome.
OBJECTS OF THE INVENTION
A main object of the invention is to efficiently treat carpal tunnel syndrome.
A further object of this invention is to produce a therapy device which will allow for rapid rehabilitation of stiff fingers and hand.
Another object of this invention is to produce a device with a tension mechanism which is adjustable to produce greater or lesser tension-pressure or force on the hand as required.
Other objects of the present invention will become apparent from a reading of the following specification taken in conjunction with the enclosed drawings.
These and other objects of the present invention will become apparent from a reading of the following specification taken in conjunction with the enclosed drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of the carpal tunnel syndrome therapy device.
FIG. 2 is a front plan view thereof.
FIG. 3 is a left side elevational view thereof.
FIG. 4 is a front plan view of the drive assembly for the carpal tunnel syndrome therapy device.
FIG. 5 is a cross-section taken along 5 — 5 of FIG. 4 .
FIG. 6 is top plan view of the drive assembly for the carpal tunnel syndrome therapy device.
FIG. 7 is a cross-section thereof taken along 7 — 7 of FIG. 6 .
FIG. 8 is a view of the chisel tip and indicator gauge assembly of the tensioning mechanism used in the carpal tunnel syndrome therapy device.
FIG. 9 is a view of indicator gauge assembly of the device shown in FIG. 8 turned 90°.
FIG. 10 is a perspective view of the housing head, tube and yoke sub-assembly of the therapy device.
FIG. 11 is a perspective view of a stem rod yoke to rod and joint sub-assembly of the therapy device.
FIG. 12 is a sectional view of the counterforce taken along 12 — 12 of FIG. 2 .
FIG. 13 is an exploded view showing the plunger release assembly.
FIG. 14 is a front plan view of the left side foot yoke and bracket.
FIG. 15 is a sectional view of the foot yoke taken along 15 — 15 of FIG. 14 .
FIGS. 16-21 are views illustrating the components of the foot yoke and the order for assembling and placement on the bracket.
FIGS. 22 and 23 are a side plan view and an end view of the torsion spring used in the foot yoke assembly.
FIG. 24 is a front plan view of the spread connector attached to the brackets of the carpal tunnel therapy device.
FIG. 25 is a sectional view thereof taken along 25 — 25 of FIG. 24 .
FIGS. 26-30 illustrate the components of the spread connector and the order for assembly of the spread connector.
FIGS. 31A-31E are a sequence for using the carpal tunnel therapy device.
DESCRIPTION
With reference to FIGS. 1 to 3 a carpal tunnel syndrome therapy device 10 is provided with carpal pads 12 and a counter force pad 14 . The carpal pads 12 are supported on a pair of carpal foots 16 which in turn are attached to a pair of carpal foot yokes 18 . The counter force pad is attached to a counter force foot 20 which in turn is attached to a pair of counter force brackets 22 . The counter force brackets 22 are joined at the top by a bracket bar 23 and joined at the bottom by a counter force foot 20 .
The carpal tunnel therapy device is provided with a drive assembly 24 (shown in detail in FIGS. 4-11 ) which is attached to a pair of carpal tunnel brackets 26 , by way of housing tube yoke 28 and stem rod yoke 30 (FIGS. 1 and 2 ). As best shown in FIGS. 4-12 , there is a drive assembly having a stem rod 36 attached to a main joint 34 which is inserted into a housing tube head 35 attached to a housing tube 38 and at the end of the housing tube there is disposed a loading screw knob 40 attached to loading screw 42 .
FIGS. 4-7 are views of the drive assembly 24 . The tension mechanism is contained in a housing tube 38 and has a loading screw knob 40 and loading screw 42 which presses an indicator bar 52 and spring spacer 60 as best shown in FIGS. 8 and 9 . With particular reference to FIGS. 8 and 9 , the compression spring 44 fits over the spring spacer 60 onto bottom support 64 of the spring spacer 60 and chisel tip 50 fits inside and over the compression spring 44 . In turn, the chisel tip 50 abuts the keeper 37 of the main joint 34 joined to stem rod 36 . Main joint 34 assembly is housed in housing head 35 .
With special reference to FIGS. 6-7 , there is shown a sectional view, taken along lines 7 — 7 of FIG. 6 , of the drive assembly 24 contained in the housing tube 38 , and main joint 34 , housing tube head 35 with stem rod 36 attached to joint 34 which abuts chisel tip 50 . Chisel tip 50 applies pressure to the joint 34 through compression spring 44 which in turn has pressure put on it through loading screw 42 and loading screw knob 40 . As the loading screw knob 40 and loading screw 42 are tightened, more and more pressure can be applied to the compression spring 44 which in turn exerts more pressure on the stem rod 36 . The force on stem rod 36 attached to stem rod yoke 30 produces a counter force on pad 14 to apply pressure to the top of the hand 41 shown in dashed lines in FIG. 1 . The amount of pressure is indicated by indicator screw head 54 and indicator marker 56 (best shown in FIG. 4 ). Note that the scale is 0-9 with 9 indicating maximum pressure for that setting.
In use the palm of the affected hand would be placed on pads 12 . The counter force pad 14 would be placed over the top of the hand using the variable height sub-assembly 69 best shown in FIGS. 12 and 13 . Once the counter force pad 14 is in place over the top of the hand, added pressure can be applied to the hand incrementally using loading screw knob 40 . A more detailed method of use and protocol are set forth below.
With particular reference to FIGS. 8 and 9 , an exploded view of the compression assembly 58 within the housing tube 38 is made up of two indicator bars 52 and a compression spring spacer 60 , compression spring 44 and chisel tip unit 62 composed of a chisel tip 50 and boss 63 . In operation the compression spring 44 is given tension by the loading screw 42 pressing against the bottom support 64 and the chisel tip 50 pressing against the main joint 34 in housing head 35 . The indicator bar 52 rises as the loading screw 42 presses on the bottom support 64 of spring spacer 60 of the compression assembly 58 . The compression mechanism is similar to that shown in U.S. Pat. No. 5,558,624.
With special reference to FIGS. 1 , 2 and 4 , there is shown as part of the housing tube 38 a viewing slot 68 showing indicator screw 54 . In FIG. 4 , the viewing slot 68 is accompanied by a scale 56 . The higher the number of the scale 56 , the higher will be the compression or tension on the stem rod 36 and the greater the pressure on the hand during therapy.
With particular reference to FIGS. 12 through 30 , various sub-assemblies of the carpal tunnel syndrome therapy device are described.
Counter Force Variable Height Adjustment Sub-assembly
With reference to FIGS. 1 , 2 , 12 and 13 , there is provided a variable height adjustment sub-assembly 69 for the counter force 70 consisting principally of the head 35 for the housing tube 38 the head being integrally capped 71 on a first end with a collar 72 which receives a spring plunger spring 73 and over which is placed a tapped spring plunger 75 which in turn receives a threaded spring plunger button 77 into the tapped end of the spring plunger 75 . The second end of the housing tube head 35 is provided with a removable plate cap 79 with collar 78 which receives a spring plunger spring 73 , a spring plunger 75 and a spring plunger button 77 . Housing tube head 35 and main joint 34 are joined and held in place by screw 76 . In use the variable height adjustment sub-assembly is mounted between two counter force brackets 22 which are provided with a contiguous series of scalloped detent openings 80 to receive the spring plunger 75 of the counter force sub-assembly. Note that spring plungers 75 have a collar 74 and the housing head 35 has a collar 72 and the plate cap 79 has a collar 78 in which each of the spring plunger springs 73 are retained.
To adjust the height of the counter force sub-assembly 70 , spring plunger buttons 77 on either side of the counter force sub-assembly are squeezed inward. This squeezing causes the spring plunger 75 and the spring plunger spring 73 to depress allowing narrower threaded portion 81 of spring plunger button 77 to line up with scalloped openings 80 allowing free movement up or down of counter force pad 14 held on counter force brackets 22 . Once the proper height is attained, the spring plunger buttons 77 can be released and the spring plunger spring 73 expands to cause the spring plunger 75 to re-engage the scalloped openings 80 in the counter force brackets 22 .
Foot Yoke Sub-assembly
With reference to FIGS. 1 , 2 and 14 - 23 , the pads 12 of the carpal tunnel syndrome therapy device 10 are attached to bracket 26 through foot yoke 18 . There are two symmetrical foot yoke sub-assemblies 84 . Each sub-assembly 84 is composed of a foot yoke 18 , a foot yoke pivot pin 86 , foot yoke torsion spring 88 , a lateral adjustment screw 90 and lateral adjustment screw housing 91 .
To assemble the foot yoke sub-assembly 84 to bracket 26 , foot yoke pin 86 is partially inserted into opening 85 of yoke as shown in FIGS. 16 and 17 . Bracket 26 with opening 95 (best shown in FIG. 24 ) is inserted into slot 83 and pin 86 is further inserted through opening 95 of bracket 26 . Spring 88 is then inserted into yoke 18 ( FIG. 18 ) and slot 87 of pin 86 is lined up with diametric fold 89 of spring 88 as best shown in cross-sectional view of FIG. 15 . Pin 86 is inserted further to protrude through opening 81 on the opposite side of yoke 18 . As shown in FIGS. 19 and 20 , lateral adjusting screw 90 is inserted through opening 59 into tapped hole 92 of the foot yoke pin 86 . The tangential tail 82 of spring 88 buts against the inner wall 53 of the foot yoke 18 to provide spring tension to the foot yoke. Once the yoke 18 is on the bracket 26 , the lateral adjusting screw housing can be attached with a fixed screw 98 or other securing means.
Adjusting lateral screw 90 provided in each yoke sub-assembly adjusts the pads 12 to accommodate the width of the palm of the hand.
Spring 88 serves to spring-load the yoke in an outward direction left and right, respectively and functions to counteract outward spreading that takes place when downward force is applied.
Spread Connector Sub-assembly
With reference to FIGS. 24-30 , the carpal tunnel syndrome therapy device is provided with spread connector 93 attached to brackets 26 to adjust the spread of the brackets and accordingly the pair of yokes 18 and pads 12 attached thereto. The main components of the spread connector assembly 93 are the spread connector outer tube 94 , spread connector spring 96 and spread connector inner tube 97 .
As shown in FIGS. 24-30 , the spread connector assembly 93 is made by inserting spring 86 over inner tube 97 ( FIGS. 26-28 ) and inserting both completely into outer tube 94 (FIGS. 29 and 30 ). The spread connector assembly is placed on bracket 26 through slots 65 and 67 and are held in place by a fixed screw 98 , of course other fasteners known in the art could be used.
The spread connector serves to adjust the spread or spacing of the brackets 26 and to spread or close to accommodate the spread of the carpal pads 12 . The spread connector also by virtue of the spring 96 holds the brackets inward and accordingly accomplishes presenting the carpal pads at the correct angularity at the initial fitting.
The stem rod 36 and housing tube 38 are attached to bracket 26 with stem rod yoke 30 held in place by a pivot pin 99 . Pivot pins 99 are also employed to position the spread connector assembly 93 on brackets 26 . While pivot pins have been used herein, other holding means such as rivets or bolts could be used.
With reference to FIGS. 31A-31E , there is shown the use of the carpal tunnel syndrome therapy device. As noted, at the start of therapy, the scale 56 is set at zero. The palm of the hand is placed on carpal pads 12 and the counter force pads 14 are placed over the top of the hand by using the variable height adjusting mechanism 69 (described in FIGS. 12 - 13 ). Once the hand is set between the carpal pad 12 and counter force pad 14 , pressure can be applied by using loading screw knob 40 (FIGS. 31 B and 31 C). On an on-going basis pressure is increased using loading screw knob 40 and the amount of pressure can be viewed in scale 56 . The amount of pressure indicated is graduated as see scale of 0-9, with 9 being the greater pressure. This pressure action is designed to further spread the carpal tunnel area.
The carpal tunnel therapy device is primarily intended to be a passive therapy device in that it is to be worn for extended periods of time to thereby relieve carpal tunnel area and thereby prevent invasive surgery.
In FIGS. 31A-31E , the vertical arrows show the height adjustment for the counter force pads 14 and the horizontal arrows show the direction of spread of the spread connector.
The therapy device of this invention is designed to be used 1-3 times a day for 30-60 minutes in each session. The treatment programs begin with lower pressure or tension on the device and progressing to higher pressure as tolerated to relieve the pain, stress, numbness brought about by the carpal tunnel syndrome.
Obviously, many modifications may be made without departing from the basic spirit of the present invention. Accordingly, it will be appreciated by those skilled in the art that within the scope of the appended claims, the invention may be practiced other than has been specifically described herein. | 1a
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CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of U.S. patent application Ser. No. 13/793,481, titled “Expandable Fusion Device and Method of Installation Thereof,” filed on Mar. 11, 2013, which is a continuation-in-part of U.S. patent application Ser. No. 12/875,637, entitled “Expandable Fusion Device and Method of Installation Thereof,” filed on Sep. 3, 2010 (now U.S. Pat. No. 8,845,731), the entire disclosure of both of which are incorporated by reference herein in their entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to the apparatus and method for promoting an intervertebral fusion, and more particularly relates to an expandable fusion device capable of being inserted between adjacent vertebrae to facilitate the fusion process.
BACKGROUND
[0003] A common procedure for handling pain associated with intervertebral discs that have become degenerated due to various factors such as trauma or aging is the use of intervertebral fusion devices for fusing one or more adjacent vertebral bodies. Generally, to fuse the adjacent vertebral bodies, the intervertebral disc is first partially or fully removed. An intervertebral fusion device is then typically inserted between neighboring vertebrae to maintain normal disc spacing and restore spinal stability, thereby facilitating an intervertebral fusion.
[0004] There are a number of known conventional fusion devices and methodologies in the art for accomplishing the intervertebral fusion. These include screw and rod arrangements, solid bone implants, and fusion devices which include a cage or other implant mechanism which, typically, is packed with bone and/or bone growth inducing substances. These devices are implanted between adjacent vertebral bodies in order to fuse the vertebral bodies together, alleviating the associated pain.
[0005] However, there are drawbacks associated with the known conventional fusion devices and methodologies. For example, present methods for installing a conventional fusion device often require that the adjacent vertebral bodies be distracted to restore a diseased disc space to its normal or healthy height prior to implantation of the fusion device. In order to maintain this height once the fusion device is inserted, the fusion device is usually dimensioned larger in height than the initial distraction height. This difference in height can make it difficult for a surgeon to install the fusion device in the distracted intervertebral space.
[0006] As such, there exists a need for a fusion device capable of being installed inside an intervertebral disc space at a minimum to no distraction height and for a fusion device that can maintain a normal distance between adjacent vertebral bodies when implanted.
SUMMARY
[0007] In an exemplary embodiment, the present invention provides an intervertebral implant. The intervertebral implant may comprise an upper endplate comprising a first upper endplate portion and a second upper endplate portion. The intervertebral implant may comprise a lower endplate comprising a first lower endplate portion and a second lower endplate portion. The intervertebral implant may comprise a front sloped actuator configured to movingly engage a front end of the upper endplate and a front end of the lower endplate. The intervertebral implant may comprise a rear sloped actuator configured to movingly engage a rear end of the upper endplate and a rear end of the lower endplate. The intervertebral implant may be configured to transition from a collapsed configuration having a first height and a first width to an expanded configuration having a second height and a second width.
[0008] In an exemplary embodiment, the present invention provides an intervertebral implant. The intervertebral implant may comprise an upper endplate. The upper endplate may comprise a first upper endplate portion comprising a front ramped surface and a rear ramped surface. The upper endplate may further comprise a second upper endplate portion comprising a front ramped surface and a rear ramped surface. The upper endplate may further comprise endplate pins connecting the first upper endplate portion and the second upper endplate portion. The intervertebral implant may further comprise a lower endplate. The lower endplate may comprise a first lower endplate portion comprising a front ramped surface and a rear ramped surface. The lower endplate may further comprise a second lower endplate portion comprising a front ramped surface and a rear ramped surface. The lower endplate may further comprise endplate pins connecting the first lower endplate portion and the second lower endplate portion. The intervertebral implant may further comprise a front sloped actuator configured to movingly engage the front ramped surface of the first upper endplate portion, the front ramped surface of the second upper endplate portion, the front ramped surface of the first lower endplate portion, and the front ramped surface of the second lower endplate portion. The intervertebral implant may further comprise a rear sloped actuator configured to movingly engage the rear ramped surface of the first upper endplate portion, the front ramped surface of the second upper endplate portion, the rear ramped surface of the first lower endplate portion, and the rear ramped surface of the second lower endplate portion. The intervertebral implant may be configured to transition from a collapsed configuration having a first height and a first width to an expanded configuration having a second height and a second width.
[0009] In another embodiment, the present invention provides a method of installing an intervertebral implant, the method comprising: introducing the intervertebral implant into an intervertebral space; and contracting an actuator assembly to cause the intervertebral implant to transition from a collapsed configuration having a first height and a first width to an expanded configuration having a second height and a second width.
[0010] In another embodiment, the present invention provides an intervertebral implant. The intervertebral implant may comprise an upper endplate comprising a first upper endplate portion and a second upper endplate portion. The intervertebral implant may further comprise a lower endplate comprising a first lower endplate portion and a second lower endplate portion. The intervertebral implant may further comprise an actuator assembly disposed between the upper endplate and the lower endplate, the actuator assembly being configured to movingly engage front ends of the upper endplate and the lower endplate and also movingly engage rear ends of the upper endplate and the lower endplate. The intervertebral implant may be configured to first transition from a collapsed configuration having a first width and a first height to a laterally expanded configuration having a second width and then transition to a vertically expanded configuration having a second height.
[0011] In another embodiment, the present invention provides an intervertebral implant. The intervertebral implant may comprise an upper endplate comprising. The upper endplate may comprise a first upper endplate portion comprising a front ramped surface and a rear ramped surface. The upper endplate may further comprise a second upper endplate portion comprising a front ramped surface and a rear ramped surface. The upper endplate may further comprise endplate pins connecting the first upper endplate portion and the second upper endplate portion. The intervertebral implant may further comprise a lower endplate. The lower endplate may comprise a first lower endplate portion comprising a front ramped surface and a rear ramped surface. The lower endplate may further comprise a second lower endplate portion comprising a front ramped surface and a rear ramped surface. The lower endplate may further comprise endplate pins connecting the first lower endplate portion and the second lower endplate portion. The intervertebral implant may further comprise a front sloped actuator assembly disposed between the upper endplate and the lower endplate. The front sloped actuator assembly may comprise a pair of front height actuators, wherein the front height actuators each comprise opposing ramped surfaces in respective engagement with the upper endplate and the lower endplate. The front sloped actuator assembly may further comprise a front width actuator that is wedge shaped and disposed between the pair of front height actuators and in moving engagement with the pair of front height actuators, wherein the front width actuator is operable to force the pair of front height actuators laterally apart. The intervertebral implant may further comprise a rear sloped actuator assembly. The rear sloped actuator assembly may comprise a pair of rear height actuators, wherein the rear height actuators each comprise opposing ramped surfaces in respective engagement with the upper endplate and the lower endplate. The rear sloped actuator assembly may further comprise a front width actuator disposed between the pair of rear height actuators and in moving engagement with the pair of rear height actuators, wherein the front width actuator is operable to force the pair of front height actuators laterally apart. The intervertebral implant may be configured to first transition from a collapsed configuration having a first width and a first height to a laterally expanded configuration having a second width and then transition to a vertically expanded configuration having a second height.
[0012] In another embodiment, the present invention provides a method of installing an intervertebral implant, the method comprising. The method may comprise introducing the intervertebral implant into an intervertebral space. The method may further comprise moving at least one of a front width actuator or a rear width actuator to cause the front width actuator and the rear width actuator to move closer to one another such that the intervertebral implant transitions from a laterally collapsed configuration having a first width to a laterally expanded configuration having a second width. The method may further comprise moving at least one of a front sloped actuator assembly or a rear sloped actuator assembly to cause the front sloped actuator assembly and the rear sloped actuator assembly to move closer to another such that the intervertebral implant transitions from a vertically collapsed configuration having a first height to a vertically expanded configuration having a second height.
[0013] Further areas of applicability of the present invention will become apparent from the detailed description provided hereinafter. It should be understood that the detailed description and specific examples, while indicating the preferred or exemplary embodiments of the invention, are intended for purposes of illustration only and are not intended to limit the scope of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] The present invention will become more fully understood from the detailed description and the accompanying drawings, wherein:
[0015] FIG. 1 is a side view of an embodiment of an expandable fusion device shown between adjacent vertebrae according to the present invention;
[0016] FIG. 2 is a front perspective view of the expandable fusion device of FIG. 1 shown in an unexpanded position in accordance with one embodiment of the present invention;
[0017] FIG. 3 is a front perspective view of the expandable fusion device of FIG. 1 shown in an expanded position in accordance with one embodiment of the present invention;
[0018] FIG. 4 is a rear perspective view of the expandable fusion device of FIG. 1 shown in an unexpanded position in accordance with one embodiment of the present invention;
[0019] FIG. 5 is a rear perspective view of the expandable fusion device of FIG. 1 shown in an expanded position in accordance with one embodiment of the present invention;
[0020] FIG. 6 is a side view of the expandable fusion device of FIG. 1 shown in an unexpanded position in accordance with one embodiment of the present invention;
[0021] FIG. 7 is a side view of the expandable fusion device of FIG. 1 shown in an expanded position in accordance with one embodiment of the present invention;
[0022] FIG. 8 is a perspective view of the central ramp of the expandable fusion device of FIG. 1 in accordance with one embodiment of the present invention;
[0023] FIG. 9 is a perspective view of the driving ramp of the expandable fusion device of FIG. 1 in accordance with one embodiment of the present invention;
[0024] FIG. 10 is a perspective of an endplate of the expandable fusion device of FIG. 1 in accordance with one embodiment of the present invention;
[0025] FIG. 11 a perspective view showing placement of the first endplate of an embodiment of an expandable fusion device down an endoscopic tube and into the disc space in accordance with one embodiment of the present invention;
[0026] FIG. 12 is a perspective view showing placement of the second endplate of the expandable fusion device down an endoscopic tube and into the disc space in accordance with one embodiment of the present invention;
[0027] FIG. 13 is a perspective view showing placement of the central ramp of the expandable fusion device down an endoscopic tube and into the disc space in accordance with one embodiment of the present invention;
[0028] FIG. 14 is a perspective view showing expansion of the expandable fusion device in accordance with one embodiment of the present invention;
[0029] FIG. 15 is a side schematic view of the expandable fusion device of FIG. 1 having different endplates;
[0030] FIG. 16 is a partial side schematic view of the expandable fusion device of FIG. 1 showing different modes of endplate expansion;
[0031] FIG. 17 is a side schematic view of the expandable fusion device of FIG. 1 with artificial endplates shown between adjacent vertebrae;
[0032] FIG. 18 is a front perspective view of an alternative embodiment of an expandable fusion device shown in an unexpanded position in accordance with one embodiment of the present invention;
[0033] FIG. 19 is a front perspective view of the expandable fusion device of FIG. 18 shown in an expanded position in accordance with one embodiment of the present invention;
[0034] FIG. 20 is a rear perspective view of the expandable fusion device of FIG. 18 shown in an unexpanded position in accordance with one embodiment of the present invention;
[0035] FIG. 21 is a rear perspective view of the expandable fusion device of FIG. 18 shown in an expanded position in accordance with one embodiment of the present invention;
[0036] FIG. 22 is a side view of the expandable fusion device of FIG. 18 shown in an unexpanded position in accordance with one embodiment of the present invention;
[0037] FIG. 23 is a side view of the expandable fusion device of FIG. 18 shown in an expanded position in accordance with one embodiment of the present invention;
[0038] FIG. 24 is a perspective of an endplate of the expandable fusion device of FIG. 18 in accordance with one embodiment of the present invention;
[0039] FIG. 25 is a perspective view of the central ramp of the expandable fusion device of FIG. 18 in accordance with one embodiment of the present invention;
[0040] FIG. 26 is a side view of the central ramp of the expandable fusion device of FIG. 18 in accordance with one embodiment of the present invention;
[0041] FIG. 27 is a top view of the central ramp of the expandable fusion device of FIG. 18 in accordance with one embodiment of the present invention;
[0042] FIG. 28 a perspective view showing placement of the central ramp of the expandable fusion device of FIG. 18 in accordance with one embodiment of the present invention;
[0043] FIG. 29 is a perspective view showing placement of the first endplate of the expandable fusion device of FIG. 18 in accordance with one embodiment of the present invention;
[0044] FIG. 30 is a perspective view showing placement of the second endplate of the expandable fusion device of FIG. 18 in accordance with one embodiment of the present invention;
[0045] FIG. 31 is a perspective view showing placement of the actuation member of the expandable fusion device of FIG. 18 in accordance with one embodiment of the present invention;
[0046] FIG. 32 is a perspective view showing expansion of the expandable fusion device of FIG. 18 in accordance with one embodiment of the present invention;
[0047] FIG. 33 is a front perspective view of an alternative embodiment of an expandable fusion device shown in an unexpanded position in accordance with one embodiment of the present invention;
[0048] FIG. 34 is a front perspective view of the expandable fusion device of FIG. 33 shown in an expanded position in accordance with one embodiment of the present invention;
[0049] FIG. 35 is a rear perspective view of the expandable fusion device of FIG. 33 shown in an unexpanded position in accordance with one embodiment of the present invention;
[0050] FIG. 36 is a rear perspective view of the expandable fusion device of FIG. 33 shown in an expanded position in accordance with one embodiment of the present invention;
[0051] FIG. 37 is a side cross-sectional view of the expandable fusion device of FIG. 33 shown in an unexpanded position in accordance with one embodiment of the present invention;
[0052] FIG. 38 is a side cross-sectional view of the expandable fusion device of FIG. 33 shown in an expanded position in accordance with one embodiment of the present invention;
[0053] FIG. 39 is a perspective of an endplate of the expandable fusion device of FIG. 33 in accordance with one embodiment of the present invention;
[0054] FIG. 40 is a rear perspective view of an alternative embodiment of an expandable fusion device shown in an unexpanded position in accordance with one embodiment of the present invention;
[0055] FIG. 41 is a rear perspective view of the expandable fusion device of FIG. 40 shown in a partially expanded position in accordance with one embodiment of the present invention;
[0056] FIG. 42 is a rear perspective view of the expandable fusion device of FIG. 40 shown in an expanded position in accordance with one embodiment of the present invention;
[0057] FIG. 43 is a side exploded view of the expandable fusion device of FIG. 40 in accordance with one embodiment of the present invention;
[0058] FIG. 44 is a side cross-sectional view of the expandable fusion device of FIG. 40 shown in an unexpanded position in accordance with one embodiment of the present invention;
[0059] FIG. 45 is a perspective view of an endplate of the expandable fusion device of FIG. 40 in accordance with one embodiment of the present invention;
[0060] FIG. 46 is a perspective view of the central ramp of the expandable fusion device of FIG. 40 in accordance with one embodiment of the present invention;
[0061] FIGS. 47-49 are perspective views of the driving ramp of the expandable fusion device of FIG. 40 in accordance with one embodiment of the present invention;
[0062] FIG. 50 is a rear perspective view of an alternative embodiment of an expandable fusion device shown in an expanded position in accordance with one embodiment of the present invention;
[0063] FIG. 51 is a side cross-sectional view of the expandable fusion device of FIG. 50 shown in an expanded position in accordance with one embodiment of the present invention;
[0064] FIG. 52 is an exploded view of the expandable fusion device of FIG. 50 in accordance with one embodiment of the present invention;
[0065] FIG. 53 is a top view of the expandable fusion device of FIG. 50 shown in an unexpanded position in accordance with one embodiment of the present invention;
[0066] FIG. 54 is a read end view of the expandable fusion device of FIG. 50 shown in an expanded position in accordance with one embodiment of the present invention;
[0067] FIG. 55 is a perspective view of an endplate of the expandable fusion device of FIG. 50 in accordance with one embodiment of the present invention;
[0068] FIG. 56 is a perspective of a central ramp of the expandable fusion device of FIG. 50 in accordance with one embodiment of the present invention;
[0069] FIG. 57 is a perspective view of a driving ramp of the expandable fusion device of FIG. 50 in accordance with one embodiment of the present invention;
[0070] FIG. 58 is a rear perspective view of an exploded expandable fusion device in accordance with one alternative embodiment;
[0071] FIG. 59 is a front perspective view of an exploded expandable fusion device in accordance with one alternative embodiment;
[0072] FIG. 60 is a top-down view of the expandable fusion device that lacks the top endplate, providing an interior view of the unexpanded expandable fusion device, in accordance with one embodiment of the present invention;
[0073] FIG. 61 is a perspective view showing placement of the tool engagement service of the expandable fusion device of FIG. 60 in accordance with one embodiment of the present invention;
[0074] FIG. 62 is a top-down cross sectional view of an expandable fusion device shown in the unexpanded position in accordance with one embodiment of the present invention;
[0075] FIG. 63 is a rear perspective view of the expandable fusion device in the expanded position in accordance with one alternative embodiment;
[0076] FIG. 64( a ) is an angled side perspective view of the expandable fusion device in the unexpanded position in accordance with one alternative embodiment;
[0077] FIG. 64( b ) is an angled side perspective view of the expandable fusion device in the expanded position in accordance with one alternative embodiment;
[0078] FIG. 65 is a top-down perspective view of the expandable fusion device in the unexpanded position in accordance with one alternative embodiment;
[0079] FIG. 66 is a rear perspective view of an exploded expandable fusion device in accordance with one alternative embodiment;
[0080] FIG. 67 is side view of an exploded expandable fusion device in accordance with one embodiment of the present invention;
[0081] FIG. 68 is a side cross-sectional view that lacks one front height actuator and one rear height actuator as well as one half of the upper and lower endplates, in order to show the interior of the expandable fusion device of FIG. 66 in accordance with one embodiment of the present invention;
[0082] FIG. 69 is a front perspective view of an expandable fusion device shown in the unexpanded position in accordance with one embodiment of the present invention;
[0083] FIG. 70 is a side cross-sectional view of the expandable fusion device in the expanded position in accordance with one alternative embodiment;
[0084] FIG. 71( a ) is top-down view of the expandable fusion device in the unexpanded position in accordance with one alternative embodiment;
[0085] FIG. 71( b ) is top-down view of the expandable fusion device in the expanded position in accordance with one alternative embodiment;
[0086] FIG. 72 is a view of the expandable fusion device with threaded instrument inserted and in the expanded position in accordance with one alternative embodiment;
[0087] FIG. 73 is an angled perspective view of the expandable fusion device in the expanded position in accordance with one alternative embodiment.
DETAILED DESCRIPTION
[0088] The following description of the preferred embodiment(s) is merely exemplary in nature and is in no way intended to limit the invention, its application, or uses.
[0089] A spinal fusion is typically employed to eliminate pain caused by the motion of degenerated disk material. Upon successful fusion, a fusion device becomes permanently fixed within the intervertebral disc space. Looking at FIG. 1 , an exemplary embodiment of an expandable fusion device 10 is shown between adjacent vertebral bodies 2 and 3 . The fusion device 10 engages the endplates 4 and 5 of the adjacent vertebral bodies 2 and 3 and, in the installed position, maintains normal intervertebral disc spacing and restores spinal stability, thereby facilitating an intervertebral fusion. The expandable fusion device 10 can be manufactured from a number of materials including titanium, stainless steel, titanium alloys, non-titanium metallic alloys, polymeric materials, plastics, plastic composites, PEEK, ceramic, and elastic materials. In an embodiment, the expandable fusion device 10 can be configured to be placed down an endoscopic tube and into the disc space between the adjacent vertebral bodies 2 and 3 .
[0090] In an exemplary embodiment, bone graft or similar bone growth inducing material can be introduced around and within the fusion device 10 to further promote and facilitate the intervertebral fusion. The fusion device 10 , in one embodiment, is preferably packed with bone graft or similar bone growth inducing material to promote the growth of bone through and around the fusion device. Such bone graft may be packed between the endplates of the adjacent vertebral bodies prior to, subsequent to, or during implantation of the fusion device.
[0091] With reference to FIGS. 2-7 , an embodiment of the fusion device 10 is shown. In an exemplary embodiment, the fusion device 10 includes a first endplate 14 , a second endplate 16 , a central ramp 18 , and a driving ramp 260 . In an embodiment, the expandable fusion device 10 can be configured to be placed down an endoscopic tube and into the disc space between the adjacent vertebral bodies 2 and 3 . One or more components of the fusion device 10 may contain features, such as through bores, that facilitate placement down an endoscopic tube. In an embodiment, components of the fusion device 10 are placed down the endoscopic tube with assembly of the fusion device 10 in the disc space.
[0092] Although the following discussion relates to the second endplate 16 , it should be understood that it also equally applies to the first endplate 14 as the second endplate 16 is substantially identical to the first endplate 14 in embodiments of the present invention. Turning now to FIGS. 2-7 and 10 , in an exemplary embodiment, the second endplate 16 has a first end 39 and a second end 41 . In the illustrated embodiment, the second endplate 16 further comprise an upper surface 40 connecting the first end 39 and the second end 41 , and a lower surface 42 connecting the first end 39 and the second end 41 . In an embodiment, the second endplate 16 further comprises a through opening 44 , as seen on FIG. 11 . The through opening 44 , in an exemplary embodiment, is sized to receive bone graft or similar bone growth inducing material and further allow the bone graft or similar bone growth inducing material to be packed in the central opening in the central ramp 18 .
[0093] As best seen in FIGS. 7 and 10 , the lower surface 42 includes at least one extension 46 extending along at least a portion of the lower surface 42 , in an embodiment. In an exemplary embodiment, the extension 46 can extend along a substantial portion of the lower surface 42 , including, along the center of the lower surface 42 . In the illustrated embodiment, the extension 46 includes a generally concave surface 47 . The concave surface 47 can form a through bore with the corresponding concave surface 47 (not illustrated) of the first endplate 14 , for example, when the device 10 is in an unexpanded configuration. In another exemplary embodiment, the extension 46 includes at least one ramped surface 48 . In another exemplary embodiment, there are two ramped surfaces 48 , 50 with the first ramped surface 48 facing the first end 39 and the second ramped surface facing the second end 41 . In an embodiment, the first ramped surface 48 can be proximate the first end 39 , and the second ramped surface 50 can be proximate the second end 41 . It is contemplated that the slope of the ramped surfaces 48 , 50 can be equal or can differ from each other. The effect of varying the slopes of the ramped surfaces 48 , 50 is discussed below.
[0094] In one embodiment, the extension 46 can include features for securing the endplate 16 when the expandable fusion device 10 is in an expanded position. In an embodiment, the extension 46 includes one or more protuberances 49 extending from the lateral sides 51 of the extension. In the illustrated embodiment, there are two protuberances 49 extending from each of the lateral sides 51 with each of the sides 53 having one of the protuberances 49 extending from a lower portion of either end. As will be discussed in more detail below, the protuberances 49 can be figured to engage the central ramp 18 preventing and/or restricting longitudinal movement of the endplate 16 when the device 10 is in an expanded position.
[0095] As illustrated in FIGS. 2-5 , in one embodiment, the upper surface 40 of the second endplate 16 is flat and generally planar to allow the upper surface 40 of the endplate 16 to engage with the adjacent vertebral body 2 . Alternatively, as shown in FIG. 15 , the upper surface 40 can be curved convexly or concavely to allow for a greater or lesser degree of engagement with the adjacent vertebral body 2 . It is also contemplated that the upper surface 40 can be generally planar but includes a generally straight ramped surface or a curved ramped surface. The ramped surface allows for engagement with the adjacent vertebral body 2 in a lordotic fashion. While not illustrated, in an exemplary embodiment, the upper surface 40 includes texturing to aid in gripping the adjacent vertebral bodies. Although not limited to the following, the texturing can include teeth, ridges, friction increasing elements, keels, or gripping or purchasing projections.
[0096] Referring now to FIGS. 2-8 , in an exemplary embodiment, the central ramp 18 has a first end 20 , a second end 22 , a first side portion 24 connecting the first end 20 and the second end 22 , and a second side portion 26 (best seen on FIG. 5 ) on the opposing side of the central ramp 12 connecting the first end 20 and the second end 22 . The first side portion 24 and the second side portion 26 may be curved, in an exemplary embodiment. The central ramp 18 further includes a lower end 28 , which is sized to receive at least a portion of the first endplate 14 , and an upper end 30 , which is sized to receive at least a portion of the second endplate 16 .
[0097] The first end 20 of the central ramp 18 , in an exemplary embodiment, includes an opening 32 . The opening 32 can be configured to receive an endoscopic tube in accordance with one or more embodiments. The first end 20 of the central ramp 18 , in an exemplary embodiment, includes at least one angled surface 33 , but can include multiple angled surfaces. The angled surface 33 can serve to distract the adjacent vertebral bodies when the fusion device 10 is inserted into an intervertebral space.
[0098] The second end 22 of the central ramp 18 , in an exemplary embodiment, includes an opening 36 . The opening 36 extends from the second end 22 of the central ramp 18 into a central guide 37 in the central ramp 18 .
[0099] In an embodiment, the central ramp 18 further includes one or more ramped surfaces 33 . As best seen in FIG. 8 , the one or more ramped surfaces 33 positioned between the first side portion 24 and the second side portion 26 and between the central guide 37 and the second end 22 . In an embodiment, the one or more ramped surfaces 33 face the second end 22 of the central ramp 18 . In one embodiment, the central ramp 18 includes two ramped surfaces 33 with one of the ramped surfaces 33 being sloped upwardly and the other of the ramped surfaces 33 being sloped downwardly. The ramped surfaces 33 of the central ramp can be configured and dimensioned to engage the ramped surface 48 in each of the first and second endplates 14 , 16 .
[0100] Although the following discussion relates to the second side portion 26 of the central ramp 18 , it should be understood that it also equally applies to the first side portion 24 in embodiments of the present invention. In the illustrated embodiment, the second side portion 26 includes an inner surface 27 . In an embodiment, the second side portion 26 further includes a lower guide 35 , a central guide 37 , and an upper guide 38 . In the illustrated embodiment, the lower guide 35 , central guide 37 , and the upper guide 38 extend out from the inner surface 27 from the second end 22 to the one or more ramped surfaces 31 . In the illustrated embodiment, the second end 22 of the central ramp 18 further includes one or more guides 38 . The guides 38 can serve to guide the translational movement of the first and second endplates 14 , 16 with respect to the central ramp 18 . For example, protuberances 49 on the second endplate 16 may be sized to be received between the central guide 37 and the upper guide 38 . Protuberances 49 of the first endplate 16 may be sized to be received between the central guide 37 and the lower guide 35 . A first slot 29 may be formed proximate the middle of the upper guide 38 . A second slot 31 may be formed between end of the upper guide 38 and the one or more ramped surfaces 33 . The protuberances 49 may be sized to be received within the first slot 29 and/or the second slot 31 when the device 10 is in the expanded position.
[0101] Referring now to FIGS. 4-7 and 9 , the driving ramp 260 has a through bore 262 . In an embodiment, the driving ramp 260 is generally wedge-shaped. As illustrated, the driving ramp 260 may comprise a wide end 56 , a narrow end 58 , a first side portion 60 connecting the wide end 56 and the narrow end 58 , and a second side portion 62 connecting the wide end 56 and the narrow end 58 . The driving ramp 260 further may comprise ramped surfaces, including an upper ramped surface 64 and an opposing lower ramped surface 66 . The upper ramped surface 64 and the lower ramped surface 66 may be configured and dimensioned to engage the ramped surface 50 proximate the second end 41 in of the first and the second endplates 14 , 16 . The first and second side portions 60 , 62 may each include grooves 68 that extend, for example, in a direction parallel to the longitudinal axis of the through bore 262 . The grooves 68 may be sized to receive the central guide 37 on the interior surface 27 of each of the side portions 24 , 26 of the central ramp 18 . In this manner, the grooves 68 together with the central guide 37 can surface to guide the translational movement of the driving ramp 260 in the central ramp 18 .
[0102] A method of installing the expandable fusion device 10 of FIG. 1 is now discussed in accordance with one embodiment of the present invention. Prior to insertion of the fusion device 10 , the intervertebral space is prepared. In one method of installation, a discectomy is performed where the intervertebral disc, in its entirety, is removed. Alternatively, only a portion of the intervertebral disc can be removed. The endplates of the adjacent vertebral bodies 2 , 3 are then scraped to create an exposed end surface for facilitating bone growth across the intervertebral space. One or more endoscopic tubes can then be inserted into the disc space. The expandable fusion device 10 can then be introduced into the intervertebral space down an endoscopic tube and seated in an appropriate position in the intervertebral disc space.
[0103] After the fusion device 10 has been inserted into the appropriate position in the intervertebral disc space, the fusion device 10 can then be expanded into the expanded position. To expand the fusion device 10 , the driving ramp 260 may move in a first direction with respect to the central ramp 18 . Translational movement of the driving ramp 260 through the central ramp 18 may be guided by the central guide 37 on each of the first and second side portions 24 , 26 of the central ramp 18 . As the driving ramp 260 moves, the upper ramped surface 64 pushes against the ramped surface 50 proximate the second end 41 of the second endplate 16 , and the lower ramped surface 66 pushes against the ramped surface 50 proximate the second end 41 of the first endplate 14 . In addition, the ramped surfaces 33 in the central ramp 18 push against the ramped surface 48 proximate the first end 41 of the first and second endplates 14 , 16 . In this manner, the first and second endplates 14 , 16 are pushed outwardly into an expanded configuration. As discussed above, the central ramp 16 includes locking features for securing the endplates 14 , 16 .
[0104] It should also be noted that the expansion of the endplates 14 , 16 can be varied based on the differences in the dimensions of the ramped surfaces 48 , 50 and the angled surfaces 62 , 64 . As best seen in FIG. 16 , the endplates 14 , 16 can be expanded in any of the following ways: straight rise expansion, straight rise expansion followed by a toggle into a lordotic expanded configuration, or a phase off straight rise into a lordotic expanded configuration.
[0105] Turning back to FIGS. 2-7 , in the event the fusion device 10 needs to be repositioned or revised after being installed and expanded, the fusion device 10 can be contracted back to the unexpanded configuration, repositioned, and expanded again once the desired positioning is achieved. To contract the fusion device 10 , the central ramp 18 is moved with respect to the central ramp 260 away from the central ramp 260 . As the central ramp 18 moves, the ramped surfaces 33 in the central ramp 18 ride along the ramped surfaces 48 of the first and second endplates 14 , 16 with the endplates 14 , 16 moving inwardly into the unexpanded position.
[0106] With reference now to FIG. 17 , fusion device 10 is shown with an exemplary embodiment of artificial endplates 100 . Artificial endplates 100 allows the introduction of lordosis even when the endplates 14 and 16 of the fusion device 10 are generally planar. In one embodiment, the artificial endplates 100 have an upper surface 102 and a lower surface 104 . The upper surfaces 102 of the artificial endplates 100 have at least one spike 106 to engage the adjacent vertebral bodies. The lower surfaces 104 have complementary texturing or engagement features on their surfaces to engage with the texturing or engagement features on the upper endplate 14 and the lower endplate 16 of the fusion device 10 . In an exemplary embodiment, the upper surface 102 of the artificial endplates 100 have a generally convex profile and the lower surfaces 104 have a generally parallel profile to achieve lordosis. In another exemplary embodiment, fusion device 10 can be used with only one artificial endplate 100 to introduce lordosis even when the endplates 14 and 16 of the fusion device 10 are generally planar. The artificial endplate 100 can either engage endplate 14 or engage endplate 16 and function in the same manner as described above with respect to two artificial endplates 100 .
[0107] With reference to FIGS. 11-14 , an embodiment for placing an expandable fusion device 10 into an intervertebral disc space is illustrated. The expandable fusion device 10 can be introduced into the intervertebral space down an endoscopic tube utilizing a tool 70 that is attached to endplate 16 , with the second endplate 16 being first placed down the tube with tool 70 and into the disc space, as seen in FIG. 11 . After insertion of the second endplate 16 , the first endplate 14 can be placed down the same endoscopic tube with tool 72 and into the disc space, as shown on FIG. 12 . Following the first endplate 14 , the central ramp 12 can be placed down the same endoscopic tube and into the disc space guided by tools 70 and 72 , as shown on FIGS. 13 and 14 .
[0108] Referring now to FIGS. 18-23 , an alternative embodiment of the expandable fusion device 10 is shown. In an exemplary embodiment, the fusion device 10 includes a first endplate 14 , a second endplate 16 , a central ramp 18 , and an actuator assembly 200 . As will be discussed in more detail below, the actuator assembly 200 drives the central ramp 18 which forces apart the first and second endplates 14 , 16 to place the expandable fusion device in an expanded position. One or more components of the fusion device 10 may contain features, such as through bores, that facilitate placement down an endoscopic tube. In an embodiment, components of the fusion device 10 are placed down the endoscopic tube with assembly of the fusion device 10 in the disc space.
[0109] Although the following discussion relates to the second endplate 16 , it should be understood that it also equally applies to the first endplate 14 as the second endplate 16 is substantially identical to the first endplate 14 in embodiments of the present invention. With additional reference to FIG. 24 , in an exemplary embodiment, the second endplate 16 has a first end 39 and a second end 41 . In the illustrated embodiment, the second endplate 16 further comprise an upper surface 40 connecting the first end 39 and the second end 41 , and a lower surface 42 connecting the first end 39 and the second end 41 . While not illustrated, in an embodiment, the second endplate 16 further comprises a through opening. The through opening, in an exemplary embodiment, is sized to receive bone graft or similar bone growth inducing material.
[0110] In one embodiment, the upper surface 40 of the second endplate 16 is flat and generally planar to allow the upper surface 40 of the endplate 16 to engage with the adjacent vertebral body 2 . Alternatively, as shown in FIG. 15 , the upper surface 40 can be curved convexly or concavely to allow for a greater or lesser degree of engagement with the adjacent vertebral body 2 . It is also contemplated that the upper surface 40 can be generally planar but includes a generally straight ramped surface or a curved ramped surface. The ramped surface allows for engagement with the adjacent vertebral body 2 in a lordotic fashion. While not illustrated, in an exemplary embodiment, the upper surface 40 includes texturing to aid in gripping the adjacent vertebral bodies. Although not limited to the following, the texturing can include teeth, ridges, friction increasing elements, keels, or gripping or purchasing projections.
[0111] In one embodiment, the second endplate 16 further comprises a first side portion 202 connecting the first end 39 and the second end 41 , and a second side portion 204 connecting the first end 39 and the second end 41 . In the illustrated embodiment, the first and second side portions 202 , 204 are extensions from the lower surface 42 . In an exemplary embodiment, the first and second side portions 202 , 204 each include ramped surfaces 206 , 208 . In the illustrated embodiment, the ramped surfaces 206 , 208 extend from the first end 39 of the second endplate 16 to bottom surfaces 210 , 212 of each of the side portions 202 , 204 . In one embodiment, the ramped surfaces 206 , 208 are forward facing in that the ramped surfaces 206 , 208 face the first end 39 of the second endplate. As previously discussed, the slope of the ramped surfaces 206 , 208 may be varied as desired for a particular application.
[0112] In an embodiment, the first and second side portions 202 , 204 each comprise at least one protuberance 214 . In an exemplary embodiment, the first and second side portions 202 , 204 each comprise a first protuberance 214 , a second protuberance 216 , and a third protuberance 218 . In one embodiment, the protuberances 214 , 216 , 218 extend from the interior surface 220 of the first and second side portions 202 , 204 . In an exemplary embodiment, the protuberances 214 , 216 , 218 extend at the lower side of the interior surface 220 . As best seen in FIG. 24 , the first and the second protuberances 214 , 216 form a first slot 222 , and the second and third protuberances 216 , 218 form a second slot 224 .
[0113] As best seen in FIG. 24 , the lower surface 42 of the second endplate 16 , in an embodiment, includes a central extension 224 extending along at least a portion of the lower surface. In the illustrated embodiment, the central extension 224 extends between the first and second side portions 202 and 204 . In an exemplary embodiment, the central extension 224 can extend from the second end 41 of the endplate 16 to the central portion of the endplate. In one embodiment, the central extension 224 includes a generally concave surface 226 configured and dimensioned to form a through bore with the corresponding concave surface 226 (not illustrated) of the first endplate 14 . The central extension 224 can further include, in an exemplary embodiment, a ramped surface 228 . In the illustrated embodiment, the ramped surface 228 faces the first end 39 of the endplate 16 . The ramped surface 228 can be at one end of the central extension 224 . In an embodiment, the other end of the central extension 224 forms a stop 230 . In the illustrated embodiment, the stop 230 is recessed from the second end 41 of the second endplate 16 .
[0114] Referring to FIGS. 25-27 , in an exemplary embodiment, the central ramp 18 includes a body portion 232 having a first end 234 and a second end 236 . In an embodiment, the body portion 232 includes at least a first expansion portion 238 . In an exemplary embodiment, the body portion 232 includes a first expansion portion 238 and a second expansion portion 240 extending from opposing sides of the body portion with each of the first and second expansion portions 238 , 240 having a generally triangular cross-section. In one embodiment, the expansion portions 238 , 240 each have angled surfaces 242 , 244 configured and dimensioned to engage the ramped surfaces 206 , 208 of the first and second endplates 14 , 16 and force apart the first and second endplates 14 , 16 . In an embodiment, the engagement between the angled surfaces 242 , 244 of the expansion portions 238 , 240 with the ramped surfaces 206 , 208 of the first and second endplates 14 , 16 may be described as a dovetail connection.
[0115] The second end 236 of the central ramp 18 , in an exemplary embodiment, includes opposing angled surfaces 246 . The angled surfaces 246 can be configured and dimensioned to engage the ramped surface 228 in the central extension 224 in each of the first and second endplates 14 , 16 . In other words, one of the angled surfaces 246 can be upwardly facing and configured, in one embodiment, to engage the ramped surface 228 in the central extension 224 in the second endplate 16 . In an embodiment, the engagement between the angled surfaces 246 of the second end 236 of the central ramp 18 with the ramped surface 228 in the first and second endplates 14 , 16 may be described as a dovetail connection.
[0116] The second end 236 , in an exemplary embodiment, can further include an extension 252 . In the illustrated embodiment, the extension 252 is generally cylindrical in shape with a through bore 254 extending longitudinally therethrough. In one embodiment, the extension 252 can include a beveled end 256 . While not illustrated, at least a portion of the extension 252 can be threaded.
[0117] Referring still to FIGS. 25-27 , the central ramp 18 can further include features for securing the first and second endplates 14 , 16 when the expandable fusion device 10 is in an expanded position. In an embodiment, the body portion 232 of the central ramp 18 includes one or more protuberances 248 , 250 extending from opposing sides of the body portion 232 . As illustrated, the protuberances 248 , 250 , in one embodiment, can be spaced along the body portion 232 . In an exemplary embodiment, the protuberances 248 , 250 can be configured and dimensioned for insertion into the corresponding slots 222 , 224 in the first and second endplates 14 , 16 when the device 10 is in an expanded position, as best seen in FIGS. 19 and 21 . The protuberances 248 , 250 can engage the endplates 14 , 16 preventing and/or restricting movement of the endplates 14 , 16 with respect to the central ramp 18 after expansion of the device 10 .
[0118] With reference to FIGS. 20-23 , in an exemplary embodiment, the actuator assembly 200 has a flanged end 253 configured and dimensioned to engage the stop 232 in the central extension 224 of the first and the second endplates 14 , 16 . In an embodiment, the actuator assembly 200 further includes an extension 254 that extends from the flanged end 253 . In a further embodiment, the actuator assembly 200 includes a threaded hole 256 that extends through the actuator assembly 200 . It should be understood that, while the threaded hole 256 in the actuator assembly 200 is referred to as threaded, the threaded hole 256 may only be partially threaded in accordance with one embodiment. In an exemplary embodiment, the threaded hole 256 is configured and dimensioned to threadingly receive the extension 252 of the central ramp 18 .
[0119] With additional reference to FIGS. 28-32 , a method of installing the expandable fusion device 10 of FIGS. 18-27 is now discussed in accordance with one embodiment of the present invention. Prior to insertion of the fusion device, the disc space may be prepared as described above and then one or more endoscopic tubes may then be inserted into the disc space. The expandable fusion device 10 can then be inserted into and seated in the appropriate position in the intervertebral disc space, as best seen in FIGS. 28-32 . The expandable fusion device 10 can be introduced into the intervertebral space down an endoscopic tube (not illustrated), with the central ramp 18 being first placed down the tube and into the disc space, as seen in FIG. 28 . After insertion of the central ramp, the first endplate 14 can be placed down an endoscopic tube, as shown on FIG. 29 , followed by insertion of the second endplate 16 , as shown on FIG. 30 . After the second endplate 16 , the actuator assembly 200 can then be inserted to complete assembly of the device 10 , as best seen in FIG. 31 .
[0120] After the fusion device 10 has been inserted into and assembled in the appropriate position in the intervertebral disc space, the fusion device 10 can then be expanded into the expanded position. To expand the fusion device 10 , the actuator assembly 200 can be rotated. As discussed above, the actuator assembly 200 is in threaded engagement with the extension 250 of the central ramp 18 . Thus, as the actuator assembly 200 is rotated in a first direction, the central ramp 18 moves toward the flanged end 253 of the actuator assembly 200 . In another exemplary embodiment, the actuator assembly 200 can be moved in a linear direction with the ratchet teeth as means for controlling the movement of the central ramp 18 . As the central ramp 18 moves, the angled surfaces 242 , 244 in the expansion portions 238 , 240 of the central ramp 18 push against the ramped surfaces 206 , 208 in the first and second side portions 202 , 204 of the first and second endplates 14 , 16 . In addition, the angled surfaces 246 in the second end 236 of the central ramp 18 also push against the ramped surfaces 228 in the central extension 224 of each of the endplates 14 , 16 . This is best seen in FIGS. 22-23 .
[0121] Since the expansion of the fusion device 10 is actuated by a rotational input, the expansion of the fusion device 10 is infinite. In other words, the endplates 14 , 16 can be expanded to an infinite number of heights dependent on the rotational advancement of the actuator assembly 200 . As discussed above, the central ramp 16 includes locking features for securing the endplates 14 , 16 .
[0122] In the event the fusion device 10 needs to be repositioned or revised after being installed and expanded, the fusion device 10 can be contracted back to the unexpanded configuration, repositioned, and expanded again once the desired positioning is achieved. To contract the fusion device 10 , the actuator assembly 200 can be rotated in a second direction. As discussed above, actuator assembly 200 is in threaded engagement with the extension 250 of the central ramp 18 ; thus, as the actuator assembly 200 is rotated in a second direction, opposite the first direction, the central ramp 18 moves with respect to the actuator assembly 200 and the first and second endplates 14 , 16 away from the flanged end 253 . As the central ramp 18 moves, the first and second endplates are pulled inwardly into the unexpanded position.
[0123] Referring now to FIGS. 33-38 , an alternative embodiment of the expandable fusion device 10 is shown. In the illustrated embodiment, the fusion device includes a first endplate 14 , a second endplate 16 , a central ramp 18 , and an actuator assembly 200 . The fusion device 10 of FIGS. 33-38 and its individual components are similar to the device 10 illustrated on FIGS. 18- 23 with several modifications. The modifications to the device 10 will be described in tum below.
[0124] Although the following discussion relates to the second endplate 16 , it should be understood that it also equally applies to the first endplate 14 as the second endplate 16 is substantially identical to the first endplate 14 in embodiments of the present invention. With additional reference to FIG. 39 , in an exemplary embodiment, the lower surface 42 of the second endplate 16 has been modified. In one embodiment, the central extension 224 extending from the lower surface 42 has been modified to include a second ramped surface 258 rather than a stop. In an exemplary embodiment, the second ramped surface 258 faces the second end 41 of the second endplate 16 . In contrast, ramped surface 228 on the central extension 228 faces the first end 39 of the second endplate. The concave surface 228 connects the ramped surface 228 and the second ramped surface 258 .
[0125] With reference to FIGS. 35-38 , in an exemplary embodiment, the actuator assembly 200 has been modified to further include a driving ramp 260 . In the illustrated embodiment, the driving ramp 260 has a through bore 262 through which the extension 254 extends. In an embodiment, the driving ramp 260 is generally wedge-shaped. As illustrated, the driving ramp 260 may comprise a blunt end 264 in engagement with the flanged end 253 . In an exemplary embodiment, the driving ramp 260 further comprises angled surfaces 266 configured and dimensioned to engage the second ramped surface 258 of each of the endplates 14 , 16 and force apart the first and second endplates 14 , 16 .
[0126] Referring now to FIGS. 40-44 , an alternative embodiment of the expandable fusion device 10 is shown. In the illustrated embodiment, the fusion device 10 includes a first endplate 14 , a second endplate 16 , a central ramp 18 , an actuator assembly 200 , and a driving ramp 300 . As will be discussed in more detail below, the actuator assembly 200 functions, in an embodiment, to pull the central ramp 18 and the driving ramp 300 together, which forces apart the first and second endplates 14 , 16 . In an embodiment, the expandable fusion device
[0127] Although the following discussion relates to the first endplate 14 , it should be understood that it also equally applies to the second endplate 16 as the second endplate 16 is substantially identical to the first endplate 14 in embodiments of the present invention. With reference to FIGS. 40-45 , in an exemplary embodiment, the first endplate 14 has a first end 39 and a second end 41 . In the illustrated embodiment, the first endplate 14 further comprises an upper surface 40 connecting the first end 39 and the second end 41 , and a lower surface 42 connecting the first end 39 and the second end 41 . While not illustrated, in an embodiment, the first endplate 14 may comprise further comprises a through opening. The through opening, in an exemplary embodiment, is sized to receive bone graft or similar bone growth inducing material.
[0128] In one embodiment, the upper surface 40 of the first endplate 14 is flat and generally planar to allow the upper surface 40 of the endplate 14 to engage with the adjacent vertebral body 2 . Alternatively, as shown in FIG. 15 , the upper surface 40 can be curved convexly or concavely to allow for a greater or lesser degree of engagement with the adjacent vertebral body 2 . It is also contemplated that the upper surface 40 can be generally planar but includes a generally straight ramped surface or a curved ramped surface. The ramped surface allows for engagement with the adjacent vertebral body 2 in a lordotic fashion. While not illustrated, in an exemplary embodiment, the upper surface 40 includes texturing to aid in gripping the adjacent vertebral bodies. Although not limited to the following, the texturing can include teeth, ridges, friction increasing elements, keels, or gripping or purchasing projections.
[0129] In one embodiment, the first endplate 14 further comprises a first side portion 202 connecting the first end 39 and the second end 41 , and a second side portion 204 connecting the first end 39 and the second end 41 . In the illustrated embodiment, the first and second side portions 202 , 204 are extensions from the lower surface 42 . In an embodiment, the first and second side portions each have an interior surface 302 and an exterior surface 304 . In an exemplary embodiment, the first and second side portions 202 , 204 each include one or more ramped portions. In the illustrated embodiment, the first and second side portions 202 , 204 include first ramped portions 306 , 308 at the first end 39 of the endplate 14 and second ramped portions 310 , 312 at the second end 41 of the endplate. The first and second side portions 202 , 204 each can include a bridge portion 314 connecting the first ramped portions 306 , 308 and the second ramped portions 310 , 312 . In an embodiment, the first ramped portions 306 , 308 abut the exterior surface 304 of the respective side portions 202 , 204 , and the second ramped portions 310 , 312 abut the interior surface 302 of the respective side portions 202 , 204 . As illustrated, the first ramped portions 306 , 308 may include tongue portions 316 , 318 with the tongue portions 316 , 318 extending in an oblique direction with respect to the upper surface 40 of the endplate 14 . As further illustrated, the second ramped portions 310 , 312 may include tongue portions 320 , 322 that extend in an oblique direction with respect to the upper surface 40 of the endplate 14 .
[0130] As best seen in FIG. 45 , the lower surface 42 of the second endplate 16 , in an embodiment, includes a central extension 224 extending along at least a portion of the lower surface. In the illustrated embodiment, the central extension 224 extends between the first and second side portions 202 and 204 . In an exemplary embodiment, the central extension 224 can extend generally between the first ramped portions 306 , 308 and the second ramped portions 310 , 312 . In one embodiment, the central extension 224 includes a generally concave surface 226 configured and dimensioned to form a through bore with the corresponding concave surface 226 (not illustrated) of the second endplate 16 .
[0131] With reference to FIGS. 43 and 44 , the actuator assembly 200 includes a head portion 324 , a rod receiving extension 326 , and a connecting portion 328 that connecting portions that connects the head portion 324 and the rod receiving extension 326 . As illustrated, the head portion 324 may include one or more instrument gripping features 330 that can allow it to be turned by a suitable instrument. In addition, the head portion 324 has a larger diameter than the other components of the actuator assembly 200 to provide a contact surface with the driving ramp 300 . In the illustrated embodiment, the head portion 324 includes a rim 332 that provides a surface for contacting the driving ramp 300 . As can be seen in FIG. 44 , in an exemplary embodiment, the rod receiving extension 326 includes an opening sized and dimensioned to receive the extension 336 of the central ramp 18 . In an embodiment, the rod receiving extension 326 includes threading for threadingly engaging the extension 336 . In another embodiment, the rod receiving extension 326 includes ratchet teeth for engaging the extension 336 . In the illustrated embodiment, the head portion 324 and the rod receiving extension 326 are connected by connecting portion 328 which can be generally cylindrical in shape.
[0132] With reference to FIGS. 43, 44, and 46 , the central ramp 18 includes expansion portion 334 and extension 336 . As best seen in FIG. 46 , the expansion portion 334 may include an upper portion 338 and side portions 340 , 342 that extend down from the upper portion 338 . In an embodiment, each of the side portions 340 , 342 include dual, overlapping ramped portions. For example, side portions 340 , 342 each include a first ramped portion 344 that overlaps a second ramped portion 346 . In the illustrated embodiment, the first ramped portion 344 faces the extension 336 while the second ramped portion 344 faces away from the extension 336 . In one embodiment, angled grooves 348 , 350 are formed in each of the first and second ramped portions 344 , 346 . In another embodiment, the angled grooves 348 , 350 are sized to receive the corresponding tongues 316 , 318 , 320 , 322 in the first and second endplates with angled grooves 348 receiving tongues 320 , 322 in the second endplate 16 and angled grooves 350 receiving tongues 316 , 318 in the first endplate 14 . Although the device 10 is described with tongues 316 , 318 , 320 , 322 on the endplates 14 , 16 and angled grooves 348 , 350 on the central ramp 18 , it should be understood that that device 10 can also be configured with grooves on the endplates 14 , 16 and tongues on the central ramp 18 , in accordance with one embodiment of the present invention.
[0133] In an exemplary embodiment, the extension 336 is sized to be received within the rod receiving extension 326 of the actuator assembly 200 . In one embodiment, the extension 336 has threading with the extension 336 being threadingly received within the rod receiving extension 326 . In another embodiment, the extension 336 has ratchet teeth with the extension 336 being ratcheted into the rod receiving extension 336 . In an embodiment, the extension 336 include nose 352 at the end of the extension 336 .
[0134] With reference to FIGS. 47-49 , in an exemplary embodiment, the driving ramp 300 includes an upper portion 354 having an upper surface 356 and an oblique surface 358 . In an embodiment, the driving ramp 300 further includes side portions 360 , 362 that extend from the upper portion 354 connecting the upper portion 354 with the lower portion 364 of the driving ramp 300 . As best seen in FIGS. 48-49 , the driving ramp 300 further includes a bore 366 , in an exemplary embodiment, sized to receive the connection portion 328 of the actuator assembly 200 . In one embodiment, the driving ramp 300 moves along the connection portion 328 when the actuator assembly 200 is pushing the driving ramp 300 . In an exemplary embodiment, the driving ramp 300 further includes contact surface 368 that engages the rim 332 of the head portion 324 of the actuator assembly 200 . In the illustrated embodiment, the contact surface 368 has a generally annular shape.
[0135] In an exemplary embodiment, the side portions 360 , 362 of the driving ramp 300 each include overlapping ramped portions. For example, the side portions 360 , 362 each include first ramped portions 370 that overlap second ramped portions 372 . In the illustrated embodiment, the first ramped portions 370 face central ramp 18 while the second ramped portions 372 face the opposite direction. In one embodiment, angled grooves 374 , 376 are formed in each of the first and second ramped portions 370 , 372 . FIG. 48 is a perspective view of the driving ramp 300 that shows the top ends of the angled grooves 374 in ramped portions 370 . FIG. 49 is a perspective view of the driving ramp 300 that shows the top ends of the angled grooves 376 in ramped portions 372 . In an exemplary embodiment, the angled grooves 374 , 376 are sized to receive corresponding tongues 316 , 318 , 320 , 322 in the first and second endplates 14 , 16 with angled grooves 370 receiving tongues 316 , 318 in the second endplate 16 and angled grooves 372 receiving tongues 320 , 322 in the first endplate 14 . Although the device 10 is described with tongues 316 , 318 , 320 , 322 in the first and second endplates 14 , 16 and angled grooves 370 , 372 , 374 , 376 on the driving ramp 300 , it should be understood that that device 10 can also be configured with grooves on the second endplate 16 and tongues on the driving ramp 300 , in accordance with one embodiment of the present invention.
[0136] Turning now to FIGS. 40-42 , a method of installing the expandable fusion device 10 of FIGS. 40-49 is now discussed in accordance with one embodiment of the present invention. Prior to insertion of the fusion device, the disc space may be prepared as described above. The expandable fusion device 10 can then be inserted into and seated in the appropriate position in the intervertebral disc space. The expandable fusion device 10 is then introduced into the intervertebral space, with the end having the expansion portion 334 of the central ramp 18 being inserted. In an exemplary method, the fusion device 10 is in the unexpanded position when introduced into the intervertebral space. In an exemplary method, the intervertebral space may be distracted prior to insertion of the fusion device 10 . The distraction provides some benefits by providing greater access to the surgical site making removal of the intervertebral disc easier and making scraping of the endplates of the vertebral bodies 2 , 3 easier.
[0137] With the fusion device 10 inserted into and seated in the appropriate position in the intervertebral disc space, the fusion device can then expanded into the expanded position, as best seen in FIG. 42 . To expand the fusion device 10 , an instrument is engaged with the head portion 324 of the actuator assembly 200 . The instrument is used to rotate actuator assembly 200 . As discussed above, actuator assembly 200 is threadingly engaged with the extension 336 of the central ramp 18 ; thus, as the actuator assembly 200 is rotated in a first direction, the central ramp 18 is pulled toward the actuator assembly 200 . In an exemplary embodiment, the actuator assembly 200 is moved in a linear direction with the ratchet teeth engaging as means for controlling the movement of the actuator assembly 200 and the central ramp 18 . As the central ramp 18 is pulled towards the actuator assembly 200 , the first ramped portions 344 of the central ramp 18 push against the second ramped portions 310 , 312 of the second endplate 16 and the second ramped portions 346 of the central ramp 18 push against first ramped portions 306 , 308 of the first endplate 14 . In this manner, the central ramp 18 acts to push the endplates 14 , 16 outwardly into the expanded position. This can best be seen in FIGS. 40-42 . As the endplates 14 , 16 move outwardly the tongues 316 , 318 , 320 , 322 in the endplates 14 , 16 ride in the angled grooves 348 , 350 with the tongues 320 , 322 in the second endplate 16 riding in angled grooves 348 and the tongues 316 , 318 in the first endplate 14 riding in angled grooves 350 .
[0138] As discussed above, the actuator assembly 200 also engages driving ramp 300 ; thus, as the actuator assembly 200 is rotated in a first direction, the actuator assembly 200 pushes the driving ramp 300 towards the central ramp 18 in a linear direction. As the driving ramp 300 is pushed towards the central ramp 18 , the first ramped portions 370 of the driving ramp 300 push against the first ramped portions 306 , 308 of the second endplate 16 and the second ramped portions 372 of the driving ramp 300 push against the second ramped portions 310 , 312 of the first endplate 14 . In this manner, the driving ramp 300 also acts to push the endplates 14 , 16 outwardly into the expanded position. This can best be seen in FIGS. 40-42 . As the endplates 14 , 16 move outwardly the tongues 316 , 318 , 320 , 322 in the endplates 14 , 16 ride in the angled grooves 370 , 372 with the tongues 316 , 318 in the second endplate 16 riding in angled grooves 370 and the tongues 320 , 322 in the first endplate 14 riding in angled grooves 372 .
[0139] Since the expansion of the fusion device 10 is actuated by a rotational input, the expansion of the fusion device 10 is infinite. In other words, the endplates 14 , 16 can be expanded to an infinite number of heights dependent on the rotational advancement of the actuator assembly 200 .
[0140] Referring now to FIGS. 50-54 , an alternative embodiment of the expandable fusion device 10 is shown. In the illustrated embodiment, the fusion device 10 includes a first endplate 14 , a second endplate 16 , a central ramp 18 , an actuator assembly 200 , and a driving ramp 300 . As will be discussed in more detail below, the actuator assembly 200 functions, in an embodiment, to pull the central ramp 18 and the driving ramp 300 together, which forces apart the first and second endplates 14 , 16 . In an embodiment, the expandable fusion device may contain features, such as a through bore, that facilitate placement down an endoscopic tube. In an embodiment, the assembled fusion device 10 may be placed down the endoscopic tube and then expanded.
[0141] Although the following discussion relates to the first endplate 14 , it should be understood that it also equally applies to the second endplate 16 as the second endplate 16 is substantially identical to the first endplate 14 in embodiments of the present invention. It should be understood that, in an embodiment, the first endplate 14 is configured to interlock with the second endplate 16 . With additional reference to FIG. 55 , in an exemplary embodiment, the first endplate 14 has a first end 39 and a second end 41 . As illustrated, the first end 39 may be wider than the second end 41 . In the illustrated embodiment, the first endplate 14 further comprises an upper surface 40 connecting the first end 39 and the second end 41 , and a lower surface 42 connecting the first end 39 and the second end 41 . As best seen in FIG. 54 , the lower surface 42 can be curved concavely such that the first and second endplates 14 , 16 form a through bore when the device 10 is in a closed position. In an embodiment, the first endplate 14 may comprise a through opening 44 . The through opening 44 , in an exemplary embodiment, is sized to receive bone graft or similar bone growth inducing material.
[0142] In one embodiment, the upper surface 40 of the first endplate 14 is flat and generally planar to allow the upper surface 40 of the endplate 14 to engage with the adjacent vertebral body 2 . Alternatively, as shown in FIG. 15 , the upper surface 40 can be curved convexly or concavely to allow for a greater or lesser degree of engagement with the adjacent vertebral body 2 . It is also contemplated that the upper surface 40 can be generally planar but includes a generally straight ramped surface or a curved ramped surface. The ramped surface allows for engagement with the adjacent vertebral body 2 in a lordotic fashion. As illustrated, in an exemplary embodiment, the upper surface 40 includes texturing to aid in gripping the adjacent vertebral bodies. For example, the upper surface 40 may further comprise texturing 400 to engage the adjacent vertebral bodies. Although not limited to the following, the texturing can include teeth, ridges, friction increasing elements, keels, or gripping or purchasing projections.
[0143] In one embodiment, the first endplate 14 further comprises a first side portion 202 connecting the first end 39 and the second end 41 , and a second side portion 204 connecting the first end 39 and the second end 41 . In the illustrated embodiment, the first and second side portions 202 , 204 are extensions from the lower surface 42 . In an embodiment, the first and second side portions 202 , 204 each include an interior surface 302 and an exterior surface 304 . In an embodiment, the first end 39 of the first endplate 14 is generally designed and configured to fit over the second end 41 of the second endplate 16 when the device 10 is in a closed position. As illustrated, the first and second side portions 202 , 204 each may include first ramped portions 306 , 308 , second ramped portions 310 , 312 , and/or central ramped portion 402 .
[0144] In an embodiment, the first ramped portions 306 , 308 are proximate the first end 39 of the endplate 14 . In accordance with embodiment of the present invention, the first ramped portions 306 , 308 of the first endplate 14 are generally designed and configured to fit over the second ramped portions 310 , 312 of the second endplate 16 when the device 10 is in a closed position. In an exemplary embodiment, the first ramped portions 306 , 308 generally face the first end 39 and can extend in an oblique direction with respect to the upper surface 40 , for example. As illustrated, the first ramped portions 306 , 308 may include tongue portions 316 , 318 extending in an oblique direction with respect to the upper surface 40 of the endplate 14 .
[0145] In an embodiment, the second ramped portions 310 , 312 are proximate the second end 41 of the endplate 14 . In an exemplary embodiment, the second ramped portions 310 , 312 can extend in an oblique direction with respect to the upper surface 40 and generally face the second end 41 . The first and second side portions 202 , 204 , in an embodiment, each can include a bridge portion 314 connecting the first ramped portions 306 , 308 and the second ramped portions 310 , 312 . As further illustrated, the second ramped portions 310 , 312 may include tongue portions 320 , 322 that extend in an oblique direction with respect to the upper surface 40 of the endplate 14 .
[0146] In an embodiment, the endplate 14 further may include a central ramped portion 402 proximate the bridge portion 314 . In the illustrated embodiment, the endplate 14 includes a central ramped portion 402 proximate the bridge portion 314 of the second side portion 204 . In an exemplary embodiment, the central ramped portion 402 can extend in an oblique direction with respect to the upper surface 40 and face the first end 39 of the endplate 14 . As illustrated, the first ramped portions 306 , 308 may include tongue portions 316 , 318 with the tongue portions 316 , 318 extending in an oblique direction with respect to the upper surface 40 of the endplate 14 .
[0147] With reference to FIGS. 50-52 and 54 , in an embodiment, the actuator assembly 200 includes a head portion 324 , an extension 404 , and a through bore 406 that extends longitudinally through the actuator assembly 200 . As illustrated, the head portion 324 may include one or more instrument gripping features 330 that can allow it to be turned by a suitable instrument. In addition, the head portion 324 has a larger diameter than the other components of the actuator assembly 200 to provide a contact surface with the driving ramp 300 . In the illustrated embodiment, the head portion 324 includes a rim 332 that provides a surface for contacting the driving ramp 300 . In an embodiment, the extension 404 is a generally rod-like extension. In another embodiment, the extension 404 includes ratchet teeth for engaging the extension 336 .
[0148] With reference to FIGS. 51, 52, and 56 , the central ramp 18 has a first end 408 and a second end 410 . In an embodiment, the central ramp 18 includes a first expansion portion 412 , a second expansion portion 414 , a rod-receiving extension 416 , and a through bore 418 that extends longitudinally through the central ramp 18 . In an exemplary embodiment, first expansion portion 412 can be proximate the first end 408 of the central ramp 18 . As best seen in FIG. 56 , the first expansion portion 412 may include side portions 420 , 422 . In an embodiment, each of the side portions 420 , 422 includes dual, overlapping ramped portions that extend in oblique directions with respect to the through bore 418 . For example, side portions 420 , 422 each include a first ramped portion 424 that overlaps a second ramped portion 426 . In the illustrated embodiment, the first ramped portion 424 faces the rod-receiving extension 416 while the second ramped portion 426 faces the opposite direction. In one embodiment, angled grooves 428 , 430 are formed in each of the first and second ramped portions 424 , 426 . In an exemplary embodiment, the angled grooves 428 , 430 are sized to receive the corresponding tongues 316 , 318 , 320 , 322 in the first and second endplates 14 , 16 with angled grooves 428 receiving tongues 320 , 322 in the second endplate 16 and angled grooves 430 receiving tongues 316 , 318 in the first endplate 14 . Although the device 10 is described with tongues 316 , 318 , 320 , 322 on the endplates 14 , 16 and angled grooves 428 , 430 on the central ramp 18 , it should be understood that that device 10 can also be configured with grooves on the endplates 14 , 16 and tongues on the central ramp 18 , in accordance with one embodiment of the present invention.
[0149] In an embodiment, the second expansion portion 414 is located on the rod-receiving extension 416 between the first end 408 and the second end 410 of the central ramp 18 . In an exemplary embodiment, the second expansion portion 414 includes central ramped portions 432 . In one embodiment, the second expansion portion 414 includes two central ramped portions 432 on opposite sides of the rod-receiving extension 416 . In an exemplary embodiment, the central ramped portions 424 extend in an oblique direction with respect to the through bore 418 and face the second end 410 of the central ramp 18 .
[0150] The rod-receiving extension 416 extends from the first expansion portion 412 and has an opening 434 at the second end of the central ramp 18 . In an embodiment, the rod-receiving extension 416 is sized and configured to receive the extension 404 of the actuator assembly 200 . In an embodiment, the rod-receiving extension 416 has threading with the rod-receiving extension 416 threadingly receiving extension 404 of the actuator assembly 200 . In another embodiment, the rod-receiving extension 416 has ratchet teeth with the extension 404 being ratcheted into the rod-receiving extension 416 .
[0151] With reference to FIGS. 50-52 and 57 , in an exemplary embodiment, the driving ramp 300 includes an upper portion 354 having an upper surface 356 and an oblique surface 358 . In an embodiment, the driving ramp 300 further includes a bore 366 , in an exemplary embodiment, sized to receive the extension 404 of the actuator assembly 200 . In the illustrated, embodiment, the upper portion 354 has a hole 436 that extends through the upper surface 356 to the bore 366 . Set screw 438 may be inserted through the hole 436 to secure the driving ramp 300 to the actuator assembly 200 . In one embodiment, the driving ramp 300 further includes contact surface 368 that engages the rim 332 of the head portion 324 of the actuator assembly 200 . In the illustrated embodiment, the contact surface 368 has a generally annular shape.
[0152] In an embodiment, the driving ramp 300 further includes side portions 360 , 362 that extend from the upper portion 354 connecting the upper portion 354 with the lower portion 364 of the driving ramp 300 . In an exemplary embodiment, the side portions 360 , 362 of the driving ramp 300 each include a ramped portion 438 . In the illustrated embodiment, the ramped portion 438 faces central ramp 300 . In an embodiment, the ramped portion 438 is configured and dimensioned to engage the ramped portions 306 , 308 at the first end 39 of the second endplate 16 . In one embodiment, angled grooves 440 are formed in the ramped portions 316 , 318 . In an exemplary embodiment, the angled grooves 440 are sized to receive the corresponding tongues 316 , 318 in the second endplate 16 . Although the device 10 is described with tongues 316 , 318 on the second endplate 16 and angled grooves 440 on the driving ramp 300 , it should be understood that that device 10 can also be configured with grooves on the second endplate 16 and tongues on the driving ramp 300 , in accordance with one embodiment of the present invention.
[0153] A method of installing the expandable fusion device 10 of FIGS. 50-57 is now discussed in accordance with one embodiment of the present invention. Prior to insertion of the fusion device, the disc space may be prepared as described above. The expandable fusion device 10 can then be inserted into and seated in the appropriate position in the intervertebral disc space. In an embodiment, the device 10 is assembled prior to insertion. The expandable fusion device 10 can be introduced into the intervertebral space, with the end having the first end 408 of the central ramp 18 being inserted. In an exemplary method, the fusion device 10 is in the unexpanded position when introduced into the intervertebral space. In an exemplary method, the intervertebral space may be distracted prior to insertion of the fusion device 10 . The distraction provides some benefits by providing greater access to the surgical site making removal of the intervertebral disc easier and making scraping of the endplates of the vertebral bodies 2 , 3 easier.
[0154] With the fusion device 10 inserted into and seated in the appropriate position in the intervertebral disc space, the fusion device can then expand into the expanded position. To expand the fusion device 10 , an instrument is engaged with the head portion 324 of the actuator assembly 200 . The instrument is used to rotate actuator assembly 200 . As discussed above, actuator assembly 200 is threadingly engaged with the rod receiving extension 416 of the central ramp 18 ; thus, as the actuator assembly 200 is rotated in a first direction, the central ramp 18 is pulled toward the actuator assembly 200 . In an exemplary embodiment, the actuator assembly 200 is moved in a linear direction with the ratchet teeth engaging as means for controlling the movement of the actuator assembly 200 and the central ramp 18 .
[0155] As the central ramp space 18 is pulled towards the actuator assembly 200 , the central ramp 18 acts to push endplates 14 , 16 outwardly into the expanded position. By way of example, the first ramped portions 424 , second ramped portions 426 , and central ramped portions 432 push against the corresponding ramped portions in the first and second endplates 14 , 16 . The first ramped portions 424 in the first expansion portion 412 of the central ramp 18 push against the second ramped portions 310 , 312 of the second endplate 16 with the corresponding tongues 320 , 322 in the second ramped portions 310 , 312 of the second endplate 16 riding in angled grooves 428 in the first rampep portions 424 in the first expansion portion 412 . The second ramped portions 426 in the first expansion portion 412 push against the first ramped portions 316 , 318 of the first endplate 14 with the corresponding tongues 316 , 318 in first ramped portions 316 , 318 of the first endplate 14 riding in angled grooves 430 in the second ramped portions 426 in the first expansion portion 412 . The central ramped portions 432 in the second expansion portion 414 push against the central ramped portion 402 in the first and second endplates 14 , 16 .
[0156] As discussed above, the actuator assembly 200 also engages driving ramp 300 ; thus, as the actuator assembly 200 is rotated in a first direction, the actuator assembly 200 pushes the driving ramp 300 towards the central ramp 18 in a linear direction. As the driving ramp 300 is pushed towards the central ramp 18 , the driving ramp 300 also acts to push the endplates 14 , 16 outwardly into the expanded position. By way of example, the ramped portions 438 of the driving ramp 300 push against ramped portions 306 , 308 at the first end 39 of the second endplate 16 . As the endplates 14 , 16 move outwardly, the tongues 316 , 318 in the ramped portions 306 , 308 of the second endplate 16 ride in the angled grooves 440 in the ramped portions 438 of the driving ramp 300 .
[0157] It should also be noted that the expansion of the endplates 14 , 16 can be varied based on the differences in the dimensions of the various ramped portions in the central ramp 18 , the driving ramp 300 , and the first and second endplates 14 , 16 . As best seen in FIG. 16 , the endplates 14 , 16 can be expanded in any of the following ways: straight rise expansion, straight rise expansion followed by a toggle into a lordotic expanded configuration, or a phase off straight rise into a lordotic expanded configuration.
[0158] In the event the fusion device 10 needs to be repositioned or revised after being installed and expanded, the fusion device 10 can be contracted back to the unexpanded configuration, repositioned, and expanded again once the desired positioning is achieved. To contract the fusion device 10 , the instrument can be used to rotate the actuator assembly 200 in a second direction that is opposite the first direction. Rotation of the actuator assembly 200 results in movement of the central ramp 18 and the driving ramp 300 away from one another. As the central ramp 18 and the driving ramp 300 move, the endplates 14 , 16 move inwardly into the unexpanded position.
[0159] Although the preceding discussion only discussed having a single fusion device 10 in the intervertebral space, it is contemplated that more than one fusion device 10 can be inserted in the intervertebral space. It is further contemplated that each fusion device 10 does not have to be finally installed in the fully expanded state. Rather, depending on the location of the fusion device 10 in the intervertebral disc space, the height of the fusion device 10 may vary from unexpanded to fully expanded. It should be noted that, as well as the height being varied from an unexpanded state to an expanded state, the fusion 10 may be positioned permanently anywhere between the expanded state and the unexpanded state.
[0160] Referring now to FIGS. 58-65 , an alternative embodiment of the expandable fusion device 10 is shown. In the illustrated embodiment, the fusion device 10 includes an upper endplate 480 , a lower endplate 485 , and actuator assembly 445 . The actuator assembly 445 comprises a front sloped height actuator 450 , a rear sloped height actuator 455 , and a linear actuator 460 . In an embodiment the linear actuator 460 functions to pull the front sloped actuator 450 and the rear sloped actuator 455 together, which forces apart the upper endplate 480 and lower endplate 485 .
[0161] With reference to FIGS. 58-59 , in an exemplary embodiment of fusion device 10 , the actuator assembly 445 comprises a front sloped actuator 450 , a rear sloped actuator 455 , and a linear actuator 460 . As illustrated, the linear actuator 460 may comprise a head portion 465 and an extension 466 . In an embodiment, the extension 466 is a generally rod-like extension that comprises surface threads 470 . It should be understood that, while the surface threads 470 of the linear actuator 460 are referred to as threaded, the surface threads 470 may only be partially threaded in accordance with one embodiment. The linear actuator 460 of the actuator assembly 445 may extend through an opening 456 in the rear sloped actuator 455 where the surface threads 470 of the linear actuator 460 engage the complimentary threads 500 of the extension 475 of the front sloped actuator 450 . Thus, as the linear actuator 460 is rotated in a first direction, the actuator assembly 445 pulls the front sloped actuator 450 towards the rear sloped actuator 455 and consequently also towards the head portion 465 of the linear actuator 460 in a linear direction. As the front sloped actuator 450 is pulled towards the rear sloped actuator 455 , the sloped surfaces 454 , 459 respectively, of the front sloped actuator 450 and the rear sloped 455 actuator push the upper 480 and lower 485 endplates outwardly into the expanded position.
[0162] With reference to FIGS. 58-59 and 63 , in an exemplary embodiment, the upper and lower endplates 480 , 485 may comprise two portions, such as two opposing mirrored halves. Both the upper endplate 480 and lower endplate 485 may comprise a front end 481 and a rear end 482 . The front and rear ends 481 , 482 of each portion of each endplate may be substantially similar to the front and rear ends 481 , 482 of every other portion of every other endplate. It should be understood that that references to the front and rear ends 481 , 482 of each endplate are with respect to the front and rear of the expandable fusion device 10 , which is with respect to the direction of placement into an intervertebral disc space with the front of the expandable fusion device 10 placed into the space first, followed by the rear of the expandable fusion device 10 . Each portion of the upper and lower endplates 480 , 485 further may comprise front ramped surface 483 and rear ramped surface 484 , as a component of the front and rear ends 481 , 482 of each portion of the upper and lower endplate 480 , 485 . The front ramped surface 483 may be located on the front end 481 of each half of the upper and lower endplates 480 , 485 . The rear ramped surface 484 may be located on the rear end 482 of each half of the upper and lower endplates 485 . With additional reference to FIGS. 60 and 61 , in the illustrated embodiment, the front and rear ends 481 , 482 of each portion of upper and lower endplates 480 , 485 contains a slot 490 that engages the corresponding elevated and angled tongues 495 of the front sloped actuator 450 and the rear sloped actuator 455 . The elevated and angled tongues 495 may be substantially identical in design and function for both the front sloped actuator 450 and the rear sloped actuator 455 . Because the elevated and angled tongues 495 are angled at a slant that directs away from the center of the expandable fusion device, as the front sloped actuator 450 is pulled towards the rear sloped actuator 455 by rotation of the linear actuator 460 , the ramped sections 454 , 459 of the front and rear sloped actuators 450 , 455 , in conjunction with the elevated and angled tongues 495 of the front and rear sloped actuators 450 , 455 pushes both portions of the upper and lower endplates 480 , 485 outward simultaneously in both horizontal and vertical directions.
[0163] With reference to FIGS. 58-62 , front sloped actuator 450 may comprise a front end 451 and a rear end 453 . The front end 451 may comprise opposing sloped surfaces 452 . In some embodiments, the front end 451 of the front sloped actuator 450 is the section of the expandable fusion device 10 that is first inserted into an intervertebral disc space. The front sloped actuator 450 may also comprise a rear end 453 connected to extension 475 from the front slope actuator 450 . The rear end 453 of the front sloped actuator 450 also may comprise opposing sloped surfaces 454 . The opposing sloped surfaces 454 of the rear end 453 of the front sloped actuator 450 may be sloped towards the rear sloped actuator 455 . The opposing sloped surfaces 454 of the rear end 453 of the front sloped actuator 450 also comprises the elevated and angled tongues 495 that engage the slots 490 of the halves of the upper and lower endplates 480 , 485 , as described in the preceding paragraph. The front sloped actuator 450 also comprises a threaded screw opening 463 . As illustrated, the extension 475 from the front sloped actuator 450 may comprise extending threaded prongs 476 a, 476 b. The extension 475 is generally located in the center of the actuator assembly 445 , and with respect to the front end 451 of the front sloped actuator 450 , the extension 475 extends longitudinally towards the rear sloped actuator 455 and the linear actuator 460 . The extension 475 may be sized and configured to receive the extension 466 of the linear actuator 460 . The extension 475 may comprise threads 500 that engage with the threads 470 of the extension 466 of the linear actuator 460 . Turning the linear actuator 460 , rotates the threads 470 of the linear actuator 460 , which are threadingly engaged to the threads 500 of the extension 475 of the front sloped actuator 450 , and consequently can push or pull the extension 475 and therefore the front sloped actuator 450 towards or away from the rear sloped actuator 455 and the linear actuator 460 , dependent upon which direction the linear actuator 460 is rotated.
[0164] With continued reference to FIGS. 58-62 , rear sloped actuator 455 may comprise an opening 456 . The opening 456 may be disposed in the center of the rear sloped actuator 455 and may run longitudinally throughout the entirety of the rear sloped actuator 455 . The opening 456 may be sized to receive the extension of the 475 of the front sloped actuator 450 with the extension 466 of the linear actuator 460 disposed therein. The rear sloped actuator 455 also contains a front side 458 which faces the extension 475 of the front sloped actuator 450 . The front side 458 of the rear sloped actuator 455 has opposing sloped surfaces 459 , that are sloped towards the extension 475 and consequently the front sloped actuator 450 . The front side 458 of the rear sloped actuator 455 also comprises the elevated and angled tongues 495 that engage the slots 490 of the halves of the upper 480 and lower 485 endplates, as described above. As best seen in FIGS. 61 and 63 , in an exemplary embodiment, the rear sloped actuator 455 comprises tool engagement surfaces 510 . Tool engagement surface 510 is a surface for engagement of a placement and positioning tool (not shown) which allows for insertion and adjustment of the fusion device 10 into an intervertebral space as best shown in FIG. 1 . Tool engagement surfaces 510 may be located horizontally on opposing sides of sloped rear actuator 455 .
[0165] As discussed above, the linear actuator 460 may comprise a head portion 465 and an extension 466 . Surface threads 470 may be disposed on the extension 466 of the linear actuator 460 . Surface threads 470 are complimentary to and engage the threads 500 of the extension 475 of the front sloped actuator 450 . In another embodiment, the extension 466 includes ratchet teeth for engaging the front sloped actuator 450 . Linear actuator 460 also comprises opening 468 in the head portion 465 of linear actuator 460 . In the illustrated embodiment, the opening 468 includes one or more instrument gripping features 472 that can allow it to be turned by a suitable instrument. Linear actuator 460 may disposed in the opening 456 of the rear sloped actuator 455 with the extension 466 running through the opening 456 . The head portion 465 may be of a diameter that is too large to pass through the opening 456 and thus allows the linear actuator 460 to reach an endpoint where it, or from another perspective the front sloped actuator 450 , cannot be drawn closer through rotation of the linear actuator 460 .
[0166] As best seen in FIGS. 60-62 , in an exemplary embodiment, the front sloped actuator 450 comprises an extension 475 further comprising threads 500 that engage the surface threads 470 of the linear actuator 460 . Thus, as the linear actuator 460 is rotated in a first direction by a threaded instrument (not shown), the front sloped actuator 450 moves toward the flanged end 465 of the linear actuator 460 . In the event the fusion device 10 needs to be repositioned or revised after being installed and expanded, the fusion device 10 can be contracted back to the unexpanded configuration, repositioned, and expanded again once the desired positioning is achieved. To contract the fusion device 10 , the thread locking screw 460 can be rotated in a second direction. As discussed above, actuator assembly 445 is in threaded engagement with the extension 475 of the front sloped actuator 450 ; thus, as linear actuator 460 is rotated in a second direction, opposite the first direction, the front sloped actuator 450 moves with respect to the actuator assembly 445 and the upper and lower endplates 480 , 485 away from the flanged end 465 .
[0167] With reference to FIGS. 58-59, and 63 , in an exemplary embodiment the upper and lower endplates 480 , 485 may further comprise endplate pins 515 . As illustrated, the upper and lower endplates 480 , 485 may each comprise two endplate pins 515 . Endplate pins 515 may rest in slots disposed in each portion of the upper and lower endplates 480 , 485 . In the illustrated embodiment, the endplate pins 515 connect the portions of the upper endplate 480 and the portions of the lower endplate 485 . Endplate pins 515 can provide for even and simultaneous movement of endplate portions. With specific reference to FIGS. 64( a ) and 64( b ) , endplate pins 515 can be seen in both the unexpanded fusion device configuration as shown in FIG. 64( a ) and the expanded fusion device configuration as shown in FIG. 64( b ) .
[0168] In an exemplary embodiment, FIG. 65 depicts bone graft hole 520 , which is shown disposed in upper endplate 480 . Bone graft hole 520 in conjunction with threaded hole 470 of the linear actuator 460 provides space for bone grafts that may be used in the intervertebral fusion procedure.
[0169] A method of installing the expandable fusion device 10 of FIGS. 58-65 is now discussed in accordance with one embodiment of the present invention. Prior to insertion of the fusion device 10 , the disc space may be prepared as described above. The expandable fusion device 10 can then be inserted into and seated in the appropriate position in the intervertebral disc space. In an embodiment, the device 10 is assembled prior to insertion. The expandable fusion device 10 can be introduced into the intervertebral space, with the end having the first end of the front sloped actuator 450 being inserted. In an exemplary method, the fusion device 10 is in the unexpanded position when introduced into the intervertebral space. In an exemplary method, the intervertebral space may be distracted prior to insertion of the fusion device 10 . The distraction provides some benefits by providing greater access to the surgical site making removal of the intervertebral disc easier and making scraping of the endplates of the vertebral bodies 2 , 3 easier as depicted in FIG. 1 .
[0170] With the fusion device 10 inserted into and seated in the appropriate position in the intervertebral disc space, the fusion device 10 can then expand into the expanded position. To expand fusion device 10 , an instrument may be engaged with the instrument gripping features 472 the linear actuator 460 . The threaded instrument may rotate the linear actuator 460 in the first direction, drawing the front sloped actuator 450 and the rear sloped actuator 455 together and contracting the actuator assembly 455 . In an exemplary embodiment the front sloped actuator 450 and the linear actuator 460 may be drawn together in a linear fashion with the threads 500 of the extension 475 of the front sloped actuator 450 engaging the surface threads 470 of the linear actuator 460 as a means for controlling the movement of the contraction of the actuator assembly 445 and consequently the expansion of the upper and lower endplates 480 , 485 , which expand horizontally and vertically with contraction of the actuator assembly 445 .
[0171] It should also be noted that the expansion of the upper and lower endplates 480 , 485 may be varied based on the differences in the dimensions of the sloped surfaces 454 and 459 and the direction of the angle in the elevated and angled tongues 495 . As best seen in FIG. 16 , the upper and lower endplates 480 and 485 can be expanded in any of the following ways: straight rise expansion, straight rise expansion followed by a toggle into a lordotic expanded configuration, or a phase off straight rise into a lordotic expanded configuration.
[0172] Although the preceding discussion only discussed having a single fusion device 10 in the intervertebral space, it is contemplated that more than one fusion device 10 can be inserted in the intervertebral space. It is further contemplated that each fusion device 10 does not have to be finally installed in the fully expanded state. Rather, depending on the location of the fusion device 10 in the intervertebral disc space, the height of the fusion device 10 may vary from unexpanded to fully expanded. It should be noted that, as well as the height being varied from an unexpanded state to an expanded state, the fusion 10 may be positioned permanently anywhere between the expanded state and the unexpanded state.
[0173] Referring now to FIGS. 66-73 , an alternative embodiment of the expandable fusion device 10 is shown. In the illustrated embodiment, the fusion device 10 includes an upper endplate 570 , a lower endplate 580 , and a collective actuator assembly 520 . The collective actuator assembly 520 comprises a front sloped actuator assembly 530 , a rear sloped actuator assembly 540 , and threaded locking screws 550 . In an embodiment a threaded instrument 560 functions to pull the front sloped actuator assembly 530 and the rear sloped actuator assembly 540 together, which forces apart the upper endplate 570 and lower endplate 580 .
[0174] With reference to FIGS. 66-68 and 71 , in an exemplary embodiment of fusion device 10 , the collective actuator assembly 520 comprises a front sloped actuator assembly 530 , a rear sloped actuator assembly 540 , and threaded locking screws 550 . The threaded locking screws 550 have flanged ends 551 and surface threads 552 that extend at least partially through the collective actuator assembly 520 . It should be understood that, while the surface threads 552 of the threaded locking screws 550 are referred to as threaded, the surface threads 552 may only be partially threaded in accordance with one embodiment. The threaded locking screws 550 of the collective actuator assembly 520 may rest in an opening 541 in the rear width actuator 542 of the rear sloped actuator assembly 540 where the surface threads 552 of the threaded locking screws 550 engage threaded screw openings 595 of the front height actuator 532 of the front sloped actuator assembly 530 . The threaded instrument 560 ( FIG. 72 ) may extend through an instrument opening 561 in the rear width actuator 542 of the rear sloped actuator assembly 540 . As the threaded instrument 560 is rotated in a first direction, the collective actuator assembly 520 pulls the front sloped actuator assembly 530 towards the rear sloped actuator assembly 540 and consequently also towards the flanged ends 551 of the threaded locking screws 550 in a linear direction. As the front sloped actuator assembly 530 is pulled towards the rear sloped actuator assembly 540 , the front width actuator 536 and the rear width actuator 542 are pulled together. As they are pulled together, the front and rear width actuators 536 , 542 drive apart the portions of the upper endplate 570 and the portions of the lower endplate 575 . More particularly, the front and rear width actuators 536 542 engage the front height actuators 532 and the rear height actuators 546 to force them horizontally outward, which in tum engage the upper and lower endplates 570 , 575 to force them horizontally outward. The front stop pins 533 may have one end disposed in the retaining bores 534 of the front height actuator 532 and opposite ends disposed in the front stop pint track 535 of the front width actuator 536 . The front stop pins 533 may slide in the front stop pin track 535 of the front width actuator 536 until they reach the end of the front stop pin track 535 and movement of the front width actuator 536 is stopped, thus restricting lateral expansion of the device 10 , as best seen on FIG. 68 . Simultaneously, the rear stop pins 543 disposed in the retaining bores 544 of the rear width actuator 542 , slide in the rear stop pin tracks 545 of the rear height actuators 546 until they reach the end of the rear stop pin tracks 545 and movement of the rear width actuator 542 is stopped, as best seen on FIGS. 68 and 71 . When the front width actuator 536 is stopped, the front sloped actuator assembly 530 may be pulled towards the rear sloped actuator assembly 540 , by simultaneously turning threaded locking screws 550 . As threaded locking screws 550 are rotated simultaneously in a first direction, the sloped surfaces 537 , 547 respectively, of the front height actuators 532 and the rear height actuator 546 push the upper 570 and lower 580 endplates vertically outward into the expanded position.
[0175] With reference to FIGS. 66-68 , in an exemplary embodiment, the upper and lower endplates 570 , 580 may split into two portions, such as being bifurcated into two opposing mirrored halves. The portions of the upper endplate 570 maybe substantially identical to the portions of the lower endplate 580 in embodiments of the present invention. Both the upper and lower endplates 570 , 580 may comprise front and rear ends 571 , 572 . The front and rear ends 571 , 572 of each portion of each endplate may be substantially similar to the front and rear ends 571 , 572 of every other portion of every other endplate. It should be understood that that references to the front and rear ends 571 , 572 of each endplate are with respect to the front and rear of the expandable fusion device 10 , which is with respect to the direction of placement into an intervertebral disc space with the front of the expandable fusion device 10 placed into the space first, followed by the rear of the expandable fusion device 10 . Each portion of the upper and lower endplates 570 , 580 further comprises front and rear ramped surface portions 573 , 574 , as a component of the front and rear ends 571 , 572 of each portion of the upper and lower endplate 570 , 580 respectively. The front ramp surface 573 is located on the front end 571 of each portion of the upper and lower endplates 570 , 580 . The rear ramp surface 574 is located on the rear end 572 of each portion of the upper and lower endplates 570 , 580 . The front and rear ends 571 , 572 of each half of upper endplate 570 contains a slot 575 that engages the corresponding elevated tongues 590 of the front height actuator 532 and the rear height actuator 546 of the front sloped actuator assembly 530 and the rear sloped actuator assembly 540 respectively. The elevated tongues 590 may be substantially identical in design and function for both the front height actuator 532 and the rear height actuator 546 .
[0176] As best seen in FIGS. 66-67 and 69 , the front sloped actuator assembly 530 may comprise a front width actuator 536 . As illustrated, the front width actuator 536 may be wedge-shaped. The front width actuator 536 may further comprise a sloped front end 538 . The sloped front end 538 may be the section of the expandable fusion device 10 that is first inserted into an intervertebral disc space. The front width actuator 536 may further comprise a front stop pin track 535 that is complimentary to the front stop pins 533 . The front width actuator 536 may also comprise a threaded instrument opening 539 . The threaded instrument opening 539 also comprises threads that engage the threaded instrument 560 . The front sloped actuator assembly 530 may also comprise a pair of front height actuators 532 . The front height actuators 532 may be mirrored analogues that have substantially the same function. The front width actuator 536 may be disposed between the pair of front height actuators 532 . The front height actuators 532 comprise a sloped surface 537 and elevated tongues 590 that vertically expand the upper 570 and lower 580 endplates. The front height actuators 532 additionally comprise a threaded screw opening 595 . The threaded screw opening 595 engages the threaded locking screws 550 . When threaded locking screws 550 are turned in a first direction, upper 570 and lower 580 endplates are expanded vertically, due to the contraction of the front sloped actuator assembly 530 and the rear sloped actuator assembly 540 . Front height actuators 532 may additionally comprise retaining bores 534 , wherein the front stop pins 533 are disposed.
[0177] Rear sloped actuator assembly 540 may comprise a rear width actuator 542 . As illustrated, the rear width actuator 542 may be generally wedge-shaped. The rear width actuator 542 may further comprise an instrument opening 561 wherein the threaded instrument 560 may be inserted to operate the expandable fusion device 10 . The rear width actuator 542 may additionally comprise openings 541 . Threaded locking screws 550 may be inserted into openings 541 of the rear width actuator 542 and run through the collective actuator assembly 520 to connect to the threaded screw openings 595 in the front height actuators 532 . Rear width actuator 542 may additionally comprise retaining bores 544 which house the rear stop pins 543 . The rear stop pins 543 are fixed in the retaining bores 544 and do not move relative to and apart from the retaining bores 544 . The rear stop pins 543 and retaining bores 544 may be present in pairs, located on the top and bottom of the rear width actuator 542 . Rear stop pins 543 connect the rear width actuator 542 to the rear height actuators 546 . Rear height actuators 546 comprise rear stop pin tracks 545 in which the rear stop pins 543 may be disposed. When the threaded instrument 560 is turned in a first direction to contract the collective actuator assembly 520 and draw the front sloped actuator assembly 530 and the rear sloped actuator 540 , the rear stop pins 543 slide in the rear stop pin tracks 545 to expand the upper and lower endplates 570 , 580 horizontally, until the rear stop pins 543 contact the end of the rear stop pin tracks 545 . The rear sloped actuator assembly 540 may also comprise a pair of rear height actuators 546 . The rear height actuators 546 may be mirrored analogues that have substantially the same function. The rear width actuator 542 may be disposed between the pair of rear height actuators 546 . Rear height actuators 546 may comprise a sloped surface 547 and elevated tongues 590 that vertically expand the upper 570 and lower 580 endplates. Sloped surface 547 is sloped towards the front sloped actuator assembly 530 . Elevated tongues 590 engage the corresponding slots 575 of the upper 570 and lower 580 endplates.
[0178] As discussed above, the threaded locking screws 550 of the collective actuator assembly 520 , may each comprise a flanged end 551 and surface threads 552 . Surface threads 551 are disposed on the front end 553 of the threaded locking screws. The front end 553 of the threaded locking screws 550 are longitudinally opposite the flanged ends 551 of the threaded locking screws 550 . Surface threads 551 are complimentary to and engage the threads of the threaded screw openings 595 of the front height actuators 532 of the front sloped actuator assembly 530 . Threaded locking screws 550 also comprise an instrument opening 554 in the flanged ends 551 of the threaded locking screws 550 . In an exemplary embodiment, the instrument opening 554 is configured and dimensioned to receive a locking screw instrument (not shown). Threaded locking screws 550 are disposed in the threaded screw openings 541 of the rear width actuator 542 with the front end 553 running through the threaded screw openings 541 . The flanged ends 551 may be of a diameter that is too large to pass through the threaded screw openings 541 and thus allows the threaded locking screws 550 to reach an endpoint where it, or from another perspective the front sloped actuator assembly 530 , cannot be drawn closer through rotation of the threaded locking screws 550 .
[0179] As best seen in FIG. 68 , as the threaded locking screws 550 are rotated in a first direction by a locking screw instrument (not shown), the front height actuators 532 are pulled towards the flanged ends 551 of the threaded locking screws 550 . In the event the fusion device 10 needs to be repositioned or revised after being installed and expanded, the upper 570 and lower 580 endplates of fusion device 10 can be contracted back to the unexpanded configuration, repositioned, and expanded again once the desired positioning is achieved. To contract the endplates 570 , 580 of fusion device 10 , the threaded instrument 560 and the threaded locking screws 550 can be rotated in a second direction. As discussed above, rear sloped actuator assembly 540 is in threaded engagement with the front sloped actuator assembly 530 ; thus, as the threaded instrument 560 is rotated in a second direction, opposite the first direction, the front sloped actuator assembly 530 is pushed away from the rear sloped actuator assembly 540 and the upper 570 and lower 580 endplates are pulled inward horizontally, this may continue until the front stop pins 533 and the rear stop pins 543 reach the end of their collective stop pin tracks 535 and 545 respectively. When the upper 570 and lower 80 endplates have been contracted to their initial unexpanded horizontal positions, the threaded locking screws 550 can be turned in a second direction opposite the first direction. Rotating the threaded locking screws 550 in a second direction will continue to push the front sloped actuator assembly 530 away from the rear sloped actuator assembly 540 . This can continue, until the endplates 570 , 580 are fully contracted into the default unexpanded configuration.
[0180] With reference to FIGS. 66-68 , in an exemplary embodiment the upper and lower endplates 570 , 580 each comprise endplate pins 600 . As illustrated, the upper and lower endplates 570 , 580 each comprise two endplate pins 600 . Endplate pins 600 rest in slots disposed in each half of the upper and lower endplates 605 , 610 . Endplate pins 600 connect the halves of the upper endplate 470 and the halves of the lower endplate 580 . Endplate pins 600 provide for even and simultaneous movement of endplate halves.
[0181] In an exemplary embodiment, FIGS. 71( a )-71( c ) depict bone graft hole 615 in the upper and lower endplates 570 , 580 . Bone graft hole 615 in conjunction with the threaded instrument opening 561 provides space for bone grafts that may be used in the intervertebral fusion procedure.
[0182] A method of installing the expandable fusion device 10 of FIGS. 66-72 is now discussed in accordance with one embodiment of the present invention. Prior to insertion of the fusion device, the disc space may be prepared as described above. The expandable fusion device 10 can then be inserted into and seated in the appropriate position in the intervertebral disc space. In an embodiment, the device 10 is assembled prior to insertion. The expandable fusion device 10 can be introduced into the intervertebral space, with the end having the first end of the front sloped actuator 450 being inserted. In an exemplary method, the fusion device 10 is in the unexpanded position when introduced into the intervertebral space. In an exemplary method, the intervertebral space may be distracted prior to insertion of the fusion device 10 . The distraction provides some benefits by providing greater access to the surgical site making removal of the intervertebral disc easier and making scraping of the endplates of the vertebral bodies 2 , 3 easier as depicted in FIG. 1 .
[0183] With the fusion device 10 inserted into and seated in the appropriate position in the intervertebral disc space, the fusion device 10 can then expand into the expanded position. To expand fusion device 10 , a threaded instrument is inserted into the threaded instrument opening 561 and the threaded instrument opening 539 of the rear sloped actuator assembly 540 and the front sloped actuator assembly 530 respectively. The threaded instrument is rotated in the first direction, drawing the front sloped actuator assembly 530 and the rear sloped actuator 540 together and contracting the collective actuator assembly 520 . In an exemplary embodiment the front sloped actuator assembly 530 and the rear sloped actuator assembly 540 are drawn together in a linear fashion with the threads of the threaded instrument opening 539 of the front sloped actuator assembly 530 engaging the surface threads 561 of the threaded instrument 560 as a means for controlling the movement of the contraction of the collective actuator assembly 520 and consequently the horizontal expansion of the upper 570 and lower 580 endplates, which expand horizontally with contraction of the collective actuator assembly 520 . When horizontal expansion of endplates 570 and 580 has reached its maximum, threaded locking screws 550 may be rotated in a first direction simultaneously to further draw the front actuator assembly 530 towards the rear actuator assembly 540 . This contraction of the collective actuator assembly 520 expands the upper 570 and lower 580 endplates until they reach their maximum vertical expansion.
[0184] It should also be noted that the expansion of the upper 570 and lower 580 endplates may be varied based on the differences in the dimensions of the sloped surfaces 537 and 547 . As best seen in FIG. 16 , the upper 570 and lower 580 endplates may be expanded in any of the following ways: straight rise expansion, straight rise expansion followed by a toggle into a lordotic expanded configuration, or a phase off straight rise into a lordotic expanded configuration.
[0185] Although the preceding discussion only discussed having a single fusion device 10 in the intervertebral space, it is contemplated that more than one fusion device 10 can be inserted in the intervertebral space. It is further contemplated that each fusion device 10 does not have to be finally installed in the fully expanded state. Rather, depending on the location of the fusion device 10 in the intervertebral disc space, the height of the fusion device 10 may vary from unexpanded to fully expanded. It should be noted that, as well as the height being varied from an unexpanded state to an expanded state, the fusion 10 may be positioned permanently anywhere between the expanded state and the unexpanded state.
[0186] The invention being thus described, it will be obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention, and all such modifications as would be obvious to one skilled in the art are intended to be included within the scope of the following claims. Although individual embodiments are discussed, the invention covers all combinations of all those embodiments. | 1a
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CROSS-REFERENCE TO RELATED APPLICATIONS
This is a continuation of U.S. patent application Ser. No. 10/496,327, filed on May 21, 2004, which is a National Stage Application under 35 USC 365 of PCT/EP02/12988 filed on Nov. 20, 2002, which claims priority from Italian Application No. MI2001A002481, filed on Nov. 23, 2001.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention concerns an innovative pharmaceutical form for controlled drug release. In particular, it refers to systems obtained by the assembly of individual release modules, of which the capacity to release the drug in time and in space depends on the way in which the modules have been assembled. The modular structure offers high reproducibility of manufacture and flexibility of release.
2. The Prior Art
The pharmaceutical industry views with great interest the new forms of administration, which are able to release the drug in a pre-programmed way. This technology is known as controlled drug release and it has provided numerous innovative products for the industry and the market. Despite the solutions proposed for the various problems of administration, the variety of the existing drugs and their different requirements continuously create the need for new forms of administration. It is therefore of great interest to be able to find a drug release system that can be adapted to different active principles, changing its characteristics by simple modifications in manufacture.
The number of drugs that have to overcome important problems of administration in order to become products is increasing constantly. It is reasonable to imagine that the near future of pharmacological therapy belongs to the drugs of biotechnological origin which, on account of their chemical structure, present important problems of administration. Nor must one forget the economic and medical value linked to the revaluation of the old molecules, which in innovative forms of administration often find new therapeutic applications. Lastly it is now a common practice to propose the new drugs in the opportune release package, delivering the same through the most suitable pharmaceutical form.
As a result of this scenario, there are various problems to be dealt with concerning drug release control in time and in space. A high number of formula would therefore be necessary, in particular for products intended for administration by mouth, which are the majority of the forms of dosing used in pharmacotherapy, since they are well accepted by patients.
Many of these oral pharmaceutical forms with controlled release have however demonstrated low bioavailability in studies in vivo. This has often been attributed to an unsuitable release speed, to the incomplete liberation of the active principle by the form itself, or to a too short period of permanence in the gastroenteric tract in which absorption takes place.
The patent literature is full of inventions which attempt to solve these problems in an innovative manner.
However, a characteristic shared by all these solutions of the prior art is that a determined drug release curve is obtained with a specific therapeutic formula characterized by a weighted quantity of excipients which are mixed with (or added to) the active principle in such a way as to influence its release. Consequently a modification, even only a marginal one, of the release characteristics generally requires reformulation of the product. For example, in the ambit of coated tablets, a modification of the thickness of the outer layer is necessary, or a modification of the layer's composition, if the speed of release is to be modified. Consequently, the formulae known in the prior art do not allow an adaptation of their release curve to certain requirements without the simultaneous modification of their composition. This general principle also applies in cases where the modification of the release characteristic does not occur by modifying the excipients contained in the formula, but, instead, by choosing determined polymorphs or suitable granule sizes of the active principle.
These products generally come up against a precise problem of controlled release which is overcome with specific means for the environment in which release must occur. For example, in the documentation collected according to the International Patent Classification (IPC), in particular in the groups PCT A61K 9/00, 9/20, it is possible to find quoted numerous patents dedicated to the problem of release with space control, by means of gastro-retentive formulae.
This case deals with the necessity of having a release system, for oral drug administration, that is able to delay the gastrointestinal transit, for example by prolonging the time of permanence in the stomach. To achieve the aim of delayed transit in the digestive tract, various technological solutions have been proposed.
For example, the adhesive properties of certain polymers have been used in order to interact with the gastric and intestinal epithelium. This has allowed the construction of so-called bioadhesive systems. However, these involve certain problems, due in particular to the too localized release of the drug, with possible irritations of the mucosa.
Another solution has concentrated on the planning of systems that are able to float on the gastric content, remaining longer in the stomach. Systems of this type have been formulated with polymers that are able to swell, forming a stable gel in contact with the gastric fluid. The drug is released from these systems by diffusion through the barrier of gelled polymer. These systems therefore present an overlapping between the release of the drug and the mechanism which determines floating.
Other solutions have led to “double layer” systems, in which one layer, containing a hydrophilic polymer and an effervescent mixture, is intended to give floatability to the system, while the other layer is composed of the active principle incorporated in a hydrophilic matrix to prolong its release. This solution, instead, presents the limitation that the floating layer is activated slowly and develops a weak buoyancy. Two objects therefore do not appear to have been solved in the development of these floating systems: the first is the possibility of lifting a high quantity of substance, the second is the object of making the time of immersion necessary to obtain floating as short as possible.
The control of gastrointestinal transit is however only part of the characteristics which a versatile and innovative controlled drug release system ought to possess. In fact most of the systems are made to control the drug release speed, irrespective of the area in which it occurs. In this case too, the patent literature is rich in examples. Among these, one example is illustrated in U.S. Pat. No. 5,534,263.
So, from what has been seen above, there is still a necessity for systems which, my means of simple and reproducible manufacture, allow a variation of drug release in different areas of the gastroenteric tract, with easily modifiable kinetics. Preferably, these kinetics should be modifiable without varying the composition of the systems. There is also the necessity to have a system that is able to satisfy the requirements of release in a certain area of the gastrointestinal tract, controlling the kinetics with which said release occurs, so as to have a constant or pulsating release, adapted to the type of drug carried and to the therapy that is to be provided.
It is therefore an aim of the present invention to overcome the disadvantages of the prior art and to provide systems for the controlled release of an active principle which are more versatile than the currently known forms of administration and which allow the modification not only of the site but also of the kinetics of release of the active principle in the gastrointestinal tract without requiring important contrivances during their manufacture. Preferably, these systems for the controlled release of an active principle should be adaptable to the site and to the release kinetics desired in the gastrointestinal tract without any modification of their composition.
SUMMARY OF THE INVENTION
These and other aims that will appear more clearly below are achieved by a module for controlled drug release in the gastrointestinal tract, composed of a matrix of biocompatible polymers comprising optionally an active principle and excipients generally recognized as safe, said module being of cylindrical or polyhedric shape characterized in that it has
in the case of cylindrical shape, at least one concave cylinder base;
in the case of polyhedric shape, at least one concave face of the polyhedron.
A preferred embodiment of the present invention is composed of a module for controlled drug release in the gastrointestinal tract, composed of a matrix of biocompatible polymers comprising optionally an active principle and excipients generally recognized as safe, said module being of cylindrical or polyhedric shape characterized in that it has
in the case of cylindrical shape, one of the two bases of the cylinder concave and the other convex;
in the case of polyhedric shape, at least one of the faces of the polyhedron concave and at least one other of the faces of the polyhedron convex.
According to a preferred but not exclusive embodiment of the present invention, at least two modules assembled as describe above are provided, or at least one module as described above assembled with a cylindrical/polyhedric element with flat bases. While the modules according to the invention—when administered in non assembled form—must always comprise at least one active principle, instead, in the assemblies according to the invention, it is also possible to incorporate further modules according to the invention which are however without active principle (so-called “auxiliary” modules). This is possible in all those cases in which the assembly already comprises, at least one module according to the invention containing active principle or at least one cylindrical/polyhedric element with a flat base, also containing active principle. Hence, on account of its utility in the construction of an assembly according to the invention, also the “auxiliary” module according to the invention is to be understood as a module “for controlled drug release in the gastrointestinal tract”.
Returning now to the particular geometry of the modules according to the invention, according to a preferred embodiment, the concave base/face of a first cylindrical/polyhedric module according to the present invention is configured in such a way as to be able to accommodate a corresponding convex base/face of a second module according to the invention to give an assembly between the two modules. Preferably, the joint thus obtained between the two modules is not visible from the outside of the resulting assembly. Preferably, this joint is also sufficiently strong from a mechanical point of view to hold the two modules together in conditions of use. Moreover, according to the same or according to a further preferred embodiment of the invention, the concave base/face of a first cylindrical/polyhedric module according to the present invention is configured in such a way as to allow to obtain an assembly with an internal (that is totally isolated) cavity to be obtained if said concave base/face is placed adjacent to a planar base/face of a second module according to the invention (or of a cylindrical or polyhedric-element), or if said concave base/face of said first module is placed adjacent to a concave base/face of the second module according to the invention. The internal cavity produced in the resulting assembly (obtained then by subsequent gluing/welding of the adjacent bases/faces)—in the case of concave bases/faces placed adjacent to each other—is larger than the one obtained in the case of a concave face/base placed adjacent to a flat one.
According to a further aspect of the present invention, a method is provided for the production of a module according to the present invention comprising the following steps:
the provision of a biocompatible polymer in a granule size suitable for compacting by pressure, and, optionally,
the provision of an active principle and of optional excipients generally recognized as safe,
the mixing of the components provided,
the compression of the mixture of components or of only the granules of biocompatible polymer in a tablet press provided with at least one convex punch for giving a concave base/face to the compressed module thus obtained.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention described and claimed in the present patent application is further illustrated in the enclosed Figures, which refer to a preferred but not exclusive embodiment of the invention and in which:
FIG. 1 is a schematic representation of a side section of an individual module according to the present invention with a cylindrical shape, having one base concave and the other base convex;
FIG. 2 is a representation of the three-dimensional side view of the same module according to the present invention;
FIG. 3 is a schematic representation of a side section of the punches that may be used for making the individual modules according to the present invention (in particular the one represented in FIG. 1 or 2 ) by compression;
FIG. 4 is a three-dimensional side view of four individual modules according to the invention stacked in such a way that the convex base fits into the concave base to give a single assembly according to the present invention;
FIG. 5 is a three-dimensional side view of four individual modules according to the invention assembled with the concave bases reciprocally fitted together to give two assemblies according to the present invention;
FIG. 6 is the graphic representation of the comparison, according to example 1, between the release of the drug acyclovir (in percentage, shown on the Y axis; in time (min), shown on the X axis) by an element with a cylindrical shape and flat bases (rhombi) and by an individual module with a cylindrical shape having one concave base and one convex base according to the invention (circles);
FIG. 7 is the graphic representation of the comparison, according to examples 2 and 3, between the release of the drug acyclovir (in percentage, shown on the Y axis; in time (min), shown on the X axis) by four individual modules according to the invention with a cylindrical shape having one concave base and one convex base (circles) and by an assembly according to the present invention composed of four modules having one concave base and one convex base assembled in such a way that the convex faces fit into the concave ones to give a long cylinder as in FIG. 4 (rhombi) and by two assemblies according to the present invention composed in turn of two modules with a cylindrical shape having one concave base and one convex base according to the invention, assembled in such a way that the concave bases face each other reciprocally, as in FIG. 5 (squares).
Even though not explicitly represented in the FIGS. 1-7 it is however implied that, according to further preferred embodiments of the present invention, the individual modules according to the invention with a cylindrical shape may have two concave bases or one flat base and the other concave. Even though not explicitly represented in the FIGS. 1-7 it is however implied that, according to further preferred embodiments of the present invention, the individual modules, instead of being cylindrical, may also be polyhedric (for example they may form tetrahedrons, prisms or cubes), at least one of the faces of the polyhedron being concave and, optionally, at least one other of the faces of the polyhedron being convex. For example, a polyhedric module according to the present invention may be cubic and have one concave face and one convex face, or have two concave faces, or two convex faces and three concave faces, and so on.
SOME ASPECTS OF THE INVENTION
According to the invention described in the present patent application, a new kit is therefore provided for the preparation of new drug release systems having characteristics such as to satisfy various requirements of time or space control of release. These new systems are made according to a modular principle, based on a construction unit called a module (release module or “auxiliary” module). Like a brick used for building a wall, the (release or “auxiliary”) module is a unitary element which has an autonomous function of its own, but which, when grouped together with other like or similar modules, it gives rise to a system which releases the drug with different kinetics, or in different tracts of the gastrointestinal apparatus, depending on how the individual modules have been assembled. For the present invention it is essential that the module (release or “auxiliary”) be composed of a matrix with a cylindrical or polyhedric shape, characterized in that at least one base/face of the matrix is concave. According to a preferred embodiment of the invention, it is essential that the module (release or “auxiliary”) be composed of a matrix with a cylindrical or polyhedric shape, characterized in that at least one base/face of the matrix is concave and at least one other convex. This matrix is a non disintegrating monolith, composed of a mixture of active principle (and eventually of excipients generally recognized as safe) with a biocompatible polymer which in some applications may be a hydrophilic polymer, which gels and/or swells in the presence of an aqueous solvent. The preferred technique for manufacturing the matrix is that of the compression of powders. It is important to note that the particular geometry of the bases or faces of the cylindrical or polyhedric matrix which forms the release module is already itself an element for the control of the speed of release of the drug from the same. For example, especially when the polymer is of the hydrophilic type, the two bases of the cylindrical module, of which, for example one is concave and the other convex, alter the swelling of the module and therefore the drug release kinetics. With respect to a “simply cylindrical”, element, that is a cylindrical tablet with flat base with an identical composition, the geometry of the module with the bases modified according to the present invention produces with the same weight varied kinetics, since in the initial stages the swelling of the matrix does not take place isotropically.
But the point which more than any other qualifies the invention described in the present patent application is that the innovative geometric shape of the release modules allows further elements to be provided for exerting space and time control of the release from the system. In fact, according to a preferred embodiment of the present invention, by fitting the convex face of one module into the concave face of another, different release modules may easily be stacked one on another, to produce a long cylinder. Generally, such stacked modules are introduced preferably, but not necessarily, in a hard gelatine capsule to assist their administration by mouth. In the gastrointestinal tract, during the drug release phase when the optional capsule has been disintegrated, the stacked modules, depending on the biocompatible polymer material of which the matrix is made—and depending on the quality of the join obtained by the assembly of the convex faces with the respective concave faces—separate or do not separate into the individual modules.
In particular, in some conditions, for example due to the adhesive properties of the gelled hydrophilic polymers, the stacked release modules may remain stuck together, forming a so-called assembly according to the present invention and producing release kinetics different from that obtained with separate modules. However, it should be stressed that even with non-adhesive polymers, depending on the hardness of the modules and on the geometric design of the concave and convex faces, it is possible to obtain a fairly stable and lasting mechanical join so as to give assemblies according to the present invention which, during the drug release phase, also do not separate into the individual modules. Moreover, even in cases where the adhesive or mechanical properties of the polymers used are poor, to obtain an assembly according to the present invention which allows a variation of the drug release kinetics, it is always possible to reinforce the join between the modules by gluing or welding (for example thermal welding or with ultrasounds) of the individual modules so that the assembly thus obtained has the shape of a long cylinder, the component modules of which cannot come apart. This more stable assembly is obtained, for example, by placing a small quantity of solvent or of adhesive solution between one module and the other, before introducing them in the gelatine capsule.
The inventors of the present patent application have also found that, since it is possible to stack the modules differently from simply fitting a convex face into a concave one, the possibilities of release control are even greater. For example, in the case where two modules are welded together with a solvent or an adhesive solution, placing the two concave faces in contact (“joining”), a two-module system is created which has an air chamber inside it. This obtains immediate floating of the system with two welded modules when it is immersed in water. Also these two-module systems can be administered directly or after having been inserted in a rigid gelatine capsule.
In addition, since the two modules welded by the concave faces give rise to a system with a cylindrical shape ( FIG. 5 ) which has two convex bases, it is possible to add further modules, fitting their concave bases against the two convex bases of the floating system. The result obtained is a system, still floating, which contains more drug and possesses a still different release kinetic. The inventors of the present patent application have also found that the cavity formed when gluing together two modules according to the present invention, concave face against concave face, before welding of the two modules, can be filled with a dispersion of a drug in an excipient, preferably presenting a low melting point such as semi-synthetic glycerides or cacao butter. This combination allows an assembly which carries a further dose of drug destined to be released after a certain period of time, or in a different area of the gastrointestinal tract, in the moment in which the system is then demolished.
Lastly in the case where, individual modules having a different form and composition are assembled with the modules which possess two modified faces, further drug release systems are obtained which produce different kinetics and different space-time behaviors. In particular, in the case of the assemblies according to the invention—and preferably in the case where said assemblies contain cavities (to guarantee the floating of the assembly or to carry drugs released only at the moment of demolition of the matrix)—it is also possible to use, for the construction of the assemblies, further to the release modules according to the invention as described above, at least one further module according to the invention (so-called “auxiliary” module) which is also composed of a matrix of biocompatible polymers but without a active principle. Lastly, said “auxiliary” modules according to the invention (like their respective equivalents comprising instead the active principle) can also be combined with “simply” cylindrical elements, that is with flat bases (or with “simply” polyhedric elements, that is with flat faces), also composed of a matrix of biocompatible polymers and comprising an active principle, thus obtaining further assemblies according to the present invention. It has been seen how, using the new modules of the present invention, it is possible to construct—even incorporating elements with a traditional geometry (e.g. tablets)—new assemblies with modified drug release kinetics, for example new floating assemblies.
It has also been seen how the present invention, with respect to the prior technique, allows various advantages to be obtained, for example:
the extreme ease of manufacture of the tablet to be used as the release or auxiliary module (e.g. in the case of the cylindrical module with one concave base and the other convex) with the ordinary techniques for compressing powders;
the manufacture of different drug release systems by simply combining together some of these modules having a precise composition and a particular geometry, fitting the convex face into the concave one, obtaining respective assemblies;
the possibility of constructing release systems with a very elongated cylindrical shape, favoring the assembly of the modules with an adhesive solution to give respective assemblies;
the possibility of time and space control of the release of active principle by the modules according to the invention, deriving from the modular principle and in particular from the specific way in which the modules have been assembled, without changing the composition and the geometry of the individual modules;
the obtaining of varied drug release kinetics according to the number and respective position of the modules in the release system;
the obtaining of a prolonged release in a specific site of the stomach, in the case where two modules have been joined together to create a cavity in the assembly obtained, allowing it to float;
the obtaining of a system able to provide a delayed impulse of active principle for release in the colon, in the case where the cavity between two assembled modules is filled with a preferably semi-solid mixture comprising an active principle;
the increased possibility of flexibility of release by mixing modules with a different composition or different geometry in the assemblies.
DETAILED DESCRIPTION OF THE INVENTION
An important aspect of the invention is the release module and its manufacture. For reasons of ease and versatility of the product, using classical techniques and ordinary compressing machines, it has been possible to produce a release module having the shape of a cylindrical polymer matrix with one concave base and the other convex ( FIGS. 1 and 2 ). One of the reasons for this new geometry is that it favors the assembly of the release modules, to obtain a system that cannot be made directly, in which to change the kinetics according to the type of assembly.
To increase the capacity of the release modules to remain assembled together and to control drug release, a component may be introduced into the composition such as a swelling and gelling hydrophilic polymer, generally, but not necessarily, with a high molecular weight. In this case the composition of the module is that of a hydrophilic matrix. These types of polymer are easily available on the market, for example, as illustration without limitation, hydroxypropylmethylcellulose, known by the commercial name METHOCEL® hydroxypropyl methylcellulose in grades K4M, K15M and K100M (Dow Chemical Company); or other polymers such as xanthan gum, pectin, carrageenans, guar gum. The quantity of these polymers used to obtain the control of the release of active principle by the release module is that commonly described in the literature, and varies preferably between 20 and 60% weight/weight referred to the total composition of the matrix which may also comprise excipients generally considered safe as well as the active principle which may be any one of the active principles contemplated by the Pharmacopoeia for oral administration. With respect to the total composition, the contribution of the active principle varies preferably between 80% and 0.0001% weight/weight.
The inventors of the present patent application have found that the assembly of the release modules making up the finished system (“assembly”) can be easily obtained, including in the release module a polymer with strong adhesive properties such as sodium carboxymethylcellulose, carboxypolymethylene, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polymethacrylate or others. In this way, the release system can be obtained by inserting the release modules in a hard gelatine capsule, in the sequence concave face against convex face, so that they are in close contact with each other in forming the assembly. When the gelatine capsule is immersed in the gastric fluid at 37° C., the gelatine component softens and dissolves, creating, around the pile of modules inserted in the capsule, a layer of sticky material which holds them together for a brief period due to the complete dissolving of the gelatine. During this period the gastric fluid also comes in contact with the modules included in the capsule. They are thus able to gel on the outside, giving rise to a sticky layer which welds them very firmly together. A cylindrical assembly is thus obtained (with one concave base and the other convex, as in FIG. 4 ), having the same base area as the modules of which it is composed, with a height smaller than the sum of the individual heights of the single modules. This cylinder, which possesses an unusual geometry for pharmaceutical forms, may (in the case of polymers with a low apparent density), but need not, show the capacity to float due to the intrinsic property of the modules of which it is composed. It is subject to a very slow phenomenon of swelling and dissolving, which guarantees slow drug release and self-destruction only at the end of the drug release period.
Since the individual modules are assembled to obtain various release systems, in some situations it is preferable that they are assembled in such a way as to produce an assembly in which the various individual modules are even more firmly fitted and stuck together. In this case the gluing of the modules fitted convex face into concave face ( FIG. 4 ) is further strengthened with a solution or suspension of a biocompatible polymer such as ethylcellulose, cellulose acetate phthalate or other polymers, but also with an aqueous solution of water-soluble polymers such as high-viscosity carboxymethylcellulose. Alternatively, the welding of the modules may also be obtained by means of thermal welding or ultrasound welding.
Moreover, the inventors of the present patent application have found that, in the case where the modules are welded two by two, concave face against concave face, the resulting assembly, due to the formation of an insulated internal cavity ( FIG. 5 ), besides presenting a varied release kinetics, shows the immediate capacity to float in water (that is even if the apparent density of the polymer matrix exceeds the density of water). This gluing is achieved: by placing in contact the concave faces of the cylindrical modules, on which a small amount of adhesive polymer solution has been applied, or by means of thermal welding or ultrasound welding.
The inventors of the present patent application have also discovered the possibility of creating a floating release system by combining cylindrical modules with one concave and one convex base (or with one concave base and the other flat, or with two concave bases), with other “simple” cylindrical elements with flat bases. The modules with a concave and a convex base according to the invention are intended to give floating capacity (and therefore so-called “auxiliary” modules can, but need not, be used, that is to say modules without active principle, that is composed of biocompatible polymers possibly mixed with excipients generally recognized as safe), whereas the cylindrical elements with flat bases are intended for drug release. This can be achieved by stacking the release element between two or more floating modules depending on its weight. In fact, by placing both flat faces of the release element in contact with a concave base of the floating module, two float chambers are created which are able to develop a total buoyancy able to render floating the new assembly thus obtained. In particular, for the functioning of the finished assembly the release element must be firmly glued to two or more floating modules. In this case the swelling of the two or more floating modules does not interfere with drug release, which takes place through the exposed surface of the release element. After the floating phase, the whole system is slowly destroyed.
In this variation, to further strengthen the floating power, the floating module may be composed of a mixture of a hydrophilic polymer and a low-density hydrophobic component (that is one that reduces the apparent density of the overall polymer matrix). By contact with the gastric fluid or with water, it rapidly reaches a stable floating situation. In order to ensure the correct functioning of the floating element, the composition of the mixture that must provide the hydrostatic thrust is essential. The inventors of the present patent application have found that the maximum result can be obtained by mixing a hydrophobic substance with a hydrophilic one, so as to give the module the lowest possible true density, together with a certain hydrophobia which favors the immediate floating of the element. As a hydrophilic substance for making the floating layer it is possible to use gellable and soluble biocompatible polymers such as: polyvinylpyrrolidone, hydroxypropylmethylcellulose, carboxymethyl cellulose, hydroxypropylcellulose, hydroxyethylcellulose, carboxypolymethylene, gums such as guar gum, xanthan gum, chitosanes, gum arabic, gum tragacanth, sodium and calcium alginates, gelatine, pectins. The hydrophobic substances that can be used may be: hydrogenated oils, cetyl, myristic and stearyl alcohol, esters of fatty acids such as glyceryl mono- or distearate.
To further increase the buoyancy of the floating module it is also possible to include a mixture of salts able to develop CO 2 by contact with gastric fluid: in this case the swelling of the polymer determines the formation of a gelled structure which retains the bubbles of CO 2 that have formed, further reducing the apparent density of the polymer matrix. The effervescent mixture may be composed of substances that produce CO 2 such as: calcium carbonate, calcium bicarbonate, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate.
Lastly, as concerns the composition of the drug release element (cylindrical or polyhedric, with flat bases/faces), as in the case of the release modules provided by the present invention, it can be given by a mixture of active principle, possible excipients generally recognized as safe and a biocompatible polymer, preferably gellable such as polyvinylpyrrolidone, hydroxypropylmethylcellulose, carboxymethyl-cellulose, sodium and calcium alginates, gum arabic, gum tragacanth.
EXAMPLE 1
The first example describes the manufacture and operation of a release module containing acyclovir. It is intended for the preparation of a system composed of a capsule containing various modules stacked in such a way as to give an assembly containing a total quantity of 400 mg of acyclovir.
The unitary formula for preparing 1250 modules, was the following:
X 1 MODULE (mg) Acyclovir 100 Hydroxypropylmethylcellulose 29.5 Sodium carboxymethylcellulose 29.5 NaHCO 3 12.3 Talc 6.2 Mg stearate 1.8
a) Preparation of the Acyclovir Granulate and Mixing of the Components
125 g of acyclovir are blended with about 33 ml of a solution 8% p/v of sodium carboxymethylcellulose (Blanose 7LF). The granulate is obtained by forcing the mixture through the 500μ mesh of the net of an oscillating granulator. The granules are stove-dried with air circulating at 35° C. for about 8 hours. The remaining components of the formula are added to the acyclovir granulate and the whole is mixed in a Turbula for about 40 minutes.
b) Compression
The production of the module by compression is carried out with an alternative tablet press, using special punches with diameter 7.4 mm, the drawing of which is shown in FIG. 3 . The weight of each module was 191.5 mg, the diameter 7.5 mm and the mean height 5.5 mm.
c) Acyclovir Release Speed
The speed at which acyclovir is released from the release module was determined at 37° C. in artificial gastric fluid with the Apparatus 2 USP 24, vane 50 rpm. The profile of the release of acyclovir from the release module is shown in FIG. 6 (circles). About 30% of the drug was released after 120 minutes and about 70% after 500 minutes. The kinetics of release from this module, which has one concave and one convex face, was faster than that of a cylindrical matrix with flat faces ( FIG. 6 , rhombi) having the same composition, prepared with a set of punches with diameter 7.4 mm from the same quantity of mixture. Such comparative result is shown in FIG. 6 .
EXAMPLE 2
Four release modules, prepared according to the technique described in Example 1, were stacked one on another, with the convex faces fitted into the concave faces and stuck with a 0.5% hydroalcoholic solution (2:8) of hydroxypropylmethylcellulose phthalate ( FIG. 4 ). The speed at which acyclovir is released from the capsule was determined at 37° C. in artificial gastric fluid with the Apparatus 2 USP 24, vane 50 rpm.
The release of acyclovir from this stacked system of four modules is shown in FIG. 7 (rhombi), in comparison with the release from the individual modules (circles). In the first 500 minutes the drug release from the four stacked and glued modules was slower and more linear than the release presented by the individual modules.
EXAMPLE 3
Four release modules, prepared according to the technique described in Example 1, were glued two by two, concave face against concave face, wetting the edges of these faces with a 5% hydroalcoholic solution (2:8) p/v of hydroxypropylmethylcellulose phthalate and joining them with a light pressure, to form two assemblies of two modules ( FIG. 5 ).
These assemblies float immediately in the dissolving fluid. The release of acyclovir from these two assemblies ( FIG. 7 , squares) was faster and more linear than that obtained with the four stacked and glued modules ( FIG. 7 , rhombi).
EXAMPLE 4
The example illustrates the preparation of a floating release system which contains the float modules separate from the release elements. For the preparation of 500 floating systems, the following substances are used in the quantities indicated:
Composition of the Release Element
Aluminium hydroxide 95 g Polyvinylpyrrolidone 4 g Magnesium stearate 1 g
Composition of the Floating Module
HydroxypropylmethylCellulose 75 g (METHOCEL ® K 100M) Hydrogenated castor oil (Cutina HR) 15 g Sodium carbonate 5 g Tartaric acid 5 g
Preparation of the Drug Release Element
Granulate the aluminium hydroxide and the active principle with a 1% aqueous solution of polyvinylpyrrolidone. Dry, calibrate on sieve 25 # . Mix with magnesium stearate and compress the mixture with a tablet press equipped with flat punches with diameter 7.4 mm.
Preparation of the Floating Module
Mix the components according to the quantities indicated in a Turbula® mixer for 15 minutes and compress the mixture with a tablet press equipped With punches with a concave and a convex face with diameter 7.4 mm.
Preparation of the Floating Release Systems
For the preparation of the finished assembly, rigid gelatine capsules are used, of the type Snap Fit™ 00, with internal diameter 8 mm and a total closed capsule height of 23.4 mm. The floating modules and the release elements are stuck together by means of a 12.5% solution of cellulose acetate phthalate in acetone, before being inserted in the capsule in the following sequence:
1 floating module
1 release element
1 floating module.
A thin film of adhesive solution is applied on the concave base of a floating module; the flat base of the release element is stuck onto this. The gluing operation is repeated, sticking a second floating module onto the second flat base of the release element.
EXAMPLE 5
For the preparation of 500 floating systems, the following substances are used in the quantities indicated:
Composition of the Release Element
Aluminium hydroxide 95 g Polyvinylpyrrolidone 4 g Magnesium stearate 1 g
Composition of the Floating Module
Crospovidone (Kollidon ® CL) 96 g Tartaric acid 20 g Sodium carbonate 24 g HydroxypropylmethylCellulose 54 g (METHOCEL ® K4M) Talc 4 g Magnesium stearate 2 g
Preparation of the Floating Modules
Let half the dose of Kollidon® CL absorb a quantity equal to its own weight of a 1% aqueous solution of METHOCEL® K4M hydroxypropyl methylcellulose in which the sodium carbonate has been dissolved. Let the mixture dry partly at 80° C. for 30 minutes, sieve it, complete drying and sieve it again.
Let the remaining quantity of Kollidon® CL absorb a quantity equal to its own weight of a 1% aqueous solution of METHOCEL® K4M hydroxypropyl methylcellulose in which the tartaric acid has been dissolved. Let the mixture dry partly at 80° C. for 30 minutes, sieve it, complete drying and sieve it again.
To the two mixtures, add the METHOCEL® K4M hydroxypropyl methylcellulose, the talc and the Mg stearate and mix for 20 minutes in a Turbula® mixer. Compress the mixture with a tablet press equipped with punches with a concave and a convex face with diameter 7.4 mm.
Preparation of the Release Element
Granulate the aluminium hydroxide with the active principle and with a 1% aqueous solution of polyvinylpyrrolidone. Dry, calibrate on sieve 25 # and compress the mixture with a tablet press equipped with flat punches with diameter 7.4 mm.
Preparation of the Finished Systems
For the preparation of the finished system, rigid gelatine capsules are used, of the type Snap Fit™ 00, with internal diameter 8 mm and a total closed capsule height of 23.4 mm. The floating modules and the release elements are stuck together by means of a 12.5% solution of cellulose acetate phthalate in acetone, before being inserted in the capsule in the following sequence:
1 floating module
1 release element
1 floating module.
A thin film of adhesive solution is applied on the base of a release element; the concave base of the floating element is stuck onto this. The gluing operation is repeated, sticking a second floating module onto the second base of the release element.
Accordingly, while only a few embodiments of the present invention have been shown and described, it is obvious that many changes and modifications may be made thereunto without departing from the spirit and scope of the invention. | 1a
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CROSS-REFERENCE TO RELATED APPLICATION
This application is a Continuation-in-Part application of application Ser. No. 480,565, filed Mar. 30, 1983, now U.S. Pat. No. 4,441,640, patented Apr. 10, 1984, by the inventor herein entitled NON-SPILLABLE DRINKING CONTAINER. The subject in its entirety of this parent application is incorporated herein by reference.
BACKGROUND OF THE INVENTION
The present invention is directed to a stackable non-spillable drinking container which includes the inventive concepts disclosed in the parent application and further provides the important advantages of stackability and reduced manufacturing cost.
In the past there had been a need for an effective non-spillable drinking container. There are many applications where such a drinking container would be extremely desirable. Applications include anywhere where there is a need to prevent spills of fluids being drunk, such as soda pop or juice, and there is some increased reason for the likelihood of spillage. For example, soda pop dispensed in movie theaters in drinking cups often results in the spillage by children of some or all of the soda pop on the floor, carpeted aisles, or even the seats, especially during the drinking process. Even with respect to adults, very often the adults will discard the cup of soda on the floor before the cup is completely empty. Unfortunately, the cup is often kicked or bumped over by a patron or otherwise upset before it is removed by the cleaning personnel at the end of the day. This results in a sticky mess on the floor of the theater which involves additional costs in cleaning, and is further likely to reduce the life of items such as carpeting and seat coverings.
Additionally, such a non-spillable drinking container is highly desirable in other applications where there is an increased probability of spillage during drinking, such as in hospitals and nursing homes with debilitated patients and in moving vehicles such as airplanes, boats, ships, trains and automobiles.
In many applications, it is highly desirable for the non-spillable drinking container to be disposable. In other words, once it is used by a movie theater patron or a hospital patient, it may be discarded, there being no intent to retrieve the containers, clean them and reuse them. However, in order for a drinking container to be disposable, it is desirable to keep the cost of manufacture of the container as low as possible. Furthermore, it is highly desirable that a drinking container be stackable to reduce the cost of shipment and storage of the large number of containers which may be utilized where a container is disposable after use.
A non-spillable liquid drinking container is shown in U.S. Pat. No. 2,948,453-Drown. Drown discloses a capable cup in which a perforated straw is spring mounted within a cylindrical tube within the cup. Downward pressure on the straw forces a portion of the straw out of the cylindrical tube to enable flow of liquid through the straw.
The prior art does not disclose a non-spillable drinking container which does not allow spillage even should it be dropped to the floor in a turned down manner. The non-spillable liquid drinking container disclosed in the Drown patent has a removable top and furthermore, if it hit the floor in an upside down manner, the drinking straw would be forced against the spring allowing flow out through the straw. In accordance with the present invention, there is no need to exercise any manual control and the non-spillable drinking container of the present invention automatically provides a non-spill function.
SUMMARY OF THE INVENTION
In accordance with the present invention, a stackable non-spillable drinking container is provided wherein the cost of manufacture and use is reduced both in the manufacture and assembly of the components and in the shipment and storage of the containers prior to use.
The present invention provides a stackable drinking container wherein the container, once assembled, is always in the condition where spills may be avoided, even where a reasonable amount of pressure is applied to the container, or the container is dropped upside down.
Briefly and basically, in accordance with the present invention, there is provided a stackable non-spillable liquid drinking container. A container of linearly increasing cross-section is provided with an open mouth at its larger end and a closed bottom at or near the smaller end. In a preferred embodiment, this container will be of a frustro-conical shape, although it is understood that various other cross-sectional shapes other than that of a cone may be provided, such as hexagonal, octagonal, square, rectangular, etc. A base plate is provided with an expandable diaphragm mounted over substantially one surface of the base plate. The expandable diaphragm is provided with perforations therethrough which are normally closed in the unexpanded state of the expandable diaphragm and which are open when the expandable diaphragm is stretched by movement of a central portion of said diaphragm away from the surface of the base plate. The expandable diaphragm includes means for attachment to a drinking tube. Once the tube is attached to the expandable diaphragm, the base plate is secured in juxtaposition to the bottom of the container. A top for the container is securably mountable over the open mouth of the container. The top includes means for moveably mounting the tube through the top with means for forming a seal between the moveable tube and the top.
BRIEF DESCRIPTION OF THE DRAWINGS
For the purpose of illustrating the invention, there are shown in the drawings forms which are presently preferred; it being understood, however, that this invention is not limited to the precise arrangements and instrumentalities shown.
FIG. 1 is a view in perspective, partially broken away, of a stackable non-spillable drinking container fully assembled in accordance with the present invention.
FIG. 2 is a view in perspective of the assembly of a stackable non-spillable drinking container in accordance with the present invention.
FIG. 3 is a cross-sectional elevation view taken along a center line of a non-spillable drinking container in accordance with the present invention with the expandable diaphragm shown in its expanded state.
FIG. 4 is a broken away cross-sectional view illustrating an alternate embodiment which utilizes a sanitary cover over the drinking tube.
FIG. 5 is a broken away cross-sectional view illustrating an alternate embodiment of the present invention utilizing an alternate means for securing the base plate in juxtaposition to the bottom of the container.
FIG. 6 is a cross-sectional plan view taken along line 6--6 of FIG. 5 of an alternate embodiment of the present invention illustrating another alternative means of securing the base plate in juxtaposition to the bottom of the container.
FIG. 7 is a broken away cross-sectional view illustrating an alternate top for the container.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Referring now to the drawings, wherein like numerals indicate like elements, there is shown in FIGS. 1, 2 and 3 a stackable non-spillable drinking container 110. The present invention may be understood best by simultaneously referring to FIGS. 1, 2 and 3, FIG. 1 being an assembled container with the expandable diaphragm in the unexpanded condition, FIG. 2 being an assembly view and FIG. 3 being a cross-sectional view of an assembled container with the expandable diaphragm in the expanded condition.
The overall non-spillable stackable drinking container is comprised of a container 112 with a top 114 which is securably mountable to the container. Container 112 is formed of a linearly increasing cross-section. The degree of linear increase of cross-sectional size may be preferably selected to maximize the stackability of container 112. Container 112 may be comprised of a sidewall 116 with an open mouth 113 at its larger cross-sectional area and a closed bottom 118 at or near the smaller end. Although bottom 118 is shown being formed flat with the lower ends of sidewall 116, it is understood that the sidewall 116 may project for a slight distance beyond bottom 118 if so desired. Sidewall 116 preferably may be frustro-conical in shape. However, it is understood that the increasing cross-sectional area of container 112 may be provided with other cross-sectional shapes, including, but not limited to, hexagonal, octagonal, rectangular, square, etc. The primary concern is to provide a container 112 of linearly increasing cross-sectional area proceeding from the closed bottom to the open top to provide stackability. However, as discussed hereinafter, top 114 is preferably threadably securably mounted over open mouth 113 of container 112, and the selection of a shape other than frustro-conical for container 112 would require that top 114 be mounted by means other than screw threads, such as a snap on top or a slideable closure.
In accordance with the invention described in the parent application, of which this application is a Continuation-in Part Application, the stackable non-spillable drinking container is provided with an expandable diaphragm 126 having a plurality of perforations 140 which may be slits which may be opened when the drinker pulls upwardly in the direction of arrow 146. Normally slits 140 are closed when expandable diaphragm 126 is not in its expanded condition. The perforations 140 in expandable diaphragm 126 may be in the form of slits 140 as shown in FIGS. 1, 2 and 6. Preferably, these slits, in the unexpanded condition of diaphragm 126 may be formed to have their longitudinal direction perpendicular to the imaginary radial lines of diaphragm 126. Therefore, when there is an upward tension in the direction of arrow 146 on a central portion of diaphragm 126, perforations or slits 140 would be forced open to their maximum condition as diaphragm 126 is expanded. When tube 120 is retracted in the direction of arrow 144 by the release of the upward tension 146 by the lips of the drinker, diaphragm 126 is in its unexpanded condition and perforations or slits 140 are closed. When tube 120 is pulled upwardly in the direction of arrow 146 by the lips or fingers of a drinker, expandable diaphragm 126 is expanded opening perforations 140 which allows fluid flow through the open perforations 140 and up through tube 120 into the mouth of the drinker. When tube 120 is released, it is retracted in the direction of arrow 144 by the elastic forces of contracting diaphragm 126 which may be assisted by sealing means 134 when it is in the form of a bellows 133.
In accordance with the invention described herein, a base plate 125 is provided. An expandable diaphragm 126, as previously described, is mounted to one surface or side of base plate 125. Expandable diaphragm 126 is provided with a means for attaching tube 120 to it. In a preferred embodiment, this attachment means may be the combination of rim 121 formed on the lower end of tube 120 and an opening 130 in a central portion of expandable diaphragm 126. The expandable diaphragm, with its combined base plate 125, may be readily attached to tube 120 by slanting or cocking the expandable diaphragm with respect to rim 121 as shown at 132 in FIG. 2 and forceably inserting rim 121 through opening 130. Once the expandable diaphragm 126 and base plate 125 are attached to the lower end of tube 120, the unit may be inserted into container 112 in juxtaposition to the bottom 118 of container 112 as shown in the various figures, particularly FIG. 3.
Base plate 125, with expandable diaphragm 126 thereon, is held in juxtaposition to closed bottom 118 of container 116 by a securing means which may be in the form of a bead 127 through which base plate 125 is snapped. Securing means may be in the form of a retaining bead 127 which completely encircles the inside surface of sidewall 116. Alternatively, as shown in FIGS. 5 and 6, the securing means retaining the base plate in position may be in the form of a plurality of fingers or projections 132 formed around the inside surface of sidewall 116 near its lower end. The base plate 125 may also be formed of a special shape, such as the base plate having a relatively substantial thickness with the edges having a configuration, such as slants, with the inside of container 112 having a mating slanting surface 128. This provides the advantage of additional rigidity and support for the baseplate with respect to the inside of the container. However, this is a preferred embodiment which is not essential. An alternate embodiment is shown in FIG. 5 wherein the base plate 150 is of a thinner cross-section without special configuration on its edges.
FIG. 5 also discloses an alternate means for securing the base plate in juxtaposition to the bottom of the container, which may be utilized with or without projections 132 as previously discussed. As shown in FIG. 5, a snap type fastener in the form of arrowhead structure 152 is formed on the bottom 154 of container 172 which is adapted to mate with opening 156 in base plate 150. Arrowhead 152 may snappily engage alternate baseplate 150 by snapping through opening 156 formed in base plate 150. Preferably, such an arrowhead retaining structure would be centrally located to obviate any need for manual alignment and would project into the opening of tube 120. A ball or other shape snap, instead of an arrowhead, may serve equally well. Other means of securing the base plate to retain it in juxtaposition to the bottom of the container will be readily apparent to those skilled in the art.
Once the base plate is securly mounted in the bottom of the container with tube 120 attached to diaphragm 126, top 114 may be secured over opening 113. Preferably, top 114 may be threadably engaged to the upper end of sidewall 116 by mating threads 117 on sidewall 116 and threads 115 of top 114. Top 114 is provided with a sealing means 134 which may be comprised of a bellows 133, the sealing action of which may be enhanced by a sealing bead 123 on tube 120. The tube 120 is mounted through an opening in top 114 with sealing means 134 providing a seal between the outer surface of tube 120 and the opening through top 114. Sealing means 134 is of the type which allows movement of tube 120 in a direction toward or away from base plate 125 and/or 118 of container 112. In a preferred embodiment as shown in FIGS. 1 through 3, sealing means 134 may be comprised of a bellows type structure 133 constructed of a suitably thin flexible synthetic plastic material. The structure of top 114 and bellows 133 may be molded from a suitable flexible synthetic plastic material as a single unit, but other materials and methods of fabrication are understood to be within the bounds and spirit of the present invention.
Bead 123 on tube 120 provides the dual function of enhancing the seal between the bellows structure 133 and the outer surface of tube 120 and of enabling the spring action of the bellows 133 to provide an additional force in the direction of arrow 144 retaining tube 120 in the direction of arrow 144 thereby ensuring that tube 120 is maintained at its lower end in juxtaposition to base plate 125. This assists in maintaining diaphragm 126 in its unexpanded condition when a drinker is not applying a force to tube 120 in the direction of arrow 146.
The embodiment of the invention as illustrated in FIGS. 1 through 3 provides the important advantage of stackability of the container. It is noted that the drawings are not necessarily to scale and that a greater degree of increase of cross-sectional dimension for length of travel along the axis of frustro-conical container 112 may be desired to provide the maximum degree of stackability. In other words, containers 112 may be inserted one into another to decrease the amount of volume necessary in warehousing and shipping a specified number of containers from a manufacturer to a user, such as a movie theater operation, and decreases the amount of storage area necessary by the end user for storing the containers until the time that they are used. The embodiment of the present invention as shown in FIGS. 1 through 3, in addition to providing the significant advantage of stackability, provides an important advantage of increased economy in manufacture.
In accordance with the present invention, it is contemplated that the present invention may be utilized in various manners. One manner of usage is to provide the container of the present invention to the dispenser or user of the liquid in four components which may be readily assembled around the time of the filling of the container. The four components would be the container 112, the base plate 125 with expandable diaphragm 126 attached thereto, drinking tube 120 and top 114 or 160. The dispenser, such as an attendant at a snack counter in a movie theater, or an end user, such as a person about to take a drink onto a bus or boat, would insert the rim 121 of tube 120 into expandable diaphragm 126 as previously described with respect to FIG. 2. The base plate 125 with expandable diaphragm 126 and tube 120 attached thereto would be inserted into container 112 and secured to the bottom thereof by a suitable securing means such as retaining bead 127, projections 132, arrow head latch 152 or other suitable securing means. Once the container 112 is filled, top 114 would be inserted over tube 120 and secured to the top of container 112 by screwing top 114 thereto by means of threads or secured thereon by other suitable securing means.
All of the components of the drinking container may be manufactured by a suitable molding process such as blow molding or injection molding. However, diaphragm 126 may be comprised of rubber which may be adhesively bonded to base plate 125. However, preferably, diaphragm 126 may be molded from an elastic synthetic material and sonically welded around its periphery to base plate 125. Unitary molding of a complete unit of an expandable diaphragm on a base plate is possible with greater difficulty. Throughout, it is understood that reference to base plate 125 includes various other shapes of base plates, such as base plate 150 illustrated in FIG. 5. Furthermore, as discussed above, container 112 may be of other suitable cross-sectional shapes, such as hexagonal, octagonal or the like, and, in such instances, the base plate and expandable diaphragm would be of a mating configuration.
Container 112 may be molded from a synthetic plastic material in an inexpensive manner as is well known in the art. In a similar manner, top 114 with bellows structure 133 may be inexpensively molded as a unit. The lower end of bellows 133 would be molded to form a tight fit on tube 120 to provide a sealing function. Furthermore, it is recognized that any increased pressure in container 112, such as by squeezing the container, would further tighten the seal between bellows 133 and tube 120 by causing compression of the bellows structure 133 on the external surface of tube 120 at multiple points.
Rim 121 on the lower end of tube 120 may be of various suitable configurations sufficient to provide a means of attachment of the tube to the expandable diaphragm. Particularly, in a preferred embodiment, rim 121 may be an oval or tear dropped shape to enhance the ease of insertion of rim 121 into opening 130 of expandable diaphragm 126.
In addition to the use of the container in accordance with the present invention as aforesaid, wherein it would be assembled by the dispenser or end user, the container may be utilized for the prepackaged shipment of liquids. In such a case, means would be provided for sealing the upper end of tube 120 where it extends outside of container 112. One method of providing such a seal or sanitary cover is illustrated in FIG. 4. The portion of tube 120 extending out of tube 112 is provided with a removable cover 124 for sanitary purposes. Cover 124 may be readily removed, or it may be made of a sufficiently thin and tearable material to enable rapid removal by the tearing with ease of cover 124 thereby enabling drinking through tube 120 by a consumer. If desired, the container and its contents may be made sterile at the time of filling.
Another embodiment of the present invention is illustrated in FIG. 7 wherein a top 160 is illustrated. Top 160 is formed in the shape of a portion of a sphere, the surface of which is provided with an extremely slippery surface. The purpose of top 160 is to preclude the removal or at least the easy removal of the top under certan circumstances, such as by children in movie theaters wherein the top may be removed for various reasons with the resulting increased possibility of an undesired spill. Top 160 does not provide a good gripping surface for turning in view of its circumference being provided with an uncomfortable edge rather than a flattened gripping surface. The top 160 may be installed by dispenser, such as an attendant in a movie theater snack shop by utilizing a special high friction gripping cloth to initially install the cap after filling.
In view of the above, the present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof and, accordingly, reference should be made to the appended claims, rather than to the foregoing specification as indicating the scope of the invention. | 1a
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is related to U.S. application Ser. No. (Docket 83783), filed ______, by Tingey, et al., and entitled, “Case For Carrying And Storing Light And Moisture Protected Product;” and U.S. application Ser. No. (Docket 83171), filed------, by Tingey, et al., and entitled, “Package And Method Of Making Same For Storing And Displaying Product”
FIELD OF INVENTION
[0002] The invention relates to the field of packaging. More particularly, the invention concerns a package for storing and displaying product, such as photographic film product and the like, in an easily accessible and convenient case.
BACKGROUND OF THE INVENTION
[0003] One way to display photographic products, such as camera film, for retail sale is in a full paperboard structure, commonly called a carton. An example of such a carton is one that is described and illustrated in U.S. Pat. No. 5,474,183, entitled “Carton For Enclosing And Displaying Articles,” by Warren et al., Dec. 12, 1995. Commonly, when such a carton is opened to gain access to the product inside, the carton flaps are rendered useless thereafter leaving no reasonable way to secure the unused product inside the carton. Moreover, it is well known that these cartons do not provide much protection from tampering or moisture.
[0004] Another well-known practice for displaying photographic product is to enclose the product in a flexible material package that once opened is destroyed, leaving no method to secure the unused product inside the flexible package. Single unit, hermetically sealed plastic film containers packed within cartons or flexible display packages provide physical and moisture protection but individual containers are cumbersome to handle and transport when multiple rolls of film are required. Additionally, in high humidity conditions, because of the hermetic seal, moisture may become entrapped in the product container having exposed film therein. In the case of 35 mm film there is no means provided to determine the exposure status of the film. If multiple rolls of the same variety of films are sealed within individual plastic containers they may be mistakenly used after they have been exposed, ruining both the initial and subsequent sets of images.
[0005] Yet another method disclosed in U.S. Pat. No. 5,139,165, entitled “Carton For Enclosing And Displaying Articles,” by Warren et al., Dec. 12, 1995, describes a single piece, molded rigid container that can be opened with one hand, can be sealed against moisture, and provides protection from external force and heat by using air gaps provided by internal support structures. It also includes the use of shrink-wrap as an external protection layer to ensure the “virginity” of the enclosed product. These techniques provide no means to indicate if any or all of the enclosed cartridges of photographic film have been used or are fresh, nor does it provide individual protection for the enclosed unused cartridges. Also, the rigid container can be resealed when closed, risking entrapping high humidity and moisture with the used and fresh film cartridges. In addition the use of shrink-wrap as an external wrapper is a limited means to provide instructions, advertising, physical protection, and physical display options such as peg hangers.
[0006] Therefore, a need persists in the art for a package that conveniently stores and displays product in a reusable product container or case that protects the product from adverse consequences of light and moisture.
SUMMARY OF INVENTION
[0007] It is, therefore, an object of the invention to provide a package that can conveniently store and display a product in a recloseable case.
[0008] It is another object of the invention to provide a package for storing and displaying a product that can be reused once all or a portion of the product contained therein is used.
[0009] Still another object of the invention is to provide a package for storing and displaying a product wrapped in a moisture and light impervious barrier material.
[0010] An important feature of the package of the invention is a display member that utilizes a transparent shell partially sandwiched between overlapped panels of the display member to securely encase a product container for display.
[0011] The present invention is directed to overcoming one or more of the problems set forth above. Briefly summarized, according to one aspect of the invention, a storage and display package has a display member having partially overlapped, closely spaced first and second panels. A reuseable article container for containing at least one article wrapped in a hermetically sealed, moisture and light barrier material. Means for removably attaching the reuseable article container to the display member is provided in the form of extended flange portions snugly sandwiched between the partially overlapped, closely spaced first and second panels of the display member.
[0012] The present invention has numerous advantages of prior developments, including: it allows packaging of product in a reusable container; it is both a simple and a convenient way to display and then store a product for later use by the consumer; it provides an easily recloseable product container that protects used and unused product stored therein; it will allow packaging of hermetically sealed photographic product in a reusable container; it provides tamper resistant and tamper evident outer display package; it contains a hinged lid, secured to the bottom portion of the package; and, it has a convenient case carrying member.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] The foregoing as well as other objects, features and advantages of this invention will become more apparent from the appended Figures, wherein like reference numerals denote like elements, and wherein:
[0014] [0014]FIG. 1 is a front view of a photographic product in a travel case and display package;
[0015] [0015]FIG. 2 is a perspective view of a photographic product in a travel case and display package;
[0016] [0016]FIG. 3 is a side, cross-sectional view of an unopened, unused, and unexposed photographic product in a travel case and display package;
[0017] [0017]FIG. 4 is a side, cross-sectional view of an unopened, unused, and unexposed photographic product in a closed travel case with display package removed and discarded;
[0018] [0018]FIG. 5 is a side, cross-sectional view of an unused and unexposed photographic product in an opened travel case, with the barrier layer wrap intact;
[0019] [0019]FIG. 6 is a side, cross-sectional view of an unused, and unexposed photographic product without the travel case and with the barrier layer wrap intact;
[0020] [0020]FIG. 7 is a side, cross-sectional view of a used and exposed photographic product in an opened travel case and with the barrier layer wrap removed and discarded;
[0021] [0021]FIG. 8 is a side, cross-sectional view of a used and exposed photographic product in a closed travel case and with the barrier layer wrap removed and discarded;
[0022] [0022]FIG. 9 is a perspective view of a closed travel case with the display package removed and discarded;
[0023] [0023]FIG. 10 is a perspective view of an opened travel case with three unused and unexposed photographic products with the barrier layer wraps intact;
[0024] [0024]FIG. 11 is a perspective view of an opened travel case with two unused and unexposed photographic products with the barrier layer wraps intact, and one used and exposed photographic product with the barrier layer wrap removed and discarded;
[0025] [0025]FIG. 12 is a perspective view of an opened travel case, three used and exposed photographic products with the barrier layer wraps removed and discarded;
[0026] [0026]FIG. 13 is a perspective view of a travel case with an integrated lanyard and an attached wrist strap;
[0027] [0027]FIG. 14 is a side view of a travel case with an integrated belt clip;
[0028] [0028]FIG. 15 is a perspective view of a separator insert; and,
[0029] [0029]FIG. 16 is a perspective view of an opened travel case with a separator insert.
DETAILED DESCRIPTION OF THE INVENTION
[0030] Turning now to the drawings, and particularly to FIGS. 1-3, the package 10 of the invention for storing and displaying a product, such as light and moisture barrier protected photographic film product, is illustrated. According to FIGS. 1, 2, and 3 , package 10 , broadly defined, has a display member 12 , a reusable product container or travel case 20 (hereinafter referred to as “case”), and a plastic shell 30 , attachable to display member 12 , that envelops the case 20 .
[0031] Referring to FIGS. 2 and 3, display member 12 , more particularly, includes a front layer 14 and a rear layer 16 . As seen in FIG. 3, front layer 14 partially overlaps rear layer 16 and forms a closely spaced gap 18 therebetween. Front layer 14 and rear layer 16 of display member 12 are preferably constructed of a paperboard stock material, although other materials, such as a wide array of plastics, may be used. According to FIG. 3, front layer 14 and rear layer 16 are designed to trap first and second extended flange portions 30 a , 30 b , respectively, of plastic shell 30 in gap 18 . Moreover, front layer 14 and rear layer 16 may be used for assembly, graphics call-outs, instructions, and retail display (not shown). Front and rear layers 14 , 16 are attached together with any appropriate heat activated or pressure sensitive adhesive, or mechanical fasteners such as staples (not shown). Although various means may be used to display package 10 , we prefer utilizing a display lanyard cut through paperboard and plastic sections to form a through-opening to facilitate retail display by providing a means to hang the package from a hook, pegboard or the like. According to FIG. 2, during assembly of package 10 , reusable case 20 is inserted into plastic shell 30 having first and second extended flange portions 30 a , 30 b . First and second extended flange portions 30 a , 30 b of plastic shell 30 are then snugly sandwiched or trapped between gap 18 formed by overlapping panel front and rear layers 14 , 16 .
[0032] Referring to FIG. 3, transparent plastic shell 30 may be constructed from a range of clear or semi-clear transparent materials. We prefer constructing plastic shell 30 from PVC or PET. Skilled artisans will appreciate that other materials, such as polyester, acrylic, etc., may also be used to construct plastic shell 30 . In our preferred embodiment of the invention, plastic shell 30 is shaped to conform to the case 20 by either vacuum-forming or molding, depending on the material selected.
[0033] Referring to FIGS. 3-5, 7 - 14 , and 16 , case 20 is sealed within display package 10 , as described above. As indicated above, plastic shell 30 encompasses rigid, reusable case 20 containing, for instance, unused photographic product 100 . Case 20 is preferably constructed of HDPE although other materials, such as polypropylene, could be used. In practice, case 20 may contain one or more rolls of unused photographic product 100 . Moreover, case 20 could be transparent, or opaque, or opaque with a transparent viewing window (not shown). Additionally, case 20 can be manufactured so that brand identification, logos, instruction, and the like, are permanently imbedded in plastic case material.
[0034] According to FIG. 3, a cross-sectional view of an unopened, unused, and unexposed photographic product 100 , sealed within barrier wrap 130 is illustrated. Unused photographic product 100 is shown stored inside case 20 that is mounted for display in package 10 . As indicated, display member 12 of package 10 has a front layer 14 and a partially overlapped rear layer 16 which could be a single hingeably attached paperboard portion (not shown) or two separate layers 14 , 16 , as shown. The inside portion of the display member may contain a coating, e.g., a thermal adhesive or thermal resin, that may be activated by heat or pressure or the entire assembly could be attached with a mechanical fastener such as a staple (not shown). As indicated, gap 18 between overlapping front and rear layers 14 , 16 traps or “sandwiches” the extended flange portions 30 a , 30 b of plastic shell 30 with the case 20 inside the shell 30 .
[0035] Referring to FIGS. 5 and 6, typically, unused photographic product 100 , such as a film roll, requires a flexible barrier wrap material 70 or container around the unused photographic product 100 to provide physical protection and a seal portion or “hermetic seal” 72 to provide barrier property protection to prevent high humidity and moisture from contacting the unused photographic product 100 . Case 20 is best used to accommodate product that is hermetically sealed and protected from light and moisture exposure. This is generally accomplished by providing a product 100 to be packaged in the package 10 of the invention that is hermetically sealed, such as by sealing individual rolls of unused photographic product 100 with a flexible barrier wrap material 70 . This flexible barrier wrap material 70 may comprise a heat sealed aluminized thermoplastic or similar material.
[0036] Referring to FIGS. 4-8, in a preferred embodiment of the invention, case 20 has a top cover 52 and bottom section 54 connected by hinge 56 that would allow opening and re-closing. Hinge 56 may be of the heat and pressure variety commonly known as a “living hinge” or a conventional mechanical hinge (not shown). Secure closure is accomplished by the mechanical engagement of bottom latching interface edge 60 and top cover latching interface 62 . Case 20 is opened with finger latch release 64 . These features allow product contained in case 20 , such as unused photographic product 100 to be removed, as well as unused product to be securely enclosed in the case 20 once the re-closure is engaged. Case 20 is intended to be used as a “travel case,” allowing the consumer to remove one roll of film, securing the remaining rolls within the case 20 using the top cover 52 , hinge 56 , bottom latching interface edge 60 , and the top cover latching interface 62 as the re-closing features.
[0037] [0037]FIG. 4 depicts closed case 20 with the enclosed unused photographic product 100 with barrier wrap material 70 . Closed case 20 provides stylish, ergonomic, and convenient containment and protection for photographic products and is designed to fit into a purse or travel bag. Each roll of unused photographic product 100 is individually sealed with a barrier wrap material 70 . Individual wrapped product allows the removal and opening of one roll of photographic product while the remaining rolls are securely wrapped and hermetically sealed. This feature also serves as a usage indicator for photographic products, like 35 mm film, that do not include an integrated usage indicator. The lack of flexible barrier wrap material 70 on rolls of film in the travel case provides a clear indication of usage. Some photographic products, like 24 mm Advance Photo System™ and 110 films, include an integrated usage indicator but do benefit from individual hermetic seals. In addition, the barrier wrap material 70 can contain printed information, not shown, indicating the properties of the contents such as film type and film speed.
[0038] [0038]FIG. 5 depicts opened case 20 with an enclosed unused photographic product 100 in barrier wrap material 70 with seal portion 72 . Opened case 20 consists of case top cover 52 , case bottom section 54 , and travel case “living” hinge 56 which may be molded as an integral part of the case 20 . Applying an upward pressure to finger latch release 64 opens case 20 . This action releases the top cover section latching interface 62 from bottom latching interface edge 60 . Case top cover 52 remains attached to case bottom section 54 via flexible case hinge 56 .
[0039] [0039]FIG. 6 depicts unused photographic product 100 in barrier layer wrap 70 having seal portion 72 . The unused photographic product 100 is enclosed in a barrier wrap material 70 and hermetically sealed via barrier layer seal 72 . In one embodiment, barrier wrap material 70 is a sheet of aluminized thermoplastic with the seal portion 72 created with heat and pressure. Other suitable barrier layer materials and sealing techniques can be used.
[0040] Referring to FIG. 7, a used photographic product 110 has been placed in case 20 . The lack of barrier wrap material 70 provides a clear indication that the photographic product 110 has been used and is being stored in case 20 for future processing.
[0041] [0041]FIG. 8 depicts a used photographic product 110 that has been placed in case 20 . Case 20 has been closed to contain and protect used photographic product 110 until it is submitted to a photo-processing lab for photo development.
[0042] [0042]FIG. 9 is a perspective view of a closed case 20 designed to hold three (3) articles, such as three (3) rolls of 24 mm IX film. It is understood that the case 20 can be designed to hold more or fewer rolls of film or other photographic products and formats.
[0043] Referring to FIG. 10, an opened case 20 containing unused photographic products 100 in sealed barrier wrap material 70 . Case 20 has all the same features as described above for protecting the product from moisture and vapor.
[0044] Referring to FIG. 11, a perspective view of an opened case 20 containing two (2) unused photographic products 100 in sealed barrier wrap material 70 and one (1) used photographic product 110 . The flexibility of case 20 for containing product in various states of use is illustrated.
[0045] [0045]FIG. 12 is a perspective view of an opened case 20 containing three (3) used photographic products 110 . The case 20 provides utility by conveniently carrying multiple rolls of unused film to a “picture taking event” such as a party or a vacation, or for transporting used film to a photo-processing lab.
[0046] Turning now to FIG. 13, a perspective view of case 20 with an optional integrated lanyard 180 and attached wrist strap 190 is illustrated. The integrated lanyard 180 may be molded as part of the case 20 or attached with adhesives or screws (not shown).
[0047] [0047]FIG. 14 is a side view of case 20 with optional integrated belt clip 200 . The integrated belt clip 200 may be molded as part of the case 20 or attached with adhesives or screws. Belt clip 200 must be configured not to interfere with the operation of case top cover 52 for opening and closing case 20 . Belt clip 200 can be used to secure the case 20 to a belt, camera strap, or windshield visor.
[0048] Referring to FIGS. 15 and 16, a separator insert 210 for isolating and maintaining product contained in case 20 is illustrated. Separator insert 210 may be used to maintain the position of the enclosed photographic products, 100 , 110 , and can also include instructions, coupons, and the like (not shown). In addition, separator 210 can be impregnated with a moisture absorbing, desiccant material such as silica gel, activated alumina, activated clay and the like. According to FIG. 16, a perspective view of separator insert 210 installed in case 20 is depicted. As shown, separator insert 210 primarily maintains the position of photographic products 100 , 110 stored in case 20 .
[0049] The invention has been described with reference to a preferred embodiment thereof. It will be appreciated, however, that a person of ordinary skill in the art can effect variations and modifications without departing from the scope of the invention.
PARTS LIST
[0050] [0050] 10 package
[0051] [0051] 12 display member
[0052] [0052] 14 front layer of display member 12
[0053] [0053] 16 rear layer of display member 12
[0054] [0054] 18 gap between overlapping front and rear layers
[0055] [0055] 20 reusable product container or travel case
[0056] [0056] 30 plastic shell
[0057] [0057] 30 a first extended flange portion
[0058] [0058] 30 b second extended flange portion
[0059] [0059] 52 top cover of case 20
[0060] [0060] 54 bottom section of case 20
[0061] [0061] 56 hinge of case 20
[0062] [0062] 60 bottom latching interface edge
[0063] [0063] 62 top cover latching interface edge
[0064] [0064] 64 finger latch release
[0065] [0065] 70 flexible barrier wrap material
[0066] [0066] 72 seal portion or hermetic seal
[0067] [0067] 100 unused photographic product
[0068] [0068] 110 used photographic product
[0069] [0069] 130 barrier wrap
[0070] [0070] 180 integrated lanyard
[0071] [0071] 190 wrist strap
[0072] [0072] 200 belt clip
[0073] [0073] 210 separator insert | 1a
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TECHNICAL FIELD
The present invention relates to painting tools and, in particular, to an apparatus for extending and holding a paint brush at multiple angles.
BACKGROUND OF THE INVENTION
The safest location for a painter is on the ground. Unfortunately, both professional and amateur painters are often called upon to paint high, hard to reach places, such as ceilings or eaves, that are not readily accessible to painters of average height. The use of a ladder is (and has been) the preferred method for facilitating painter access to such difficult and potentially dangerous locations.
It is well known that the use of ladders presents a certain danger of injury to the painter most often caused by a fall. Most such ladder related injuries are directly traced to misuse of the ladder (for example, by placing the ladder on uneven ground or by standing on the top step). In other cases, the painter is accidentally injured while properly using the ladder (for example, by tripping or slipping on the ladder while painting or climbing).
In response to the danger of injury presented by the use of ladders it is commonplace for painters to utilize extension rods, most often in conjunction with paint rollers, to paint high locations such as ceilings and eaves without having to climb a ladder. While adequately painting open, flat locations, paint rollers are not the preferred tool for painting high, delicate or hard to reach places, such as corners, edges, moldings and trim, where controlled paint application is required to achieve satisfactory results. Thus, the painter must still make use of a ladder and a paint brush to finish the painting job.
Accordingly, there is a need for an apparatus that will facilitate the use of a paint brush or other painting apparatus by a painter to access and paint, in a controlled manner, high, hard to reach places such as ceiling corners, edges, moldings and trim.
SUMMARY OF THE INVENTION
The present invention addresses the foregoing problems associated with the painting of high, hard to reach places, such as ceiling corners, edges, moldings and trim. The apparatus of the present invention comprises a paint brush holder having a threaded opening at one end for receiving a standard threaded extension rod of any desired length. Attachment of the extension rod enables the painter to reach painting heights normally accessible only from a ladder.
The paint brush holder further includes a unique handle clamp for securely retaining the handle of the paint brush or other painting apparatus at multiple angles with respect to the received extension rod. In a first position, the handle clamp secures the handle of the paint brush in an orientation parallel to the extension rod to paint a desired surface. A second position of the handle clamp angles the paint brush away from the received extension rod to paint another desired surface. The multiple angle clamp thus allows the painter to secure the paint brush at an angle with respect to the extension rod that facilitates controlled painting of high areas.
BRIEF DESCRIPTION OF THE DRAWINGS
A more complete understanding of the invention may be had by reference to the following Detailed Description when taken in conjunction with the accompanying Drawings wherein:
FIG. 1 is an exploded perspective view of the multiple angle paint brush holder of the present invention;
FIG. 2 is an assembled perspective view of the multiple angle paint brush holder of the present invention; and
FIGS. 3 and 4 illustrate the use of the multiple angle paint brush holder of the present invention by a painter to paint the edge between a ceiling and a wall.
DETAILED DESCRIPTION OF THE INVENTION
Referring now to FIG. 1, there is shown an exploded perspective view of the multiple angle paint brush holder 10 of the present invention comprising mirror image, bottom and top members 12 and 14, respectively. The members 12 and 14 are preferably integrally formed through use of a molding, shaping or other suitable fabrication process. The members 12 and 14 are comprised of a malleable or moldable material such as aluminum or plastic. It will, of course, be understood that any other material having similar performance and fabrication qualities may be utilized in constructing the members 12 and 14.
The bottom member 12 includes a first end 16 having formed therein a semi-circular shaped channel 18. Extending outwardly from the top edges 20 of the semi-circular shaped channel 18 are flanges 22 and 24. Each flange 22 and 24 includes two openings 26 adapted for insertion therethrough of a bolt 28 or other securing means of choice. The bolt 28, in conjunction with a corresponding nut 30, permanently secures the member 12 to the member 14 at the first end 16 as is more easily seen with reference to FIG. 2.
Returning to FIG. 1, the bottom member 12 further includes a second end 32, opposed from the first end 16, having formed therein a pair of generally "U" shaped channels 34 and 36. The first "U" shaped channel 34 is oriented parallel to and aligned with the semi-circular shaped channel 18 at the first end 16. The second "U" shaped channel 36 is angled away from and oriented at an acute angel β with respect to the first "U" shaped channel 34. The angle β is preferably forty-five degrees, but the second channel 36 may be formed in the second end 32 and oriented at any desired angle that will facilitate the painting process as will be described.
Extending between the first and second "U" shaped channels 34 and 36, respectively, is a web 38 including an opening 40 adapted for insertion therethrough of a bolt 42 or other securing means of choice. The bolt 42, in conjunction with a corresponding wing nut 44, releasably secures the member 12 to the member 14 at the second end 32 as is more easily seen with reference to FIG. 2.
As mentioned above the members 12 and 14 are mirror images of each other. Accordingly, the top member 14 includes the same elements as described above with respect to the bottom member 12. The corresponding elements in the top member 14 are designated by an identical reference numeral as in FIG. 1 and are distinguished from the elements in the bottom member 12 by the prime (') designation.
The multiple angle paint brush holder 10 further includes a cylindrical member 46 shown in a broken perspective view in FIG. 1. The cylindrical member 46, like the members 12 and 14, is also preferably integrally formed through use of a molding, shaping or other suitable fabrication process. Preferably, the cylindrical member 46 is comprised of a malleable or moldable material such as aluminum or plastic. The cylindrical member 46 includes an interior and exterior surface 48 and 50, respectively. The interior surface 48 of member 46 is threaded to matingly receive a correspondingly threaded extension rod (not shown, see FIGS. 3 and 4) of any desired length. The exterior surface 50 of the member 46 is a relatively smooth surface defined by an outer surface radius that substantially matches the inner surface radius of the semi-circular shaped channels 18 and 18' of the members 12 and 14, respectively.
Reference is now made to FIGS. 1 and 2, wherein FIG. 2 shows an assembled perspective view of the multiple angle paint brush holder 10 of the present invention. Cylindrical member 46 is positioned between members 12 and 14 in the semi-circular shaped channels 18 and 18'. The bolts 28, in conjunction with corresponding nuts 30, permanently secure the member 12 to the member 14 at the first end 16. As the outer surface radius of the cylindrical member 46 substantially matches the inner surface radius of the semi-circular shaped channels 18 and 18', the friction forces exerted between the top, bottom and cylindrical members following assembly of the first end 16 will function to secure and retain the cylindrical member within the first end of the multiple angle paint brush holder 10.
Alignment of the first "U" shaped channels 34 and 34' of the mirror image bottom and top members 12 and 14, respectively, forms an opening for a first brush handle clamp 56 at the second end 32. Alignment of the second "U" shaped channels 36 and 36' of the mirror image bottom and top members 12 and 14, respectively, forms an opening for a second brush handle clamp 58 at the second end 32. The second clamp 58 is angled away from and oriented at an acute angle β with respect to the first clamp 56. When the wing nut 44 is tightened, webs 38 and 38' are drawn together (as shown in FIG. 2) causing the first and second brush handle clamps 56 and 58 to tighten around the handle of any paint brush inserted therein, thus securing the paint brush within the holder 10 by means of friction force. When the wing nut 44 is untightened, the webs 38 and 38' move apart, the clamps 56 and 58 release, and the paint brush may be removed. It will, of course, be understood that the clamps 56 and 58 will retain any handled painting instrument desired, such as, mini-rollers, sponge brushes, etc.
Reference is now made to FIGS. 3 and 4 to illustrate the use and benefits of the multiple angle paint brush holder 10. Paint rollers cannot be used to efficiently and effectively paint in a controlled manner the delicate, high, hard to reach painting places such as the wall 70 or ceiling 72 immediately adjacent to a high corner 68. With use of the holder 10 of the present invention, a paint brush may be used to paint this and other difficult painting locations without the need of a ladder.
The threaded cylindrical member 46 (FIGS. 1 and 2) at the first end 16 matingly receives a correspondingly threaded extension rod 64 to enable a painter 66 to reach the high, hard to reach painting location. With the handle 60 of a paint brush 62 inserted in the opening and retained by the first clamp 56 (as shown in FIG. 3), the multiple angle paint brush holder 10 enables the painter 66 to paint the ceiling 72 immediately adjacent the corner 68 without the use of a ladder. By then switching the handle 60 of the paint brush 62 to the second clamp 58 (as shown in FIG. 4), the multiple angle paint brush holder 10 enables the painter 66 to paint the wall 70 immediately adjacent the corner 68 also without the use of a ladder. Angling of the brush 62 in the manner shown allows the painter to use nearly the full width of the secured brush to effectively and safely paint the wall 70.
Although a preferred embodiment of the paint brush holder of the present invention has been illustrated in the accompanying Drawings and described in the foregoing Detailed Description, it will be understood that the invention is not limited to the embodiment disclosed, but is capable of numerous rearrangements, modifications and substitutions without departing from the spirit of the invention as set forth and defined by the following claims. | 1a
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[0001] This application is a divisional of U.S. patent application Ser. No. 10,010,244, filed Dec. 6, 2001, which is a continuation-in-part of U.S. Ser. No. 09/931,528, filed Aug. 16, 2001, of U.S. Ser. No. 09/891,775, filed Jun. 25, 2001, and of U.S. Ser. No. 09/730,911, filed Dec. 6, 2000, the complete disclosures of which are hereby incorporated by reference herein in their entirety. This application is also related to co-owned U.S. Ser. Nos. 09/010,903, 09/010,904, 09/010,906, 09/010,908, and 09/010,912, all filed Dec. 6, 2001, the complete disclosures of which are hereby incorporated by reference herein in their entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The invention relates to endoscopic surgical procedures. More particularly, the invention relates to procedures for the transoral invagination and fundoplication of the stomach to the esophagus.
[0004] 2. State of the Art
[0005] Gastroesophageal fundoplication is a procedure for the treatment of gastroesophageal reflux disease (GERD), a condition in which gastric acids are regurgitated into the esophagus resulting in one or more of esophagitis, intractable vomiting, asthma, and aspiration pneumonia. The fundoplication procedure involves wrapping the fundus of the stomach around the lower end of the esophagus and fastening it in place. Traditionally, this procedure is accomplished via open surgery with the use of sutures to secure the plicated fundus of the stomach around the esophagus without penetrating (incising) the stomach. Although traditional fundoplication involves plicating the fundus and the esophagus, as used herein the term includes plicating the fundus to itself near the esophagus.
[0006] U.S. Pat. No. 5,403,326 to Harrison et al. discloses a method of performing endoscopic fundoplication using surgical staples or two-part surgical fasteners. The procedure disclosed by Harrison et al. involves performing two percutaneous endoscopic gastrotomies (incisions through the skin into the stomach) and the installation of two ports through which a stapler, an endoscope, and an esophageal manipulator (invagination device) are inserted. Under view of the endoscope, the esophageal manipulator is used to pull the interior of the esophagus into the stomach. When the esophagus is in position, with the fundus of the stomach plicated, the stapler is moved into position around the lower end of the esophagus and the plicated fundus is stapled to the esophagus. The process is repeated at different axial and rotary positions until the desired fundoplication is achieved. While, the procedure disclosed by Harrison et al. is a vast improvement over open surgery, it is still relatively invasive requiring two incisions through the stomach.
[0007] U.S. Pat. No. 5,571,116 to Bolanos et al. discloses a non-invasive treatment of gastroesophageal reflux disease which utilizes a remotely operable invagination device and a remotely operable surgical stapler, both of which are inserted transorally through the esophagus. According to the methods disclosed by Bolanos et al., the invagination device is inserted first and is used to clamp the gastroesophageal junction. The device is then moved distally, pulling the clamped gastroesophageal junction into the stomach, thereby invaginating the junction and involuting the surrounding fundic wall. The stapler is then inserted transorally and delivered to the invaginated junction where it is used to staple the fundic wall.
[0008] Bolanos et al. disclose several different invagination devices and several different staplers. Generally, each of the staplers disclosed by Bolanos et al. has an elongate body and a spring biased anvil which is rotatable approximately 15 degrees away from the body in order to locate the invaginated gastroesophageal junction between the body and the anvil. The body contains a staple cartridge holding a plurality of staples, and a staple firing knife. Each of the invagination devices disclosed by Bolanos et al. has a jaw member which is rotatable at least 45 degrees and in some cases more than 90 degrees to an open position for grasping the gastroesophageal junction. One of the chief disadvantages of the methods and apparatus disclosed by Bolanos et al. is that the stapler and the invagination device must both be present in the esophagus at the same time. With some of the embodiments disclosed, the presence of both instruments is significantly challenged by the size of the esophagus. In addition, the actuating mechanism of the device disclosed by Bolanos et al. is awkward. In particular, the stapler anvil is biased to the open position, and it is not clear whether or not the stapler anvil can be locked in a closed position without continuously holding down a lever. In addition, it appears that the staple firing trigger can be inadvertently operated before the anvil is in the closed position. This would result in inadvertent ejection of staples into the stomach or the esophagus of the patient.
[0009] U.S. Pat. No. 6,086,600 to Kortenbach discloses an endoscopic surgical instrument including a flexible tube, a grasping and fastening end effector coupled to the distal end of the tube, and a manual actuator coupled to the proximal end of the tube. The manual actuator is coupled to the end effector by a plurality of flexible cables which extend through the tube. The tube contains a lumen for receiving a manipulable endoscope and the end effector includes a passage for the distal end of the endoscope. The end effector has a store for a plurality of male fastener parts, a store for a plurality of female fastener parts, a rotatable grasper, a rotatable fastener head for aligning a female fastener part and a male fastener part with tissues therebetween, and a firing member for pressing a male fastener part through tissues grasped by the grasper and into a female fastener part. According to a stated preferred embodiment, the overall diameters of the flexible tube and the end effector (when rotated to the open position) do not exceed approximately 20 mm so that the instrument may be delivered transorally to the fundus of the stomach.
[0010] While transoral invagination and fundoplication apparatus and procedures have improved over the years, it is still difficult to deliver and manipulate the necessary apparatus transorally. The primary reason for the difficulty is that the overall diameter, or more accurately the cross sectional area, of the equipment is too large. Notwithstanding Kortenbach's reference to 20 mm, most of the equipment in use today is at least 24 mm in diameter. Moreover, even if the equipment could be reduced to 20 mm in diameter (314 mm 2 cross sectional area), it would still be difficult to manipulate. Those skilled in the art will appreciate that larger instruments are less pliable and that the invagination and fundoplication procedure requires that the instruments turn nearly 180 degrees. Moreover, it will be appreciated that large instruments obscure the endoscopic view of the surgical site.
[0011] Still other issues which need to be addressed in this procedure include the need to suitably grasp the fundus before application so that all layers of the fundus are plicated. Preferably, application damages the fundus so that adhesion occurs during healing.
[0012] 3. Co-Owned Technology
[0013] Previously incorporated application Ser. No. 09/730,911, filed Dec. 6, 2000, entitled “Methods and Apparatus for the Treatment of Gastric Ulcers”, discloses a surgical tool which is delivered to a surgical site over an endoscope rather than through the working lumen of an endoscope.
[0014] Co-owned provisional application Ser. No. 60/292,419, filed May 21, 2001, entitled “Methods and Apparatus for On-Endoscope Instruments Having End Effectors and Combinations of On-Endoscope and Through-Endoscope Instruments”, discloses many tools and procedures including an on-scope grasper assembly having grasping jaws, and a through-scope clip applier having jaws adapted to close about tissue and apply a clip over and/or through the tissue. In operation, the grasper jaws may grab and hold tissue, e.g., the fundus of the stomach or esophageal tissue, while the jaws of the clip applier surround a portion of the tissue held by the grasper jaws and apply a clip thereover.
[0015] Previously incorporated application Ser. No. 09/891,775, filed Jun. 25, 2001, entitled “Surgical Clip”, discloses a surgical clip having a U-shaped configuration with first and second arms, and a bridge portion therebetween. The first arm is provided with a tip preferably having a catch, and the second arm extends into a deformable retainer having a tissue-piercing end and preferably also a hook. During application, tissue is clamped, and the clip is forced over the clamped tissue and the retainer of the second arm is bent and may be pierced through the tissue. The retainer is toward and around or adjacent the tip of the first arm preferably until the hook is engaged about the catch to secure the clip to the tissue and prevent the clip and tissue from separating. The clip is provided with structure that facilitates the stacking of a plurality of clips in a clip chamber of a clip applier.
[0016] Previously incorporated application Ser. No. 09/931,528, filed Aug. 16, 2001, entitled “Methods and Apparatus for Delivering a Medical Instrument Over an Endoscope while the Endoscope is in a Body Lumen”, discloses methods and apparatus for delivering a medical instrument over the exterior of an endoscope while the endoscope is installed in the patient's body in order to allow the use of instruments which are too large to fit through the lumina of an endoscope.
[0017] The previously incorporated simultaneously filed application entitled “Flexible Surgical Clip Applier”, discloses a surgical clip applier having a pair of clip applying jaws at the distal end of an outer coil, a set of pull wires extending through the outer coil and coupled to the jaws, and a push wire extending through the outer coil. A clip chamber is provided in the distal end of the coil. A clip pusher is provided at a distal end of the push wire, and adapted to advance a clip into the jaws. The jaws include clamping surfaces which operate to compress tissue between the jaws when the jaws are closed, channels in which a distal most clip rides when the jaws are closed and the pusher is advanced thereby causing the distal most clip to be pushed over the tissue, and distal anvil portions which operate to bend a portion of the distal most clip to facilitate its retention on the clamped tissue. The clip applier is capable of providing a pushing force far in excess of a perceived possible maximum of the 200 grams (0.44 lbs) published in the art. One embodiment of the device of the invention provides a pushing force in excess of 2267 grams (5 lbs).
SUMMARY OF THE INVENTION
[0018] It is therefore an object of the invention to provide methods and apparatus for transoral invagination and fundoplication.
[0019] It is also an object of the invention to provide an apparatus for transoral invagination and fundoplication which is easy to manipulate.
[0020] It is another object of the invention to provide an apparatus for transoral invagination and fundoplication which has a relatively small cross-sectional area.
[0021] It is still another object of the invention to provide methods and apparatus for fundoplication which combine the relative advantages of staples and two-part fasteners, i.e. the small size of a staple and the greater integrity of a two-part fastener.
[0022] It is yet another object of the invention to provide methods and apparatus for transoral invagination and fundoplication which damages tissue such that adhesion occurs during healing.
[0023] In accord with these objects which will be discussed in detail below, the methods of the invention include delivering a grasper, a clip applier, and an endoscope transorally to the site of fundoplication; grasping the fundus with the grasper (or similar device, e.g. corkscrew) and pulling it into the jaws of the clip applier; closing the jaws of the clip applier over the fundus and applying a clip to the fundus. The method is repeated at different locations until the desired fundoplication is achieved. The apparatus of the invention includes a clip applier having sharp toothed jaws for grasping and damaging the fundus prior to applying the clip. The clip applier has an overall diameter of less than 7 mm and may be delivered through a 7 mm sleeve which attaches to a 12 mm endoscope having a lumen through which the grasper is delivered. The overall cross-sectional area of the apparatus is therefore approximately 152 mm 2 as compared to the 314 mm 2 of the prior art devices. Alternatively, the clip applier and the grasper may be delivered through an endoscope having two 6 mm lumina.
[0024] According to a presently preferred embodiment, the clip applier jaws are coupled to a pull wire via a linkage which increases the mechanical advantage and thus permits greater grasping force.
[0025] A plurality of clip designs is provided. Some embodiments include a pair of arms coupled by a bridge and a single locking retainer. Other embodiments include dual parallel coiled retainers. According to one embodiment, the clip has two detachable retainers which are installed in the fundus and the clip arms and bridge are removed.
[0026] Additional objects and advantages of the invention will become apparent to those skilled in the art upon reference to the detailed description taken in conjunction with the provided figures.
BRIEF DESCRIPTION OF THE DRAWINGS
[0027] FIG. 1 is a side elevational view of a clip applier according to the invention;
[0028] FIG. 2 is a side elevational view of a first embodiment of the distal end of the clip applier with the jaws in the closed position;
[0029] FIG. 3 is a side elevational view of a first embodiment of the distal end of the clip applier with the jaws in the open position;
[0030] FIG. 4 is a broken isometric view of a first embodiment of the distal end of the clip applier with one jaw removed;
[0031] FIG. 5 is a broken isometric view of a second embodiment of the distal end of the clip applier with a clip of the type shown in FIGS. 19 and 20 ;
[0032] FIG. 6 is an isometric view of a single jaw of the second embodiment of the distal end of the clip applier;
[0033] FIG. 7 is a proximal end view of the jaw of FIG. 6 ;
[0034] FIG. 8 is a proximal end view of the two jaws of a second embodiment of the distal end of the clip applier in the closed position with the lower jaw shaded for clarity;
[0035] FIG. 9 is a broken isometric view of a third embodiment of the distal end of the clip applier suitable for use with a clip of the type shown in FIGS. 17 and 18 or 24 ;
[0036] FIGS. 10 to 14 are schematic views illustrating a method according to the invention;
[0037] FIG. 15 is a diagram illustrating the comparative cross-section of the instruments used in the method illustrated in FIGS. 5 to 10 and a typical prior art instrument;
[0038] FIG. 16 is a cross-sectional view of a dual lumen endoscope which can be used in performing the methods of the invention;
[0039] FIG. 17 is a side elevational view of a first embodiment of a clip according to the invention prior to application;
[0040] FIG. 18 is a side elevational view of the clip of FIG. 17 after application;
[0041] FIG. 19 is a side elevational view of a second embodiment of a clip according to the invention prior to application;
[0042] FIG. 20 is a side elevational view of the clip of FIG. 19 after application;
[0043] FIG. 21 is a side elevational view of a third embodiment of a clip according to the invention prior to assembly;
[0044] FIG. 22 is a side elevational view of the clip of FIG. 21 assembled prior to application;
[0045] FIG. 23 is a side elevational view of the applied portion of the clip of FIGS. 17 and 18 ;
[0046] FIG. 24 is a view similar to FIG. 23 of an alternate third embodiment of the applied portion of a clip according to the invention; and
[0047] FIG. 25 is a fragmentary, cross-sectional enlarged view of a portion of the clip applier of FIG. 5 with a portion of a clip in an applier groove and through tissue.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0048] Referring now to FIG. 1 , a clip applier 10 according to the invention generally includes a flexible wound outer coil 12 having a proximal end 14 and a distal end 16 . An end effector assembly 18 is coupled to the distal end 16 of the coil 12 and an actuator assembly 20 is coupled to the proximal end 14 of the coil 12 . A plurality of pull/push wires 58 , 60 (shown and described below with reference to FIGS. 2-4 ) extend through the coil 12 and couple the end effector assembly 18 to the actuator assembly 20 . The clip applier 10 is similar to the clip applier described in detail in previously incorporated co-owned application Ser. No. 10/010,908, entitled “Flexible Surgical Clip Applier”, filed simultaneously herewith. However, in this application, the end effector assembly 18 is designed specifically for fundoplication using a clip significantly larger than that used in the clip applier of the aforesaid co-owned application.
[0049] FIGS. 2-4 illustrate the details of the end effector assembly 18 according to a first embodiment of the invention. The end effector assembly 18 includes a pair of jaws 22 , 24 which are rotatably coupled to a clevis 26 . In particular, the clevis 26 has a central channel 28 (seen best in FIG. 4 ) which is defined by clevis arms 30 , 32 . Although the term “clevis” is used because of its general acceptance in the art of endoscopic instruments, the “clevis” 26 is preferably covered on top and bottom so that the only exit from the channel 28 is at the distal end. The jaw 22 is rotatably coupled to the clevis arm 30 by an axle 34 and the jaw 24 is rotatably coupled to the clevis arm 32 by an axle 36 . The axles 34 and 36 are dimensioned such that they do not significantly obscure the channel 28 .
[0050] The jaws 22 , 24 are substantially identical. Each jaw 22 , 24 includes a proximal tang 38 , 40 , a mounting bore 42 , 44 , a distal hook shaped anvil 46 , 48 and a plurality of medial teeth 50 , 52 . As seen best in FIG. 4 , the medial teeth 50 , 52 are arranged on one side of the jaw and a short wall 51 , 53 is arranged on the opposite side of the jaw to define a groove (or guiding channel) 54 , 56 . The grooves 54 , 56 meet the anvils 46 , 48 each of which has a helical surface. The interior (proximal) helical surfaces of the anvils act to bend the clip retainers as described below with reference to FIGS. 19-24 .
[0051] The proximal tang 38 , 40 of each jaw is coupled to a respective pull/push wire 58 , 60 via two links 62 , 64 and 66 , 68 . The links 62 , 66 are substantially L-shaped and are rotatably coupled near their elbow to the clevis arms 30 , 32 by axles 70 , 72 which do not significantly obscure the channel 28 between the clevis arms. One end of the link 62 , 66 is coupled to the pull/push wire 58 , 60 and the other end of the link 62 , 66 is rotatably coupled to one end of the link 64 , 68 . The other end of the link 64 , 68 is rotatably coupled to the tang 38 , 40 . The combined coupling of each jaw 22 , 24 to each pull/push wire 58 , 60 forms a linkage which amplifies the force from the pull/push wires to the jaws. In particular, as the jaws close, the mechanical advantage increases.
[0052] The proximal ends of the pull/push wires 58 , 60 are coupled to the actuator assembly ( 20 in FIG. 1 ) as described in previously incorporated co-owned application Ser. No. 10/010,908, entitled “Flexible Surgical Clip Applier”, filed simultaneously herewith.
[0053] A clip pusher (not shown) disposed in the interior of the coil is coupled to a push wire (not shown) which is coupled to the actuator assembly as described in previously incorporated co-owned application Ser. No. 10/010,908, entitled “Flexible Surgical Clip Applier”, filed simultaneously herewith. Unlike the previously incorporated co-owned application, the jaws of the instant clip applier are significantly longer and designed for use with clips approximately 17-20 mm long (after the clip is applied) as compared to the 5-7 mm clips shown in the previously incorporated co-owned application.
[0054] Turning now to FIGS. 5-8 , a second embodiment of the jaws 22 ′, 24 ′ is illustrated. The jaws 22 ′, 24 ′ are substantially identical to each other and are designed for use with any of the clips illustrated in FIGS. 19-24 . Each jaw 22 ′, 24 ′ includes a proximal tang 38 ′, 40 ′, a mounting bore 42 ′, 44 ′, a distal hook shaped anvil 46 ′, 48 ′ and a plurality of medial teeth 50 ′, 52 ′. The medial teeth 50 ′, 52 ′ are arranged on one side of the jaw and a short wall 51 ′, 53 ′ is arranged on the opposite side of the jaw to define a groove (or guiding channel) 54 ′, 56 ′. The grooves 54 ′, 56 ′ meet the interior surfaces of the anvils 46 ′, 48 ′ which curve about a single axis. The interior surfaces of the anvils act to bend the clip retainers as described below with reference to FIGS. 19-24 and as shown by the clip 310 in FIG. 5 . According to this embodiment, as seen best in FIGS. 6-8 , the guiding channels 54 ′, 56 ′ and the anvils 46 ′, 48 ′ are angled relative to the vertical axis of the jaw 22 ′, 24 ′. This angle causes the clip to twist as it is pushed through the jaws so that the ends of the clip are offset as shown in FIG. 5 , for example. According to the presently preferred embodiment, the guiding channels 54 ′, 56 ′ and the anvils 46 ′, 48 ′ are angled approximately 22° relative to the vertical axis of the jaw 22 ′, 24 ′. According to a method of the invention, clips for use with this embodiment of the jaws are pre-bent in the bridge area to facilitate movement through the angled channels.
[0055] FIG. 25 illustrates an enlarged portion of the clip applier of FIG. 5 showing that the clip 310 rests inside an applier groove 54 ′, 56 ′ and is bent by the anvil 48 ′ as it pierces a folded over portion of body tissue 500 .
[0056] Referring now to FIG. 9 , a third embodiment of the jaws 22 ″, 24 ″ is illustrated. The jaws 22 ″, 24 ″ are not identical to each other and are designed for use with clips of the type illustrated in FIGS. 17-18 . Each jaw 22 ″, 24 ″ includes a proximal tang 38 ″, 40 ″ and a mounting bore 42 ″, 44 ″. One jaw 22 ″ terminates with two spaced apart distal hooks 46 ″, 47 ″ and has two rows of medial teeth 50 ″. The other jaw 24 ″ terminates with a single distal hook shaped anvil 48 ″ and has two rows of medial teeth 52 ″. The medial teeth 50 ″, 52 ″ are arranged on both sides of the jaw and a groove (or guiding channel) 54 ″, 56 ″ lies between the rows of teeth. The groove 54 ″ terminates with an undercut well (not shown) as described in co-owned Ser. No. 10/010,908, whereas the groove 56 ″ continues on to the interior of the anvil 48 ″ which has a surface which curves about a single axis. Those skilled in the art will appreciate that when the jaws are closed, the anvil 48 ″ will reside between the hooks 46 ″ and 47 ″ and the teeth 50 ″ will be interleaved with the teeth 52 ″. The interior surface of the anvil 48 ″ bends the clip retainer as described below with reference to FIGS. 17-18 and as shown and described in previously incorporated co-owned applications Ser. No. 09/891,775, and Ser. No. 10/010,908.
[0057] Turning now to FIGS. 10-14 , a method of using the clip applier of the invention is illustrated in context with an existing endoscope 100 having a single lumen through which a small grasper 102 is supplied and an external working channel 104 which is attached to the scope 100 and through which the clip applier is delivered. The external working channel 104 is preferably one of the type described in previously incorporated application Ser. No. 09/931,528, filed Aug. 16, 2001, entitled “Methods and Apparatus for Delivering a Medical Instrument Over an Endoscope while the Endoscope is in a Body Lumen”.
[0058] According to a method of the invention, after the endoscope assembly is delivered transorally to the procedural site, as shown in FIG. 10 , the fundus is grasped by the graspers and pulled in between the open jaws of the clip applier. The jaws of the clip applier are then closed onto the invaginated fundus as shown in FIG. 11 . As the jaws are closed the medial teeth of the jaws puncture the invaginated fundus as shown in FIGS. 11 and 12 . When the jaws are completely closed (or closed as much as possible), they are preferably locked, the grasper is optionally released, and the clip pusher is activated to push forward, advance, and/or slide, with or without tissue contact, a clip 106 as shown in FIG. 12 and as described in the previously incorporated, co-owned, simultaneously filed application and discussed in detail hereinafter.
[0059] After the clip 106 is applied, the jaws of the clip applier are opened as shown in FIG. 13 and the clip 106 remains in place and plicates the fundus. Depending on the location of the clip and the nature of the patient's condition, a single clip may be sufficient. If other clips are deemed desirable by the practitioner, the clip applier is removed and re-loaded with another clip. After re-delivering the clip applier, the procedure may be repeated at another location as shown in FIG. 14 . Given the size of the clips of the invention, anywhere from 1-4 clips will typically be used.
[0060] According to one aspect of the invention, the medial teeth on the jaws of the clip applier are long enough and sharp enough to damage the fundus sufficiently such that when the fundus heals adhesion occurs, binding the plicated fundus to the extent that the clip may no longer be needed. Thus, preferably, the teeth are long enough to pierce all layers of the fundus.
[0061] From the foregoing, those skilled in the art will appreciate that the methods of the invention may be performed with different types of graspers. In particular, alternative grasping devices such as a “cork screw” grasper can be used in conjunction with the clip applier of the invention to perform the methods of the invention.
[0062] It will also be appreciated that the clip applier of the invention may be attached to an endoscope in other ways as described in previously incorporated application Ser. No. 09/931,528, filed Aug. 16, 2001, entitled “Methods and Apparatus for Delivering a Medical Instrument Over an Endoscope while the Endoscope is in a Body Lumen”.
[0063] As mentioned above, the clip applier of the invention has an outside diameter of approximately 6 mm. As shown in FIGS. 10-14 , the clip applier is used in conjunction with an endoscope having an outside diameter of approximately 12 mm. To accommodate the clip applier, an exterior working channel having an exterior diameter of approximately 7 mm is optionally coupled to the endoscope as described in the previously incorporated co-owned applications Ser. No. 09/931,528 and 60/292,419.
[0064] FIG. 15 is a scale representation of the cross-sectional area of the 12 mm endoscope 100 with the attached external 7 mm working channel 104 , shown in horizontal shading. The cross sectional area of a prior art device 108 having an exterior diameter of approximately 24 mm is shown in diagonal shading. From FIG. 15 , it will be appreciated that the methods and apparatus of the invention allow for a substantially smaller device which is more easily delivered transorally and which is more easily manipulated. The overall cross-sectional area of the apparatus of the invention is approximately 152 mm 2 as compared to the 314 mm 2 of the prior art devices.
[0065] As mentioned, the clip applier of the invention may also be used with a dual lumen endoscope. FIG. 16 is a scale representation of a dual lumen endoscope 110 having an optical lumen 112 and two 6 mm working lumina 114 , 116 . As compared to the device 108 in FIG. 15 , the endoscope 110 has a substantially smaller cross-sectional area than the prior art device.
[0066] The clips used by the clip applier of the invention are substantially longer than the clips described in the previously incorporated co-owned applications, Ser. No. 09/891,775 and the simultaneously filed application, which are approximately 7 mm in length and adequate for general surgical applications. The retainer portion of the clips of the present invention is substantially longer in order to assure that all of the layers of the fundus are punctured.
[0067] Turning now to FIGS. 17 and 18 , a first embodiment of a surgical clip 210 according to the invention includes first and second arms 212 , 214 , respectively, and a bridge portion 216 therebetween such that the arms and bridge portion are in a generally U-shaped configuration. The first arm 12 is provided with an end catch 220 , and the second arm 214 extends (or transitions) into a deformable retainer 222 having a tissue piercing tip 224 and a plurality of catch engagements, e.g. 226 , 228 . The arms define an open space 230 between them. The clip 210 is preferably made from a unitary piece of titanium, titanium alloy, stainless steel, tantalum, platinum, other high Z (substantially radiopaque) materials, nickel-titanium alloy, martensitic alloy, or plastic, although other suitable biocompatible materials may be used. The first and second arms 212 , 214 , as well as the bridge portion 216 are relatively stiff and not plastically deformable within the limits of force applied to the arms during use, while the retainer 222 is relatively easily plastically deformable by the clip applier.
[0068] Referring now to FIGS. 2-4 and 17 - 18 , when the clip 210 is pushed forward in the clip applier with the jaws 22 , 24 of the clip applier closed, the retainer 222 is bent across the opening 230 between the first and second arms 212 , 214 and into engagement with the end catch 220 of the first arm 212 as shown in FIG. 18 . The anvil formed by the grooves on the interior of the hooks 46 , 48 of the clip applier jaws guide the bending of the retainer 222 causing it to puncture the fundus and couple to the end catch 220 .
[0069] The clip 210 shown in FIGS. 17 and 18 is provided with an optional bendable barb 232 which provides a secondary stabilizing fixation point which helps keep the clip from rotating. As the clip is pushed forward over the fundus, tissue catches the barb 232 and bends it as shown in FIG. 18 .
[0070] The clip 210 is also provided with an ear 233 on the bridge 216 . The ear is used by the pushing mechanism (not shown) to grasp the end of the clip when it is loaded into the clip applier.
[0071] A second embodiment of a clip 310 according to the invention is shown in FIGS. 19 and 20 . The clip 310 has two arms 312 , 314 connected by a bridge 316 . Both arms terminate in retainers 320 , 322 , each having a sharp end 321 , 323 . The clip 310 is also provided with a pair of ears 333 , 335 on the bridge 316 . The ears are used by the pushing mechanism (not shown) to grasp the end of the clip when it is loaded into the clip applier. This embodiment is intended for use with a clip applier having hooks with interior grooves which diverge, or which are in parallel planes. With reference to FIGS. 2-4 and 15 - 16 , when the clip 310 is pushed forward, the retainer 320 is bent by the groove inside the hook 46 and the retainer 322 is bent by the groove inside the hook 48 to the configuration shown in FIG. 20 . From FIG. 20 , it will be appreciated that each retainer punctures the fundus twice substantially forming a circular fastener. Thus, it will also be appreciated that the retainers 320 , 322 are significantly longer than the retainer 222 shown in FIGS. 17 and 18 and preferably are of a length at least Π times the distance between the arms 312 , 314 . Insofar as the retainers 320 , 322 each form a complete fastener, the function of the arms 312 , 314 and the bridge 316 may be considered redundant.
[0072] FIGS. 21-23 illustrate a third embodiment of a clip 410 according to the invention. The clip 410 is similar to the clip 310 (with similar reference numerals increased by 100 referring to similar parts) except that the retainers 420 , 422 are removable from the arms 412 , 414 . The arms 412 , 414 terminate in female couplings 413 , 415 which receive ends of the retainers 420 , 422 in a slight interference fit. The clip 410 is also provided with a pair of ears 433 , 435 on the bridge 416 . The ears are used by the pushing mechanism (not shown) to grasp the end of the clip when it is loaded into the clip applier. The clip 410 is applied to the fundus in substantially the same way as described above with reference to the clip 310 . However, after the retainers 420 , 422 are bent by the anvils and the jaws are opened, the clip 410 is not released from the clip applier and the retainers are separated from the arms 412 , 414 . The resulting fastener formed by the retainers 420 , 422 is shown in FIG. 23 . This is actually two substantially parallel “b” shaped fasteners. Thus, it may only be necessary to apply a single retainer as shown in FIG. 24 , for example.
[0073] There have been described and illustrated herein several embodiments of methods and apparatus for the endoluminal treatment of gastroesophageal reflux disease. While particular embodiments of the invention have been described, it is not intended that the invention be limited thereto, as it is intended that the invention be as broad in scope as the art will allow and that the specification be read likewise. It will therefore be appreciated by those skilled in the art that yet other modifications could be made to the provided invention without deviating from its spirit and scope as so claimed. | 1a
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1. FIELD OF THE INVENTION
[0001] This invention relates to compositions and methods for enhancing the penetration of topical skin agents into the epidermal and dermal layers of the skin. More particularly, it relates to compositions containing at least one active ingredient, a skin conditioner or nutrient that can be enhanced and regulated in penetrating the skin with a polymeric emulsifier, and, alternatively, a sugar or a polyoxyethylene alcohol.
2. BACKGROUND OF THE INVENTION
[0002] In the field of therapeutic skin care, topical agents are often applied to the skin. In order to ensure their therapeutic activity, these agents must be applied onto the skin and be allowed to penetrate the epidermis and dermis. Although conceptually simple, this has often proven to be a formidable task, because of the skin's intended function as a well-designed barrier to foreign matter from the ambient environment. The outermost layer of the skin is composed of the stratum corneum, or “horny layer”, containing several layers of dead, keratinized and flattened skin cells. This layer is extremely difficult to penetrate. It contains approximately 15% water, 70 % protein and 15% lipid. The predominant protein is keratin. In the stratum corneum, a cornified envelope forms around the keratin resulting in corneocytes. Between these corneocytes are the lipids that bind the corneocytes together. From this structure, two routes become available for active ingredients to enter the skin.
[0003] Hydrophobic active ingredient are generally expected to be more apt to penetrate the skin through the intercellular lipid spaces. Hydrophilic actives, however, are expected to penetrate the stratum corneum through a transcellular pathway, i.e., through the corneocyte. However, even though there are two routes of entry, most topical actives still have difficulty penetrating the stratum corneum. Furthermore, if a composition contains actives that are hydrophobic as well as hydrophilic, the known penetration enhancing agents for one type of active may not serve to assist the penetration of the other and, in fact, may be expected to inhibit such penetration.
[0004] Another problem arises when providing formulations that enhance the penetration of topical agents: increasing the amount of active agent in the skin often produces excessive skin irritation. This, of course, is extremely undesirable, particularly for patients who are suffering inflammatory skin diseases or conditions.
[0005] Therefore, an object of this invention is to provide a delivery system that enhances the skin penetration of topically active agents.
[0006] An additional object of this invention is to provide that such delivery system not only allows for enhancing the penetration of the active but regulating delivery of the topical active as well.
[0007] Yet another object of this invention is to provide a delivery system having a low irritation profile while enhancing the skin penetration of such active ingredients.
[0008] A novel composition that enhances the penetration of hydrophilic and/or hydrophobic topically active compounds through the outermost layer of the skin would be advantageous for delivering therapeutic agents to the skin. Surprisingly, we have found novel compositions that enhance and regulate the penetration of topical active ingredients. Moreover, the compositions of this invention are unexpectedly mild and non-irritating to the skin despite the increased penetration of topical active agents.
SUMMARY OF THE INVENTION
[0009] The novel compositions of this invention may enhance the penetration of either hydrophobic or hydrophilic topical active agents. The compositions of this invention further provide a method of enhancing the penetration of both hydrophobic and hydrophilic agents, as well as a method to regulate the penetration of such agents. The novel compositions of this invention that enhance the penetration of hydrophobic active agents contains at least one hydrophobic or hydrophilic active agent, and a polymeric emulsifier. This composition may more preferably contain a sugar.
[0010] The novel compositions of this invention that enhance the penetration of hydrophilic active agents may also contain at least one hydrophilic penetration-enhancing agent such as a polyoxyethylene alcohol. Additionally, other components that aid in enhancing and regulating the penetration of such topical active agent may be added to the compositions of this invention such as the following: a polymeric emulsifier, a sugar and a polyoxyethylene alcohol. Novel compositions of this invention that possess the property of enhanced penetration that contain a hydrophobic active agent may also contain at least one hydrophilic penetration-enhancing agent such as a sugar.
[0011] The novel compositions of this invention that provide the regulation of delivery of hydrophilic and hydrophobic active agents in the same composition contain at least one hydrophobic active agent; at least one hydrophilic active agent, such hydrophilic active agent optionally being a sugar; a sugar; and polyoxyethylene alcohol.
[0012] Polymeric emulsifiers, particularly those which have been hydrophobically-modified, are useful in the compositions of this invention. In both pharmaceutical and cosmetic compositions, lotions and creams have been used as popular delivery vehicles for applying topical actives. Emulsions are two-phase systems that contain two immiscible liquids, typically oil and water. In order to stabilize oil in water, ionic or non-ionic surfactants may be used to reduce interfacial surface tensions creating oil droplets dispersed in water. Unlike traditional emulsifiers, polymeric emulsifiers operate by creating gels around the oil droplets. When these droplets come near each other, they are repelled by the gel layers. Preferably, a nonionic polymeric emulsifier, more preferably a hydrophilic cross-polymer which has been hydrophobically modified and most preferably, a hydrophobically-modified polyacrylic acid emulsifier having from about 10 to about 30 carbon atoms is used in the products and compositions of this invention. Most preferably, the polymeric emulsifier should be Pemulen*, an acrylate/C10-30 alkyl acrylate crosspolymer commercially available from B. F. Goodrich Specialty Chemicals of Cleveland, Ohio. Surprisingly, delivery systems containing lipophilic topical active ingredients formulated in the compositions of this invention in conjunction with Pemulen* provided enhanced penetration of the lipophilic topical active ingredient. Preferably, the polymeric emulsifier should be present in the compositions of this invention an amount of from about 0.01 to about 20 % by weight of the composition. More preferably, they should be present in an amount of from about 0.1 to about 5 weight percent of the composition. Most preferably, they should be present in an amount of from about 0.1 to about 1 weight percent of the composition.
[0013] Sugars have also been commonly used in pharmaceutical and cosmetic compositions as humectants. Surprisingly, in the compositions of this invention, sugars that were incorporated into such compositions for the purpose of improving the compositions' skin feel characteristics, served to enhance the penetration of hydrophobic topical active ingredients. We also found, surprisingly, that the combination of hydrophobically-modified polymeric emulsifiers and sugars enhanced the penetration of the hydrophobic active ingredients together to a greater degree than either would if used separately. Moreover, sugars that assist in enhancing penetration may be hydrophilic topically active agents themselves. Sugars that may be useful in the compositions of this invention include, for example, ascorbic acid-2-glucoside, oligosaccharides such as lactose and melibiose and the like. Preferably, the sugar should be present in the compositions of this invention an amount of from about 0.01 to about 20 % by weight of the composition. More preferably, they should be present in an amount of from about 0.1 to about 10 weight percent of the composition. Most preferably, they should be present in an amount of from about 0.1 to about 7 weight percent of the composition.
[0014] In order to enhance the penetration of hydrophilic topical actives, a polyoxyalkylene alcohol may be incorporated into the compositions of this invention. More preferably, a polyoxyethylene alcohol may be incorporated into the compositions of this invention. More preferably, such alcohols as steareth-10-20 and the like may be incorporated into the compositions of this invention. Preferably, the polyoxyalkylene alcohol should be present in the compositions of this invention an amount of from about 0.01 to about 20% by weight of the composition. More preferably, they should be present in an amount of from about 0.01 to about 5 weight percent of the composition. Most preferably, they should be present in an amount of from about 0.01 to about 2 weight percent of the composition.
[0015] In a system that contains both the hydrophobically modified acrylic acid, sugar and polyoxyethylene alcohol, unexpectedly, the compositions not only increase permeation of the topical active ingredients, but can be used to regulate the penetration of the active ingredients as well. For example, by changing the ratios of the ingredients, either hydrophobic or hydrophilic active agent penetration may be up- or down-regulated in order to enhance the therapeutic benefits of the formulations of this invention. By balancing the proportions of the elements of the compositions of the invention, proper concentrations of topical actives could be delivered, depending upon the type of benefit desired. For example, a retinoid such as retinol may be utilized in a composition to combat wrinkles and prevent photodamage while ascorbic acid-2-glucoside may be utilized for the purpose of promoting even skin tone or preventing sun-induced erythema. Therefore, under some circumstances, the retinol benefit may be up-regulated in order to provide treatment of wrinkles while the penetration into the skin of another undesirable hydrophilic component that functions as a formulation excipient (e.g. disodium EDTA that causes irritation) may be down-regulated to achieve maximum benefit. Surprisingly, although increased penetration of actives occurred, irritation was found to be minimal.
[0016] Thus, for example, in a composition wherein a hydrophobic active ingredient is desired to be delivered to a great extent into the skin and the penetration of an irritating hydrophilic excipient is desired to be down-regulated, the ratio of the hydrophobically modified acrylic acid, sugar and polyoxyethylene alcohol present in such a composition should be from about 0.001 to about 1000. The ratio of the hydrophobically modified acrylic acid to the sugar should be from about 0.001 to about 1000. The ratio of the hydrophobically modified acrylic acid to the polyoxyalkylene alcohol should be from about 0.001 to about 1000. The ratio of the sugar to the polyoxyalkylene should be from about 0.001 to about 1000. More preferably, the ratios should be as follows: the ratio of the hydrophobically modified acrylic acid, sugar and polyoxyethylene alcohol present in such a composition should be from about 0.1 to about 10. The ratio of the hydrophobically modified acrylic acid to the sugar should be from about 0.1 to about 10. The ratio of the hydrophobically modified acrylic acid to the polyoxyalkylene alcohol should be from about 0.1 to about 10. The ratio of the sugar to the polyoxyalkylene should be from about 0.1 to about 10.
[0017] The compositions of this invention assist in enhancing skin penetration of hydrophobic, also known as lipophilic, compounds. More particularly, hydrophobic vitamins such as retinol and tocopherol and the like may be incorporated into the compositions of this invention as active agents. To maximize the delivery of a lipophilic agent, the composition contains at least one topical active agent and a hydrophilic polymer that has been hydrophobically modified. The use of a sugar in combination with the hydrophobically-modified hydrophilic polymer unexpectedly further increases the delivery of the active agent.
[0018] The addition of polyoxyalkylene alcohol should increase the penetration and regulation of any hydrophilic ingredients in the composition. Despite the enhanced penetration of the topical agents, the composition is surprisingly non-irritating to the skin.
[0019] Any topical dosage form known to those of ordinary skill in the art, including, but not limited to, lotions, gels, sprays, aerosols and mousses.
[0020] The compositions of this invention should preferably contain:
[0021] (a) a topically active amount of a pharmaceutical or cosmetic active ingredient;
[0022] (b) from about 0.01% to about 20% of a non-ionic polymeric emulsifier;
[0023] (c) optionally, from about 0.01% to about 20% of a sugar; and
[0024] (d) optionally, from about 0.01% to about 20% of a polyoxyethylene alcohol.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0025] This invention provides compositions and methods to enhance and regulate the delivery of topical agents. The compositions of this invention comprises a pharmaceutical agent or cosmetic active ingredient, hydrophilic polymer that has been hydrophobically modified, optionally a sugar, optionally, polyoxyalkylene alcohol or any combination thereof. The pharmaceutical active includes any drug, hydrophobic or hydrophilic in nature, that would be appropriate for topical use. The cosmetic active includes any ingredient appropriate for cosmetics, nutrients or skin conditioners. These compositions are also non-irritating to the skin.
[0026] The pharmaceutical actives that can be used in the compositions of this invention, but not limited to, are antimicrobials, allergy inhibitors, anti-acne, analgesics, antitussives, antipruritics, anesthetics, antihistamines, anti-infective agents, inflammation inhibitors, anti-emetics, anticholinergics, vasoconstrictors, vasodilators, and wound healing promoters and the like.
[0027] The cosmetic active ingredients that can be used in the compositions of this invention, but not limited to, are vitamins (e.g., vitamin B complex; including thiamine, nicotinic acid, biotin, pantothenic acid, choline, riboflavin, vitamin B6, vitamin B12, pyridoxine, inositol, carnitine; vitamins A, C, D, E, K and their derivatives, pro-vitamins), amino acids and their derivatives, herbal extracts, retinoids, flavonoids, anti-oxidants, anti-inflammatory, skin conditioners, skin lighteners, chelating agents, cell turnover enhancers, coloring agents, fragrances, pigments and sunscreens and the like.
[0028] Preferably, the hydrophobically-modified hydrophilic polymeric emulsifiers used in the compositions of this invention are hydrophobically modified acrylic acids. Such as akylacrylates and the esters. The akyl chain lengths ranges from C2-C30.
[0029] Sugars that can be used in the compositions of this invention may include, but are not limited to, glucose, oligosaccharides, more particularly disaccharides such as fructose, melibiose, xylose, sucrose, arbutin, maltose, glucosides glycosides and derivatives thereof and the like. Sugars function in the compositions of this invention to enhance penetration of both hydrophobic and hydrophilic active ingredients.
[0030] Polyoxyethylene alcohols function in the compositions of this invention to enhance the penetration of hydrophilic active ingredients and can be used in the compositions of this invention. Such polyoxyethylene alcohols include, but are not limited to: ceteths, laureths, myreths, oleths, steareths and trideths. One particularly preferred example is steareth-10 or Brij 76 made by ICI Surfactants of Delaware, USA.
[0031] The delivery system and active ingredients are incorporated in a pharmaceutically or cosmetically acceptable vehicle. Preferably, the pH of the compositions of this invention should be from about 5 to about 9, more preferably from about 5 to about 7.
[0032] Of course, topical skin care agents known to those of ordinary skill in the art may be incorporated into the compositions of this invention, including mineral oils, animal oils, vegetable oils and silicones have all been used in cosmetic creams and lotions of the emulsion type. In addition to such oils, other emollients and surface active agents have been incorporated in the emulsions, including glyceryl trioleate, acetylated sucrose distearate, sorbitan trioleate, polyoxyethylene (1) monostearate, glycerol monooleate, sucrose distearate, polyethylene glycol (50) monostearate, octylphenoxypoly (ethyleneoxy) ethanol, deacylerin penta-isostearate, sorbitan sesquioleate, hydroxylated lanolin, lanolin, triglyceryl diisostearate, polyoxyethylene (2) oleyl ether, calcium stearoyl-2-lactylate, methyl glucoside sesquistearate, sorbitan monopalmitate, methoxy polyethylene glycol-22/dodecyl glycol copolymer (Elfacos E200), polyethylene glycol-45/dodecyl glycol copolymer (Elfacos ST99), polyethylene glycol 400 distearate and glyceryl stearate; alcohols, such as cetyl alcohol and lanolin alcohol; myristates, such as isopropyl myristate; cetyl palmitate; cholesterol; stearic acid; propylene glycol; glycerine, sorbitol and the like. Thickeners such as natural gums and synthetic polymers, as well as preservatives such as methylparaben, butyl paraben, propylparaben and phenyoxyethanol, coloring agents and fragrances also are commonly included in such compositions. Other active ingredients such as sunscreen materials and antimicrobial materials may be utilized in the compositions of the present invention provided that they are physically and chemically compatible with the other components of the compositions.
[0033] The following examples illustrate, but do not serve to limit the scope of the compositions and methods of this invention.
EXAMPLES
Example 1
Determination of Penetration and Regulation of Topical Agents
[0034] Five formulations were made containing the following ingredients:
Formulation A (Comparison formulation): Ingredient Weight Percent Water 73.86% Thickeners 1.35% Chelating agent 0.10% Panthenol 0.50% Glycerine 3.00% Whitening agent 3.00% PH adjustor 0.05% C12-15 alkyl benzoate 4.00% Octyl hydroxy stearate 1.00% Dimethicone 1.00% Cetyl alcohol 2.50% Cetearyl glucoside 1.40% Tocopheryl acetate and 0.55% Tocopherol Sunscreen 4.00% Preservative 1.25% Stabilizers 1.10% Retinol 0.04%
[0035] The following formulations B, C, D and E were made as set forth below:
Ingredient Weight Percent Formulation B: Water 78.04% Glycerin 3.00% D panthenol 0.50% Disodium EDTA 0.10% Preservative 0.73% Preservative 0.35% Acrylates/C10-30 Alkyl 0.25% Acrylate Cross-Polymer 0.40% Carbomer Ascorbic Acid 0.01% Dibutylhydroxy-toluene 0.10% Cetyl Alcohol 2.00% C 12-15 alkyl benzoate 4.00% Octyl hydroxy stearate 1.00% Dimethicone 1.00% Di-alpha tocopheryl acetate 0.50% Octyl methoxy-cinnamate 4.00% Propyl paraben 0.17% Na hydroxide (10%) 2.60% Retinol 50c 0.20% Tocopherol 0.05% Thea Sinesis Extract 1.00% Formulation C: Water 73.39% Glycerin 3.00% D panthenol 0.50% Disodium EDTA 0.10% Ascorbic Acid-2G 2.00% Phenoxyethanol 0.73% Methyl paraben 0.35% Xanthan gum 0.20% Hydroxyethylcellulose 1.15% Ascorbic Acid 0.01% Dibutylhydroxytoluene 0.10% Cetearyl glucoside 1.40% Cetyl Alcohol 2.00% C 12-15 alkyl benzoate 4.00% Octyl hydroxy stearate 1.00% Dimethicone 1.00% Di-alphatocopheryl 0.50% acetate Octyl methoxycinnamate 4.00% Propyl paraben 0.17% Na hydroxide (10%) 2.45% Retinol 50c 0.20% Polyacrylamide & laureth 0.70% 7 & C13—C14 isoparafin Tocopherol 0.05% Thea Sinesis Extract 1.00% Formulation D: Water 72.82% Glycerin 3.00% D panthenol 0.50% Disodium EDTA 0.10% Preservative 0.73% Preservative 0.35% Acrylates/C10-30 Alkyl 0.25% Acrylate Cross-Polymer 1.00% Dimethicone Cetyl Alcohol 2.00% Di-alpha tocopheryl acetate 0.50% Octyl methoxycinnamate 4.00% Propyl paraben 0.17% Na hydroxide (18%) 1.50% Retinol 50c 0.18% Ascorbic Acid-2G 6.35% Tocopherol 0.05% Thea Sinesis 1.00% Extract Formulation E: Water 71.59% Glycerin 3.00% D panthenol 0.50% Disodium EDTA 0.10% Ascorbic Acid-2G 2.00% Preservative 0.73% Preservative 0.35% Acrylates/C 10-30 Alkyl 0.25% Acrylate Cross-Polymer 0.40% Carbomer Ascorbic Acid 0.01% Dibutylhydroxy-toluene 0.10% Steareth-10 2.00% Cetyl Alcohol 2.00% C 12-15 alkyl benzoate 4.00% Octyl hydroxy stearate 1.00% Dimethicone 1.00% Di-alpha tocopheryl 0.50% acetate Octyl 4.00% methoxycinnamate Preservative 0.17% Na hydroxide (10%) 5.05% Retinol 50c 0.20% Tocopherol 0.05% Thea Sinesis Extract 1.00% Formulation F: Water 49.484 Squalane 15.000 Glycerin 10.000 Macademia Nut Oil 7.000 Pentaerythritol Tetraoctanoate 5.000 Butylene Glycol 4.000 Petrolatum 3.000 Quaternium 18 Hectorite 2.700 Polyglyceryl-2-Diisostearate 2.000 PEG 150 1.000 Retinol 0.166 Trisodium EDTA 0.100 Ascorbic Acid 0.100 Sodium Citrate 0.100 Tocopheryl Acetate 0.100 Preservative 0.100 Preservative 0.100 Butylated Hydroxytoluene (BHT) 0.050
[0036] Formulation B was made by adding water to a beaker and overcharging the beaker with 20 grams of water. The water was then purged with argon or nitrogen gas. After 10-15 minutes, 20 grams of water was removed to check for oxygen content. If there was significant measurable oxygen in the sample, the purging was continued. Once oxygen was purged from the water, glycerin, panthenol, disodium EDTA, a first preservative and ascorbic acid were added to the beaker. The acrylates/C10-30 alkyl acrylate and carbomer were then added to the water phase. The beaker was then transferred to a vacuum close kettle homogenizer under yellow lights and any residual oxygen removed. The beaker was then heated to 70-75° C. A second preservative was added and mixing continued until it dissolved. The water phase was then neutralized with NaOH (10%) and the temperature held at 70-75° C. for phasing. The remainder of the ingredients but for the Retinol, Tocopherol and Thea Sinesis Extract were combined in a separate beaker and heated to 70-75° C. When both phases were at the same temperature and homogenous, the oil phase was added to the water phase under vacuum and homogenized together. The beaked was then cooled slowly. Retinol was added when the temperature reached 55° C. and Tocopherol and Thea Sinesis extract added at 45° C. Formulation C was made in a similar manner, except that AA-2G was added in addition to the ascorbic acid and, after the ascorbic acid was added, the xanthan gum, hydroxyethylene and glycerin were added to the water phase. Formulation D was made similarly to Formulation B. Formulation E was made similarly to Formulation C except that Steareth 10 was added to the oil phase.
[0037] Formulation F was prepared by combining water, glycerin, PEG150, and butylene glycol in a beaker, and heating it to 75° C. At 75° C., Trisodium EDTA, ascorbic acid and sodium citrate was added. Combining squalene, Mac. Nut oil, pentaerythritol tetraoctanoate, petrolatum, quaternium 18 hectoriate, polyglyceryl-2-diisostearate, and heating the mixture to 80° C. while mixing. At 80° C., parabens and BHT were added to the mixture. The water phase was added to oil phase slowly and the heated was stopped. At 50° C., Vitamin E acetate and retinol were added. The whole process should be under argon and yellow light conditions.
[0038] Experiments were conducted to determine the enhanced penetration and regulation effect of the delivery system. To determine transdermal penetration, in vitro skin permeation studies were conducted using non-occluded Franz diffusion cells.
[0039] Human cadaver skin section were mounted in Franz diffusion cells containing a receptor medium composed of a phosphate buffer with 0.025% butylated hydroxytoluene and 1.5% oleth-20. The receptor capacity was 5 milliliters (ml) and the cell surface area was 0.636 cm 2 . A 400 μm dose of one of the following formulations was applied to the diffusion cell. After 24 hours, the surface of the cells were cleansed with a solution of methanol and ethyl acetate. The epidermis and dermis were separated, chopped and placed into vials containing a solution methanol and ethyl acetate and subjected to sonication to fragment the skin. After sonication, the skin fragments were analyzed using HPLC. Samples were taken at zero and 24-hour time-points. Penetration of active ingredient was calculated based upon a percentage of applied dose. For these studies, the penetration of a lipophilic agent (retinol and a hydrophilic agent (ascorbic acid 2-glucoside, or “AA2G”) were investigated.
[0040] The formulations investigated are set forth in Table 1 below:
TABLE 1 % of applied % of applied dose of retinol Enhancement dose of AA-2G Enhancement delivered into factor of retinol delivered into factor of AA-2G Composition Ingredients epidermis delivery epidermis delivery A Conventional Cetearyl Glucoside 0.175% 1.00 N/A N/A emulsifier (Control) B Hydrophobically Acrylates/C10-30 0.642% 3.67 N/A N/! modified acrylic acid alkyl acrylate emulsifier crosspolymer C Conventional Cetearyl glucoside and 0.241% 1.38 N/A N/A emulsifier and sugar AA-2G D Hydrophobically Acrylates/C10-30 1.25% 7.20 0.18% 1 modified acrylic acid alkyl acrylate and sugar crosspolymer and AA-2G E Hydrophobically Acrylates/C10-30 0.464 −2.70 1.016% 5.65 modified acrylic acid, alkyl acrylate sugar and crosspolymer, AA-2G polyoxyethylene and steareth-10 alcohol
[0041] From the above data, it can be seen that a control formulation (Formulation A) containing only cetearyl glucoside delivered only 0.175% of the applied dose of retinol into the epidermis. Surprisingly, however, when a formulation containing hydrophobically modified acrylic acid emulsifier was used (Formulation B), the percentage of retinol delivered increased to 0.642%, a 3.669 fold increase in delivery. When AA-2G and cetearyl glucoside were placed into formulation with retinol (Formulation C), the retinol permeation surprisingly increased to 0. 241 %, a 1.38-fold increase over the control formulation A. Even more surprisingly, a formulation containing both hydrophobically modified acrylic acid and AA-2G (Formulation D), although an additive effect was expected, a total delivery of retinol of 1. 26 % or a 7.2 fold increase in retinol delivery to the epidermis.
[0042] The activity of Formulation E demonstrates that the addition of a polyoxyethylene alcohol increased the penetration from 0.18% to 1.016%, or a 5.65-fold increase of delivery of AA-2G. Surprisingly, the retinol permeation decreased from 1.25% to 0.464%, a 0.36-fold decrease. Thus, the compositions of this invention afford a method of regulating the delivery of both hydrophilic and lipophilic ingredients.
Example 2
Low Level of Irritation Demonstrated by Compositions of This Invention
[0043] Those of ordinary skill in the art of formulating topical skin care compositions would expect an increase in skin irritation to accompany an increase in penetration of active ingredients. The compositions of this invention, however, were surprisingly non-irritating despite the improved penetration of active ingredients.
[0044] A standard test for skin irritation, called the “Modified Irritation Study” (MIS) was used to evaluate the delivery system using retinol as the topical agent. This test measures the irritation potential of compositions in human volunteers. Test formulations of this invention were applied to fifty test subjects three times per week for three weeks for a total of nine applications. An occlusive patch with 0.2 to 0.3 gm of each test composition was applied to the upper back of the human subject. The patches remained in place for an initial 24 hours. After 24 hours, the subject would remove the patch from the back. A 24-hour rest period, during which no test material was applied, followed the removal of a Monday and Wednesday patch application. A 48-hour rest period followed a Saturday patch removal.
[0045] After each rest period, the test areas were observed by a study coordinator and graded according to a scale of 0 to 4.0. Fresh test material and patches were applied to the identical test sites until nine induction patches were completed.
[0046] The nine application scores for each test site for each subject were summed to yield a total score for 21 days. A grand total score for a test sample was obtained by adding the 21-day totals for all subjects. The grand total scores were normalized against the positive control (Formulation F below), which received a normalized score of 100 to obtain a Normalized Irritation Score. The results of these tests are set forth in Table 2 below.
TABLE 2 Ratio of total retinol Total amount of delivered:Normalized Retinol retinol delivered Normalized Irritation Composition Ingredients Concentration (μg) Irritation Score Score A Convention emulsifier Cetearyl Glucoside 0.04% 0.21 9.88 2.1 (Control) B Hydrophobically Acrylates/C10-30 0.075% 1.44 68.4 2.1 modified acrylic acid alkyl acrylate emulsifier crosspolymer C Conventional Cetearyl glucoside and 0.075% 0.54 46.5 1.2 emulsifier and sugar AA-2G D Hydrophobically Acrylates/C10-30 0.075% 2.84 21 13.5 modified acrylic acid alkyl acrylate and sugar crosspolymer and AA-2G F Water-in-oil emulsifier Polyglyceryl-2- 0.15% N/A 100 N/A diisostearate and PEG 150
[0047] An increase in retinol penetration would generally be expected to result in higher skin irritancy, or a lower ratio of Total Retinol Delivered:Normalized Irritation Score. Ratios of the amount of retinol delivered to the irritation score were calculated to compare the formulations, i.e., they represent the amount of retinol delivered per each unit of irritation. As can be seen from the data set forth in Table 2, Formulations A, B and C are all comparable to each other. Formulation is a commercial product known to be mildly irritating. From these results with respect to Formulations A, B and C, it would appear that neither the hydrophobically modified acrylic acid emulsifier nor the sugar have an effect upon irritation mitigation.
[0048] However, surprisingly, Formulation D evidences a dramatic increase in retinol delivery per unit of irritation and, therefore, is considerably less irritating than Formulations A, B and C. We would also expect that the therapeutic index of Formulation D would be greater than that of Formulations A, B or C in light of the increased amount of retinol delivered at a lower extent of irritation. We conclude that the irritation mitigation effect is unexpectedly greater in compositions containing both hydrophobically modified acrylic acid and sugar.
[0049] Delivery of hydrophilic active ingredients using the compositions of this invention and the concomitant irritation mitigation effect may be seen exemplified below in Table 3.
TABLE 3 Ratio of total AA-2G Total Amount delivered: AA-2G AA-2G Normalized Normalized Composition Ingredients Concentration delivered (μg) Irritation Score Irritation Score D Hydrophobically Acrylates/C10-30 2% 1.08 21 0.05 modified acrylic acid alkyl acrylate and sugar crosspolymer and AA-2G E Hydrophobically Acrylates/C10-30 2% 6.09 26 0.23 modified acrylic acid, alkyl acrylate sugar and crosspolymer, AA- polyoxyethylene 2G and steareth-10 alcohol F Water-in-oil emulsifier Polyclyceryl-2- 0% N/A 100 N/A diisostearate and PEG 150
[0050] As set forth above in Table 3, one unit of irritation results in the delivery of 0.05% AA-2G. With the addition of a polyoxyethylene alcohol, however, this number unexpectedly increases to 0.23%, meaning that more AA-2G is delivered to the skin with a lower irritation, generating a greater efficacy or therapeutic index.
Example 3
Additional Formulations of the Invention
[0051] The compositions of this invention may be made by traditional preparation method. The following Table 4 illustrates compositions of this invention which we believe would serve to enhance the delivery of hydrophobic and hydrophilic active ingredients to the epidermis and dermis of the skin with relatively low levels of irritation.
TABLE 4 Ingredient Function Formulation 1 Formulation 2 Formulation 3 Water Vehicle q.s. 100% q.s. 100% q.s. 100% Glycerin Humectant About 0-about 10% About 0-about 10% About 0-about 10% Disodium EDTA Chelator About 0-about 1% About 0-about 1% About 0-about 1% Preservative Preservative About 0.1 to about 2 About 0.1 to about 2 About 0.1 to about 2 Carbomer Thickener About 0.1 to about 1% About 0.1 to about 1% About 0.1 to about 1% Pemulen Hydrophobically About 0.1 to about 1% About 0.25% About 0.25% modified polymer emulsifier Ascorbic Acid 2- Sugar 0% About 0.1% to about About 0.1% to about Glucoside 5% 5% Butylated Stabilizer About 0 to about 1% About 0-about 1% About 0-about 1% Hydroxytoluene Cetyl alcohol Emollient About 0-about 10% About 0-about 10% About 0-about 10% C12-15 alkyl benzoate Emollient About 0-about 10% About 0-about 10% About 0-about 10% Dimethicone Spreading agent About 0 to about 10% About 0 to about 5% About 2% NaOH (10%) Neutralizer q.s. pH 5-8 q.s. pH 5-8 q.s. pH 5-8 Steareth-10 Polyoxyethylene alcohol About 0 to about 5% About 0 to about 5% About 0 to about 5% Emulsifier Sunscreen Sunscreen About 0 to about 10% About 0 to about 10% About 0 to about 10%
[0052] The compositions of this invention may be administered topically, but may also be utilized in delivery of oral and parenteral formulations. | 1a
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BACKGROUND OF THE INVENTION
1. Technical Field
This invention generally relates to coated polymer materials and, more particularly, to a resorptive polymer coat having a ceramic polymer blend which, when used individually or in combination, provides a highly tunable resorption time and a means of supplying bone forming elements.
2. Discussion
The repair of separated or dislocated bone fragments or segments following bone surgeries requires realignment of the separated or dislocated fragments or segments and subsequent secure fixation for promoting proper natural rejoinder of these bone fragments or segments. The presence of relative motion of the bone fragments or segments at a fracture or osteotomy location may result in irritation of the surrounding tissues, nonunion between the bone fragments, and an extension of the time of fracture healing. It is therefore desirable to accomplish as completely as possible an immobilization of the fracture or osteotomy site. This involves the relative fixation of affected bone segments relative to each other and in relation to the surrounding bone structure.
Known methods for providing fixation between adjacent bone portions have included the use of metallic plates of varying configurations, which are secured across osteotomies or fracture sites by metallic bone screws. These devices have been made of biocompatible metals and metal alloys, such as commercially pure titanium, stainless steel and cobalt chrome molybdenum. Other materials and devices, such as wires, intramedullary nails or externally fixed pins have also been used to reduce bone fracture mobility and to improve the relative position of adjacent segments. The aim of fixation of adjacent bone portions is to immobilize the fracture or osteotomy sites in order to promote localized bone growth in the natural repair of the separation.
The disadvantages associated with the use of metallic and metallic alloy devices relate to the possible undesirable cosmetic results associated with the protrusion of these devices above the bone surface, especially in locations directly beneath the skin, that is, without any intervening soft tissue for masking the implant devices from being noticed externally. As such, the only way to remove these implant devices involves revision surgery after the localized bone area has healed. In addition, metal and metallic alloy devices often should be removed from a pediatric patient so as to prevent growth restrictions. Another disadvantage associated with using metallic implants is the lack of load transfer. As the fracture site heals, load bearing capability should transfer from the implant to the surrounding tissue. This is possible only with resorbable materials.
The use of medical implant devices made from bioresorbable materials has been described in literature and these devices have the advantage of being absorbed by the body over a period of time so as to allow for bone or fibrous material to become repaired at a fracture or osteotomy site by growing into the space created between adjacent bone portions. Many bioresorbable materials have been suggested for use in fixation of adjacent bone portions. It was believed that these materials had to be extremely strong to fixate the bone portions over a relatively long period of time. This typically meant that the osteosynthesis plate had to be relatively thick and be made out of a high molecular weight oriented material such as poly L-lactic acid in which the molecular weight would exceed 250,000. See Pihlajamaki, H., et al., “Absorbable Pins of Self-Reinforced Poly-L-Lactic Acid for Fixation of Fractures and Osteotomies,” Journal of Bone and Joint Surgery, v. 74-B, n. 6, p. 853-857, November 1992. In addition, it was believed that certain copolymers of glyceride and lactide were not appropriate for use in osteosynthesis plates because of a rapid loss of mechanical strength. Grijpma, D. W., et al., “Poly (L-lactide) Crosslinked with Spiro-bis-dimethylenecarbonate,” Polymer, v. 34, n. 7, 1993 at 1496.
While others suggest the use of non-reinforced materials, the molecular weight of the material had to be increased to maintain strength. In this regard, one author suggested using a non-oriented material having an average molecular weight of 10 6 . See Bos, R .R .M., et al., “Late Complications related to Bioresorbable Poly (L-Lactide) Plate-Osteosyntheses”, Journal of Oral Maxillofacial Surgery, Supp. 3, 51(a) 1993 at 190. However, there were certain problems which were associated with these particular osteosynthesis plates. First, such osteosynthesis plates tended to have a relatively high degree of inflammatory response and therefore had to be removed from the patient. See, Bostman, O., “Current Concepts Review—Absorbable Implants for the Fixation of Fractures,” Journal of Bone and Joint Surgery, pp. 148-153, 1991. In addition, the osteosynthesis plates had to be made relatively thick so as to provide the requisite strength and resorption time, which tended to make the osteosynthesis plates have an unwanted cosmetic appearance when implanted.
A need therefore exists for a bioresorbable fastening device for bone fixation, such as an osteosynthesis plate, that is thin enough and of a suitable material to be resorbed over a desired period of time, yet is of sufficient strength to maintain relative bone fixation over the time period needed for the natural repair of fractures or osteotomies between adjacent bone portions. A need also exists for a bioresorbable osteosynthesis plate which has adaptable resorption rates, composition, and strength. A need further exists for such a bioresorbable device to allow for the formation of one or more additional fastener openings at one or more required precise locations during the surgical procedure.
SUMMARY OF THE INVENTION
In accordance with the teachings of the present invention, a bioresorbable material is disclosed having a ceramic and polymer coating. The ceramic and polymer coating increases the tailorability and tuneability of resorption rates and properties and allows for increases in implant design flexibility by virtue of its simplicity. Also as the coating comprises of a resorbable ceramic, it helps in bone integration and formation.
In one preferred embodiment, a resorptive material includes a polymer and ceramic coating to control the osseoconductive properties of the coating. A resorbable ceramic powder is deposited onto a substrate by use of a resorbable polymer binder. It is possible to use a combination of differing ceramic compositions as well as ceramic powder particle sizes to adjust resorption properties. Similarly, it is possible to use a combination of resorbable polymeric binders in different amounts to adjust resorption time.
In another preferred embodiment, a material having a biocompatible resorbable ceramic with biologically acceptable cations such as calcium, sodium, potassium and anions of phosphates in various oxidation states, carbonates, bicarbonates and sulfates including but not limited to calcium sodium phosphate, calcium sulfate, hydroxyapatite, calcium carbonate, tricalcium phosphate and octacalcium phosphate or a mixture of resorbable ceramics.
In yet another preferred embodiment, a method of forming a resorbable coating material onto a substrate is disclosed. The method includes the steps of forming a mixture of the polymer binder, a resorbable ceramic powder and a solvent. The mixture is disposed onto the substrate at a fixed thickness. The solvent is either extracted or evaporated off, leaving a coating of ceramic powder coupled to the substrate by a polymer binder.
Use of the present invention provides a substrate material coated with a resorbable layer that affects resorption rate. The coating material is formed of a resorbable polymer binder and resorbable ceramic materials. By adjusting the volume fraction of the ceramic, the thickness of the coating, the molecular weight of the binder and the composition of the binder, the resorption rate of the coating can be significantly slowed down. As a result, the aforementioned disadvantages associated with the currently available resorbable materials have been substantially reduced or eliminated.
BRIEF DESCRIPTION OF THE DRAWINGS
The various advantages of the present invention will become apparent to one skilled in the art upon reading the following specification and by reference to the drawings in which:
FIG. 1 is a cross-section of a coated substrate conforming to the teachings of the current invention;
FIG. 2 is a cross-section of a multi-layer coating conforming to the teachings of the current invention;
FIG. 3 is a flow chart describing the method of producing the coating of the invention; and
FIG. 4 is a bone plate formed of the coated material of the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The following description of the preferred embodiments are merely exemplary in nature and are in no way intended to limit the invention, or its application, or uses. Moreover, while various specific substrate and coating structures are disclosed, it will be understood by those skilled in the art that they are merely exemplary and other specific substrate structures and coating may be used.
FIG. 1 discloses a coating 20 of the current invention disposed on a substrate 21 . The primary constituent of the coating 20 is ceramic powder 22 . Generally, the ceramic powder 22 is a bio-compatible resorbable ceramic with cations of calcium, sodium potassium and anions of phosphates in various oxidation states. Preferably, the ceramic 22 is a phosphate, carbonate, bicarbonate or sulfate including but not limited to calcium sodium phosphate, calcium sulfate, hydroxyapatite, calcium carbonate, tricalcium phosphate and octacalcium phosphate or mixtures of these resorbable ceramics.
The particle sizes of the embedded ceramic 22 being used for the coatings 20 are generally below 200 microns. It is preferable that the particles have a mean size of 50 microns with a distribution of about 25 microns. It is possible to use tailored size distribution such as a bimodal particle size distribution to modify the overall performance of the device.
The coating 20 disclosed does not require the use of a ceramic powder binder 23 in the usual sense. In normal ceramic processing, binders (usually some kind of polymer) are used to hold the ceramic powder together but later burnt off during the firing and sintering stages. The subsequent sintering processes ensure structural integrity of powder formed ceramics by joining the individual powder particles together.
The binders 23 used in the present invention, and for that matter substrate polymers, are biocompatible and resorbable polymers, copolymers or blends such as those composed of lactic acid, glycolic acid, amides, anhydrides, orthroesters, dioxanones and many others. The weight percentage and molecular weight of the binder 23 is chosen to affect the resorption rate of the final structure. As opposed to normal binders used in the formation of ceramic structures, the binders 23 are not removed from the resulting structure by means of heat and oxidation. The binder materials 23 remain within the structure until resorbed after implantation.
The binder material 23 is combined with the ceramic powder 22 by the use of a solvent 24 . The binder polymer 23 is dissolved within the solvent 24 and the ceramic powder 22 is added to form a slurry. The composition of the slurry preferably holds the ceramic powder 22 in suspension in the dissolved polymer/solvent mixture. There may be no chemical interaction between the ceramic powder 22 and this solution. In general, this slurry can also have pore forming agents such as sugar (sucrose or dextrose), salt (sodium chloride or carbonate and bicarbonate) and biologically active agents. The slurry may also have bio-compatible deflocculating agents (usually less than a 1 % if any) to assist in keeping the ceramic particles held in suspension in the solvent 24 .
Some of the usual solvents 24 that can be used are but not limited to acetone, pyrrolidone such as N-methyl- 2 -pyrrolidone, ethyl acetate and ethyl lactate. It is possible to use a mixture of solvents to adjust the density and viscosity of the solution as well as the amount of polymer binder to be dissolved. As with all biomedical applications, the solvents used should be benign and least toxic. As such, the solvent must be removed by well known processes such as vacuum drying or super critical extraction.
Usually the binder polymer 23 in the slurry is the same as the substrate polymer 21 which is to be coated. It is also envisioned that the binder polymer 23 can be different than the substrate polymer 21 . Medical application demands that the binder 23 and substrate polymer 21 be bio-compatible and resorbable. In the event that the binder and substrate polymers are different, the solvent (or mixture of solvents) to be used must be able to dissolve or at least make both the substrate polymer 21 and the binder material 23 sticky.
If the solvent were removed by evaporation, extraction or leached into another medium before application to the substrate 21 , a composite structure would form of resorbable ceramic powder 22 in a resorbable binder polymer matrix 23 . This ceramic powder 22 is bound in the polymer matrix 23 of the precipitated resorbable polymer, leaving a resorbable composite which can be used as an implant.
When the slurry is poured onto the substrate polymer 21 and is allowed to evaporate on the substrate polymer 21 , the solvents in the slurry also partially dissolves the substrate polymer 21 . Eventually, the solvent will evaporate leaving the ceramic powder 22 bound by the binder 23 and partially dissolved substrate polymer 21 .
The ratio of the binder polymer 23 to the solvent 24 can have a wide range, from very dilute to saturation. If LACTOSORB, offered by Biomet, Inc. of Warsaw, Ind., is used as binder polymer 23 , the ratio of the binder polymer 23 to solvent 24 is between 9 to 12 g to 100 ml acetone. For saturation, the ratio is 15 g/100ml acetone. In this range of solution composition, the other variable is the ceramic powder 22 volume fraction. By varying the weight percentage of ceramic powder 22 to binder polymer 23 , the percentage of polymer matrix 23 in the resulting product can be adjusted. So, the slurry could have a composition of dilute to saturated solution with particle volume fraction ranging from sparse to heavy.
The preferred composition of the slurry will depend on the application or the characteristics of the coating. Intuitively, if a longer resorption time were required, the binder polymer 23 would be close to saturation (almost 15 g of LACTOSORB per 100 ml acetone. For devices showing faster resorption, a lower concentration solution would be used. The other variable i.e., ceramic powder 22 volume fraction should not affect resorption rate, but the ceramic composition will affect resorption characteristics.
As can be seen in FIG. 2, several coating layers can be applied to the substrate. These layers can be in any order and can have varying ceramic volume fractions ranging from none to heavy loading as well as varying powder size. By varying the ceramic material, and the binder, resorption rates can be varied.
As seen in FIG. 3, the biocompatible resorbable ceramic coating 20 is formed as follows. In process step 30 , a binder polymer 23 is dissolved within a solvent 24 . In process step 31 , the ceramic powder 22 is mixed into the solvent 24 material so as to hold the ceramic powder 22 in suspension. Deflocculating additives may be used to hold the ceramic powders 22 in suspension within the mixture. In process step 32 , the mixture is then deposited onto a substrate material 21 . Should the substrate material 21 be of a polymer which is dissolvable by the particular solvent used, the surface layer of the substrate material begins to dissolve. In process step 33 , the solvent is removed by evaporation. The ceramic particles 22 are then imbedded within the dissolved surface layer of the substrate as well as in the binder material. As the ceramic powder 22 is bound into the surface of the substrate 21 , a mechanical lock is formed. If so desired, the slurry may be cast on a glass or other substrate with or without the benefit of spreading assisted by spinning. In such a case, instead of a coating, laminated structures of resorbable ceramic-polymer composites are fabricated. As before, the individual laminates can have varying particle size distribution, loading and composition.
Pore forming agents can be added to the solvent. These agents function to create pores within the binder material and allow for a variation of the resorption time.
Accordingly, a resorbable substrate material 21 having a resorbable polymer ceramic coating 20 is formed. The coating allows a user to adjust the resorption rate of the material. As seen in FIG. 4, a standard bone plate 34 is shown using the aforementioned material. Specifically, the resorption rate of a bone plate used in orthopedic procedures of the current invention can have tailorable resorption properties. The variable resorption rates lead to a significant benefit not seen in prior bone plate structures. For example, the resorption of the bone plate can be significantly slower than those bone plates formed by the substrate material alone. In particular, this can be useful in patients where bone regrowth would be expected to be much slower and, therefore, the support caused by the bone plate would need to be utilized by the patient for a much longer period of time. As mentioned before, a judicious choice of resorbable ceramic would help by supplying bone building elements.
A wide variety of features can be utilized in the various material disclosed and described above. The foregoing discussion discloses and describes a preferred embodiment of the present invention. One skilled in the art will readily recognize from such discussion, and from the accompanying drawings that various changes, modifications, and variations can be made therein without departing from the true spirit and fair scope of the invention. | 1a
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FIELD OF THE INVENTION
[0001] The present invention is directed to a convective blanket.
BACKGROUND OF THE PRESENT INVENTION
[0002] Inflatable thermal blankets are used to communicate a conditioned gas, such as heated or cooled air, to a patient and are known in the art. Such thermal blankets typically have an inflatable portion provided with an inlet port for placing the inflatable portion in fluid communication with a source of pressurized, conditioned gas such that the inflatable portion can be selectively inflated. The inflatable portion generally has an inner surface which is gas pervious, or which is otherwise adapted to communicate the conditioned gas used to inflate the blanket to the user. Such thermal blankets are often used to treat conditions such as hypothermia, or used to reduce the body temperature of a user in circumstances where the body temperature is inappropriately high. For example, where a patient is being treated for hypothermia, at least a portion of the patient's body is covered with and/or overlies the thermal blanket, and warm air is pumped into the inflatable portion. The warm air used to inflate the inflatable portion is thereafter communicated through the inner surface of the inflatable portion so as to bath the body portion covered and/or overlaid by the blanket in warm air.
[0003] Examples of such thermal blankets are disclosed in Augustine Medical, Inc. v. Gaymar Indus., Inc., 181 F.3d 1291, 50 USPQ2d 1900 (Fed. Cir. 1999). In that decision, the Federal Circuit stated “[Gaymar's convective] blankets feature an inflatable quilt-like structure. The [Gaymar] blankets attach two sheets of the same amount of flexible, lightweight material around their periphery and at various spots along their surfaces. In operation, heated air flows onto a patient's body from holes in the undersurface of the accused blankets, but the blankets do not form a self-supporting or Quonset hut-like structure. Instead, the accused blankets lie flat when inflated on a flat surface and rest substantially on a patient when in use. . . . Gaymar began selling forced-air blankets in March 1992.”
[0004] Gaymar has recognized that its convective air blankets have been positioned underneath patients, in particular infants, to obtain similar results. Other entities have attempted to capitalize on this use of the convective blankets. They have modified the blanket for just an infant, as illustrated in the Bair Hugger pediatric underbody blanket, model 555. That blanket has two drapes to form a tent of warm air that surround the patient. There are hose ports at either end of the blanket to provide options for hose placement. There is an adhesive on the bottom of that blanket and wings that are designed to tuck under the operating room table for stability. That blanket also has fluid outlets that minimize the pooling of fluids on the blanket's surface. That blanket, however, has problems because the warm air is unable, sometimes, to exhaust through all the holes due to occlusion caused by the patient. That means the warm air is sometimes directed to other holes that may overheat the patient in certain areas and under heat the patient in other areas. A cause of that problem may be the patient's weight on the blanket is greater than the air pressure penetrating into that area of the blanket. Another cause of that problem may be the patient occludes at least some of the apertures.
[0005] In U.S. Pat. No. 6,156,058; Kappel et al. disclose another variation of a pediatric convective blanket that is positioned above and/or below the patient. The Kappel et al. blanket is similar to Gaymar's original convective blanket design except it is smaller and it has at least two inlets. Kappel et al. recognizes that their blanket has problems. In particular, Kappel et al. wrote, “When placing blankets under patients, it is often the case that the weight of the patient will cause air flow to be partially or completely restricted through certain portions of the blanket. Therefore, it is desirable to include means of providing for greater and more consistent air flow through the blanket in order to supply the same amount of warming therapy to the patient.” That problem is the same problem that we disclosed for the model 555 blanket.
[0006] According to Kappel et al. that problem was solved, “By providing multiple inlet ports and exit vents, the circulating warm air has more pathways to move through the blanket and thus provide a greater and more consistent airflow through the blanket.” Notice that the model 555 and the Kappel et al. design utilize multiple inlet ports.
[0007] That solution, however, does not address other problems that are associated with patients, especially the elderly and the real young. Both sets of patients have potential incontinence issues. If a patient had incontinence issues on the blankets of Kappel et al. and/or model 555, the patient could theoretically be contacted with that incontinence issue. That is an unacceptable outcome.
[0008] Other devices for warming or cooling patients, and/or for communicating conditioned air to a patient, are disclosed in U.S. Pat. Nos. 1,777,982; 2,093,834; 3,653,083; 4,347,633; 4,472,847; 4,572,188; 4,660,388; 4,777,802; 5,106,373; 5,165,400; 5,300,101; 5,300,102; 5,336,250; 5,350,417; 5,405,371; 5,545,194; 5,674,269; 5,860,292; 6,102,936; 6,210,428 B1; 6,228,107 B1, and 6,511,501.
[0009] To address both or one of the above-identified problems, applicants have conceived and reduced to practice the disclosed invention.
BRIEF DESCRIPTION OF THE FIGURES
[0010] These and other important objectives and advantages will become evident when the detailed description of the invention is read with reference to the below-summarized drawings, in which:
[0011] FIG. 1 is an overview of one embodiment of the present invention.
[0012] FIG. 2 is a cross-sectional view of FIG. 1 taken along the lines 2 - 2 and illustrates the prior art.
[0013] FIGS. 3 a and 3 b illustrate embodiments of the present invention of FIG. 1 taken along the lines 2 - 2 .
[0014] FIGS. 4 a and 4 b are embodiments of the present invention.
[0015] FIG. 5 is an alternative embodiment of the present invention taken from FIG. 1 at box 5 .
SUMMARY OF THE INVENTION
[0016] A thermal treatment apparatus for underlying and/or covering and bathing a patient in a thermally-controlled inflating fluid is disclosed. The apparatus has an inflatable chamber, fluid inlet, and a plurality of interspaced exhaust ports. The inflatable chamber is designed to receive or overlie at least a portion of a patient and is defined by at least one upper surface material and a lower surface material. The fluid inlet is disposed in the inflatable chamber for receiving a thermally-controlled inflating fluid into the inflatable chamber. Where the inflating fluid is a gas, including and not limited to air, the plurality of interspaced exhaust ports are formed on the inflatable chamber for exhausting the inflating fluid from the inflatable chamber toward the portion of the patient position contacting the inflatable chamber. The exhaust ports can be positioned along the seal of the upper and lower materials and within an interior aperture positioned in the inflatable chamber. Filler can also be positioned within the inflatable chamber to provide support to decrease the chance of occlusion in the inflatable chamber.
DETAILED DESCRIPTION OF THE INVENTION
[0017] The present invention is directed to a convective blanket 10 . Each convective blanket 10 has similar characteristics. Those characteristics are an upper surface 12 of a cushion, a lower surface 14 of a cushion, an inflatable chamber 18 , and an inlet 20 .
[0018] The upper surface 12 and the lower surface 14 are sealed together on at least three sides 16 a, 16 b, 16 c, and possibly a fourth side 16 d. The seal can be obtained by sonic welding, heat welding, threaded together, adhesives, or any conventional method to join at least two materials together. In addition, the two surfaces 12 , 14 can be joined together at numerous other locations throughout the device 10 . These other seals are referred to as welded portions 15 . These welded portions can come in numerous sizes (normally relatively small) and shapes (circles, finger-like projections, partial circles). These welded portions are designed to facilitate the distribution and circulation of the fluid throughout the inflatable chamber. The welded portions can also have slits therein. By having slits, the cushion can be altered into various designs to have one portion of the cushion on and/or over a portion of the patient and other portions not over and/or on the patient or variations thereof.
[0019] The materials used for the upper and lower surfaces may be formed of any suitable material capable of being sealed together at selected positions and having sufficient strength to allow inflation and adequate air distribution within the inflated air chamber. The materials used for the upper and lower surfaces include and are not limited to polymeric materials, metallic, natural fibers, and combinations thereof. The material is any material that can be used in association with a patient. A preferred material for the upper surface is spunbound non-woven polypropylene with 1 (one) mil of polyethylene coating on the interior surface. That means the preferred material for the upper surface is an air impermeable material. The bottom surface is also normally an air impermeable material but both materials could be, but not normally, air permeable materials. Air permeable materials are not equivalent to air impermeable materials for many reasons. One of those reasons is that air permeable materials allow the air to exhaust all over the place. Such erratic distribution from air permeable materials is undesirable that is why air impermeable material with positioned outlets, discussed below, that direct the fluid to the desired location of the patient is superior to air permeable materials. The upper surface and the lower surface can be the same material, or alternatively a plurality of the same and/or different materials.
[0020] In addition, the blankets may be formed of various laminated layers of the above materials. For example, each upper and/or lower surface of the blankets could be a single, two-, or multi-ply layer(s) of material.
[0021] The interior inflatable chamber 18 receives a fluid. The fluid is normally a gas, and preferably air, at a desired temperature—ambient, warm, hot, cool, or cold. The fluid enters the at least one inlet 20 of the convective blanket 10 through a conduit 22 from a source 24 . The source 24 can be any device that has and/or generates a pressurized fluid that can inflate and circulate through the inflatable chamber 18 .
[0022] The fluid circulates within the interior inflatable chamber 18 and exhausts through at least one outlet 26 positioned on either or both of the upper and/or lower surfaces 12 , 14 . Preferably there are various outlets 26 interspaced on at least one surface 12 , 14 (normally the upper surface 12 ) of the convective blanket 10 .
[0023] In a preferred embodiment, the inlet 22 directs the fluid to a patient, not shown. The convective blanket 10 can be positioned above or below the patient. All of the above information is admittedly prior art and Gaymar has made versions of this product since 1992 as a blanket, a mattress, and a cushion. Obvious variations of these devices include inflatable collars, and devices positioned around the perimeter, or at least partially around the perimeter of a patient to apply a fluid to the patient for the same reasons as disclosed by Gaymar since 1992. As such, all these devices are collectively referred to as a “convective blanket” for this application.
[0024] In another embodiment of the present invention, the convective blankets may be treated with a fire retardant material. In particular, the blankets may be treated by a spraying, coating, or other appropriate technique, with the fire retardant material. Such treatment produces advantageous blankets which are both nonflammable and laser resistant. Such characteristics may be desirable for hospital settings. The fire retardant spray may be any suitable spray which will render the blanket nonflammable and laser resistant. Such a spray may be used regardless of the material from which the blanket is made. One material which has been found to be useful as a fire retardant spray for convective air warming blankets is available from Project Fire Safety, Inc. and is identified as product number MG 702. The treatment of blankets to render them nonflammable and laser resistant is applicable to pediatric and adult sized blankets, as well as any other size that may be desired.
[0025] It should be noted that while particular blankets described above have been identified for use primarily in the operating room or for use primarily outside the operating room that it will be evident to one skilled in the art that any of the blankets according to the present invention could be used in areas other than the primarily indicated area. For example, a blanket for use primarily in the operating room could also be used outside the operating room, such as in the PACU, ICU or regular hospital room, and vice versa. Further, any of the blankets described herein could also be used in a nursing home, patient's home or any place where hypothermia is a problem.
[0026] Occlusion of the interior inflatable chamber is a problem to be avoided. If occlusion occurs, the patient will not receive the desired fluid application. Such results could be deleterious to the patient.
[0027] To avoid that problem, applicants insert a filler material 40 , as shown in FIG. 3 , into the interior inflatable chamber 18 . The filler can encompass the entire interior chamber as illustrated in FIG. 3 a, or alternatively on at least one of the interior upper and/or lower surfaces (which includes both surfaces) as illustrated in FIG. 3 b. The filler is any material that (a) decreases the occlusion of the fluid from circulating throughout the interior inflatable chamber and (b) allows the fluid to circulate within at least a part of the inflatable chamber to exhaust through the outlets 26 even with a patient thereon. Examples of the filler can include and not be limited to polymeric materials, natural fibers and synthetic blends, and mixtures thereof. Specific examples include and are not limited to cotton, structural honeycomb materials from Tytex of Woonsocket, R.I.; wool, silk, rayon, polypropylene, cotton and polyester blends, polyester and cellulose blends, rayon and polyester blends, non-woven wood pulp compositions, laminated plastic and wood pulp materials, and combinations thereof. Those materials are positioned within the interior of the inflatable chamber.
[0028] The filler allows the fluid to circulate throughout the interior chamber 18 . With the filler there is a decreased chance of occlusion occurring within the interior chamber even with a patient lying on the cushion 10 . This is because the filler provides some support that allows the fluid to circulate through the interior chamber 18 when the patient (and/or object) is almost occluding the interior chamber.
[0029] The filler material 40 can also be impregnated throughout with or just be an absorbent material. An example of an absorbent material is sodium polyacrylate or variations thereof. The invention described herein can utilize these unique characteristics of polyacrylates for capturing incontinent liquids. These characteristics will prevent escape of such incontinent fluids from annoying and/or disturbing the patient and provide safety measures because of the manner the fluid is absorbed, adsorbed or bound. Super absorbents such as sodium polyacrylate will not only absorb many times its own weight of liquid but they also form a gel that binds the liquid to itself without a chemical reaction. Further, the resulting gel is elastic and is many times the volume of the polyacrylate and liquid themselves. This provides an expansion or swelling that stabilizes and immobilizes any escaping liquid from the patient as well as stabilizing the position of the patient on the cushion.
[0030] In addition, the provision of the cushion with a super absorbent material can determine the amount of the incontinent fluid by measuring the cushion in relation to a pre-used weight of the cushion (that value may be measured by the manufacturer and/or the applier (or some entity associated with the applier) of the blanket to the patient) prior to the use of the blanket with the patient. This weight measure system, which uses a conventional balance or other weight measuring device, can be beneficial to patients who must or should know the quantity of fluid that is dispersed.
[0031] The inlet is defined in the upper surface 12 , the lower surface 14 , at the seal 16 , or combinations thereof. The inlet receives the conduit 22 that transports the fluid, preferably at least pressurized, from a source to the interior chamber.
[0032] The cushion 10 can have any possible design. In one preferred embodiment, the cushion design is shaped like a cross having a top section 102 , a left section 103 , a right section 104 , a bottom section 105 and a center section 106 , as illustrated in FIG. 4 a. The design embodiment of FIG. 4 a is a preferred embodiment because it is shaped to conform into a cushion, a wrap-around blanket, and/or an incubator design, as shown in FIG. 4 b, with the addition of a sheet 130 over the incubator design. The sheet should contain the thermal energy, and ensure the patient is properly wrapped in the desired thermal environment.
[0033] Alternative design embodiments can also provide an incubator design. Those designs can be a rectangular (which includes a square) shape, a circular shape, a triangular shape, a polygonal shape, and any three dimensional shape based on the identified two dimensional shapes or combinations thereof. Those various designs can have two or more slitted welded portions to allow these designs to form into an incubator. The cross design has just been found by the applicants to be a preferred design shape but by no means the exclusive shape that can be used.
[0034] In the center section 106 is at least an aperture 110 . The aperture 110 is designed to at least receive at least one of the patient's incontinent dispersal units. That way the incontinent material (represented as arrow 180 ) from the dispersal unit can (a) miss the cushion 10 , (b) be captured by the filler material 40 within the cushion 10 if the material enters and stays within the cushion, and/or (c) pass through the cushion if the material goes through two corresponding outlets 26 a, 26 b as illustrated in FIG. 5 and allows the thermal fluid (represented by arrow 182 ) to pass through to the patient.
[0035] The center aperture 110 , and various other apertures that may be positioned about the cushion, has a plurality of fluid outlets 26 . These outlets can be positioned along the seal that joins the upper surface and the lower surface of the cushion that forms the interior chamber as illustrated in FIG. 4 a. These outlets may differ from other outlets. The difference can be that the outlet along the seal can be a semi-circle design. Why a semi-circle design? One reason is that as the inflatable chamber expands, the semi-shape (like a circle, rectangle, or polygon) design on the upper and lower surfaces becomes a complete shape. As a complete circle along the seam, there is a decreased chance the outlet will be occluded. That semi-circle design also concentrates the fluid blowing on to the patient, instead of dispersing the desired fluid to undesired locations.
[0036] Alternatively, the outlet can be a complete circle to allow the fluid to be directed toward the patient.
[0037] The blankets according to the present invention have been described as being useful in the prevention and treatment of hypothermia. It will be evident to one skilled in the art that a source of pressurized cooled air or room temperature air could also be provided to the blankets according to the present invention to control body temperature of the patient under conditions of hyperthermia.
[0038] The inflatable body 10 may be arranged around a patient in a variety of configurations to form a thermal care space. For example, the inflatable body 10 could be formed in a generally U-shaped configuration.
[0039] The fluid source can be from Gaymar's Thermacare device and/or Medi-Therm device. Both of these devices can control the temperature and the pressure, independently and/or collectively.
[0040] Preferably, the present invention is designed for an infant and/or pediatric patient but it can be used for older individuals, including adults.
[0041] Many modifications and variations of our invention will be evident to those skilled in the art. For example, thermal coverings for additional selected patient areas could be implemented depending on the location of the care site and the need for thermally maintaining other areas. It is understood that such variations may deviate from specific teachings of this description without departing from the essence of the invention, which is expressed in the following claims. | 1a
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FIELD OF THE INVENTION
The present invention relates generally to the field of systems for percutaneous thermotherapy. More particularly, the invention relates to an improved cryoprobe used in cryosurgery.
BACKGROUND OF THE INVENTION
The treatment of back pains still remains a challenge for many reasons. One of such reasons is the difficulty to permanently and exclusively cure the cause of such pains without affecting surrounding tissues in an area of a human body that is a main channel of nerve impulse.
Different causes of back pain exist. Of all chronic low back pain problems, about 20% can be attributed to the facet joints. This cause is also known as the chronic lumbar facet joint syndrome. Among patients, 90% are successfully treated through conservative procedures such as active physiotherapy and NSAIDS. For the remaining 10%, further investigation as well as a more aggressive therapeutic approach must be considered. Once the diagnosis of the facet joint syndrome is clinically made, percutaneous thermotherapy procedures may be considered, seeking a minimally invasive treatment with low morbidity and satisfactory clinical efficiency.
Discogenic back pain, another cause of back pain, is responsible for close to 60% of chronic low back pain in the general population. Once conservative treatment has been fully used, 5% of the patients remain with back pain that can be considerably invalidating. Usual treatment of this invalidating condition is spinal fusion or disc arthroplasty, both associated with considerable morbidity, off-work time, and social cost. Clinically discogenic pain patients have constant back pain that is amplified in the vertical disc loading positions, with a sitting being even worse or equal to the standing position pain. Disc pain is reproduced by pain provocation procedures such as discograms or discometry. Denervation of a portion of the disc, to relieve some if not most of the pain by a percutaneous procedure, is a known advantageous alternative with a reduction of the cited disadvantages of the more aggressive procedures.
Cryotherapy exists as therapy of discogenic back pain or facet joint syndrome since 1961. However, this technique originally used liquid nitrogen as coolant, reaching a treatment temperature of approximately −80 C.°., while the trocar was placed under fluoroscopic guidance. Limited control of the cryoanalgesia process with this combination of technology has resulted in only temporarily pain relief. Studies even showed that there does not exist statistical differences between patients who had such a treatment and patients treated with a placebo pr probe. On the other hand, a study showed that irreversible damage to the nervous structures is obtained only when temperatures reach below −140 C.°. Temperatures above −140 C.° only temporarily affect the nerve tissue.
It is therefore possible to divide thermotherapy in two types: moderate and extreme temperature thermotherapy. Moderate temperature thermotherapy only temporarily affects nerve tissues and therefore does not cause permanent damages. Consequently, pain relief is only temporary. Monitoring of such treatments is not as critical as it is with extreme temperature thermotherapy. Should the probe affect tissues that should not have been affected, the effects would only be temporary. Extreme temperature thermotherapy (either extremely high or extremely low temperatures), on the other hand, causes permanent damages to tissues. Destroying tissue with this type of treatment is desirable in order to permanently remove pain generators in a body by destroying the nerves in tissues of any nature, or to treat tumors of any kind in a minimally invasive fashion, such as percutaneously. Because of its permanent effects on the body, careful monitoring of the effects of a probe used for extreme temperature treatment is mandatory. Furthermore, cold, whose propagation is far more predictable in the human body than heat, is more often used for extreme temperature treatment. It follows that careful monitoring of a growth of an ice ball of treated tissues created by a cryoprobe is necessary, especially when treating chronic lumbar facet joint syndrome, where inadequate propagation of the ice ball could affect spinal tissues and permanently paralyze a patient. Up to now, monitoring the size of the ice ball was realized either by imagery or by temperature monitoring. Temperature monitoring is accomplished by positioning a temperature sensor that will detect a variation in a temperature of the surrounding tissues and, consequently, the presence of the ice ball. Doing so requires separately inserting in the patient's body the cryoprobe and at least one temperature sensor. Then, X-ray, or another imaging method, must be used to verify a position of the temperature sensor with respect to the cryoprobe.
Imagery monitoring typically uses technologies such as MRI, CT scanning, or ultrasound. However, simultaneously using such imagery systems while operating adds to the complexity of the operation.
Different types of cryoprobes have been suggested. For example, U.S. Pat. No. 6,551,309 describes a cryoprobe comprising, at its tip, several sensors used to monitor that the tip is cooled. However, these sensors are laid out on a thermally and electrically conductive surface and are therefore only adapted to measure the temperature of the tip of the cryoprobe but not that of the surrounding tissues. Consequently, this cryosurgery system requires the use of an MRI imaging system.
US patent application No. 20040024391 describes an apparatus and a method to protect certain tissues during a cryosurgery. This document describes a probe provided with a temperature sensor laid out on a portion remote from its tip. The temperature sensor is used to follow a change of the induced temperature to treated tissues. However, this document does not disclose placing the temperature sensor at a specific distance from the tip such as to monitor the growth of an ice ball and control the cooling by the probe accordingly. Consequently, the apparatus and method described in this document still requires the use of an imagery method such as X rays, ultrasounds, CT or MRI.
There is therefore a need for an improved system for percutaneous thermotherapy that does not require constant visual monitoring of the surgery so that such treatment may be conducted without resorting to imagery systems, which may not be available in all health facilities, and that does not require the use of an additional external temperature sensor.
SUMMARY OF THE INVENTION
It is therefore an object of the present invention to provide a system for percutaneous thermotherapy that overcomes the above drawbacks.
It is another object of the present invention to provide a system for percutaneous thermotherapy that does not necessarily require special imagery systems.
It is another object of the present invention to provide a system for percutaneous thermotherapy that automatically stops the cooling of a conductive portion of the probe when an ice ball of treated tissues has reached a predetermined size.
It is another object of an aspect of the present invention to provide an insulated portion having one or more sensors that is capable of being accurately positioned on an existing probe for thermotherapy.
According to one aspect of the invention, there is provided a cryosurgical probe that is operative to bring target nerve tissue to a temperature below about −140° C. so as to reduce or eliminate regeneration of the nerve tissue by growing an ice ball. The probe comprises a thermally conductive body, a thermally insulating body and a temperature sensor. The thermally conductive body has a conductive portion adapted to contact the tissue and form an ice ball thereat during use. The thermally insulating body is adjacent to the conductive portion onto which the ice ball forms during use. The temperature sensor is positioned at a predetermined position on the thermally insulating body with respect to the conductive portion. The predetermined position corresponds to a predetermined size of the ice ball grown in the tissue when the sensor reads a predetermined temperature. The insulating body provides sufficient thermal insulation between the conductive body and the surrounding tissue so that the sensor detects freezing of the surrounding tissue in contact with the sensor by growth of the ice ball from the conductive portion onto the insulating body.
In a variation of this aspect of the invention, the conductive body is located at a distal tip of the probe opposed to a grabbing end. Such a probe may be used for treating lumbar discs pain.
In another variation of this aspect of the invention, the insulating body is located at the distal tip of the probe opposed to the grabbing end. Such a probe may be used for treating spinal facet joint syndrome.
In another aspect of the invention, there is provided a method of manufacturing a cryosurgical probe as defined here above. The method comprises the step of determining the predetermined position as a function of a desired ice ball size and thermal characteristics of the surrounding tissue.
In yet another aspect of the invention, there is provided a sleeve for fitting to a cryosurgical probe having a conductive portion. The sleeve is operative to bring target nerve tissue to a temperature below about −140° C. so as to reduce or eliminate regeneration of the nerve tissue by growing an ice ball. The sleeve comprises a thermally insulating body and a temperature sensor. The temperature sensor is positioned on the thermally insulating body so that when the sleeve is installed on the cryosurgical probe, the temperature sensor is at a predetermined position with respect to the conductive portion of the cryosurgical probe. The predetermined position corresponds to a predetermined size of the ice ball grown in the tissue when the sensor reads a predetermined temperature. The insulating body provides sufficient thermal insulation between the conductive body and surrounding tissue that the sensor detects freezing of the surrounding tissue being in contact with the sensor by growth of the ice ball from the conductive portion onto the insulating body.
In a variation of this aspect of the invention, the sleeve has a closed ended tip and the conducting body is located at the tip. This type of sleeve may be used for treating lumbar discs pain.
In another variation of this aspect of the invention, the sleeve has a closed ended tip and the insulating body is located at the tip. This type of sleeve may be used for treating spinal facet joint syndrome.
In yet another aspect of the invention, there is provided a method of manufacturing a sleeve as defined here above. The method comprises the step of determining the predetermined position as a function of a desired ice ball size and thermal characteristics of the surrounding tissue.
In a further aspect of the invention, there is provided a system for percutaneous thermotherapy for use with a cryosurgical probe having a conductive portion. The system comprises a controller and a sleeve as defined here above. The sleeve is adapted to be placed on the probe so that the sensor is at a predetermined longitudinal position from the conductive portion. The sensor is operative to send a signal to the controller. The controller is operative to control a cooling of the conductive portion based on the signal sent by the sensor.
In another aspect of the invention, there is provided a method of manufacturing such a system for percutaneous thermotherapy. The method comprises the step of determining the predetermined position as a function of a desired ice ball size and thermal characteristics of the surrounding tissue.
In yet a further aspect of the invention, there is provided a system for percutaneous thermotherapy comprising a controller and a probe as defined here above. The sensor of the probe is operative to send a signal to the controller. The controller is operative to control a cooling of the conductive portion based on the signal sent by the sensor.
In another aspect of the invention, there is provided a method of manufacturing such a system for percutaneous thermotherapy. The method comprises the step of determining the predetermined position as a function of a desired ice ball size and thermal characteristics of the surrounding tissue.
In yet another aspect of the invention, there is provided a method for performing percutaneous cryotherapy using a cryosurgical probe. The method comprises the step of selecting an insulating body having a temperature sensor adapted to be placed at a predetermined distance from a conductive portion of the probe, based on a desired size of an ice ball of tissues surrounding the conductive portion.
In yet another aspect of the invention, there is provided a method for performing percutaneous cryotherapy that comprises the step of automatically shutting down by a controller an imposed thermal variation of a conductive portion of a cryoprobe inserted in a patient's body once a signal from a single temperature sensor placed on a thermally insulating portion of the cryoprobe for sensing a size of an ice ball in surrounding tissues has reached a threshold value.
In still another aspect of the invention, there is provided a kit comprising at least two cryosurgical probes as defined here above. Each one of the probes has its temperature sensor located at a different longitudinally distance from the conductive portion.
In yet another aspect of the invention, there is provided a kit comprising at least two sleeves as defined here above. Each one of the sleeves has its temperature sensor located at a different longitudinally position.
BRIEF DESCRIPTION OF THE DRAWINGS
These and other features of the invention will become more readily apparent from the following description in which reference is made to the appended drawings wherein:
FIG. 1 is a cross-sectional view of a probe according to an embodiment of the invention.
FIG. 2 is schematic view of a system for percutaneous thermotherapy according to another embodiment of the invention.
FIG. 3 is a schematic view of a system for percutaneous thermotherapy according to another embodiment of the invention.
FIG. 4 is a cross-sectional view of a sleeve for a standard probe for use in disc surgery according to an embodiment of the invention.
FIG. 5 is a cross-sectional view of a spine where two probes of FIG. 4 are placed for disc surgery.
FIG. 6 is a cross-sectional view of a probe for facet surgery according to another embodiment of the invention.
FIG. 7 is a cross-sectional view of a sleeve for a standard probe for use in facet surgery according to another embodiment of the invention.
FIG. 8 is a cross-sectional view of a spine where two probes of FIG. 7 are placed for facet surgery.
FIG. 9 is a cross-sectional view of a probe according to another embodiment of the invention.
FIG. 10 a is a perspective view of a kit of sleeves for standard probes for use in disc surgery according to an embodiment of the invention
FIG. 10 b is a perspective view of a kit of sleeves for a standard probes for use in facet surgery according to another embodiment of the invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention may be used for thermotherapy, either by submitting a patient to heat or to cold. Because transmission of cold in a human body is more predictable than transmission of heat, cryotherapy is more often used. Hence, the present invention will now be described with respect to a cryoprobe used for cryosurgery.
FIG. 1 generally represents a cryoprobe 10 . The cryoprobe 10 is fitted with a conductive portion 12 , a body 14 that comprises a grabbing portion 16 for holding by a surgeon, and an insulating portion 18 . The cryoprobe 10 is typically equipped with a Joule-Thomson cooler 20 for providing a high-pressure gas to a cooling chamber 22 inside the conductive portion 12 . When a high-pressure cooling gas such as argon expands in cooling chamber 22 , so as to form a cryogenic pool, it effectively cools the surface of conductive portion 12 . The conductive portion 12 is made of a thermally conductive material such as stainless steel. The function of the conductive portion 12 is to induce a zone of thermo-surgical temperature in surrounding tissues of a patient. In the case of cryotherapy, this zone of thermo-surgical temperature corresponds to a treated tissue zone having the shape of an ice ball of treated tissues 24 , created around the conductive portion 12 . Thermo surgical temperatures are temperatures that induce irreversible damages to treated tissues.
Alternatively, a high-pressure heating gas such as helium may be used for operating conductive portion 12 in a heating mode via a reverse Joule-Thomson process, so as to enable treatment by cycles of cooling-heating, and further for shortening the treatment time by thawing the ice ball of treated tissues 24 and preventing it to stick to the cryoprobe 10 when extracting the cryoprobe 10 from the patient's body.
The insulating portion 18 of the body 14 is made of an insulating material such as Teflon. Alternatively, the whole body 14 could be made of the insulating material. This allows for preventing surrounding tissues that need not be desensitized by cryotherapy from being affected by the cold. The insulating portion 18 is fitted with a temperature sensor 26 . The temperature sensor 26 senses the temperature of surrounding tissues and in use, the temperature of the ice ball of treated tissues 24 .
Turning now to FIG. 2 , a gas distribution module 28 controls the flow of pressurized gas, such as argon, into the cryoprobe 10 thorough delivery tube 30 . The gas, upon expanding into the cooling chamber 22 , cools the conductive portion 12 . The gas then returns to the gas distribution module 28 through return tube 32 . As the conductive portion 12 gets cooled, the tissues surrounding the conductive portion become frozen and the ice ball of treated tissues 24 starts forming around the conductive portion 12 . As the process continues, the ice ball grows in size. The temperature sensor 26 records a decrease in body temperature and sends a signal 34 to a controller 36 . The controller 36 compares the temperature signal 34 sent by the temperature sensor 26 with a threshold temperature. Although it may be otherwise, the water freezing temperature (0° C.) is often used as the threshold temperature. Hence, the temperature sensor 26 is used to monitor the progression of a forming front of the ice ball of treated tissues 24 . In order to correlate the temperature at the temperature sensor 26 with a size of the ice ball of treated tissues 24 , the temperature sensor 26 is placed at a predetermined position with respect to the conductive portion 12 . It is possible to correlate different temperatures than 0° C. with the size of ice ball of treated tissues 24 by modeling the response of the tissues to temperature changes as a function of time. However, it has been found that monitoring the forming front of the ice ball of treated tissues 24 is more convenient and gives a direct indication of the ice ball size. As the ice ball of treated tissues 24 continues to grow in size, the temperature further decreases at temperature sensor 26 until the signal 34 sent to the controller 36 reaches the threshold temperature. At that point, the controller 36 automatically shuts down the gas distribution module 28 , thereby stopping the growth of the ice ball of treated tissues 24 . Alternatively, the controller 36 may be set-up such that it shuts down the gas distribution module 28 only after a predetermined amount of time has elapsed after the temperature sensor 26 has read the threshold temperature or only when the temperature sensor 26 has read a predetermined shut down temperature that is different from the threshold temperature. It will be understood that when the controller 36 shuts down the gas distribution module 28 when the temperature sensor 26 reads the threshold temperature, it is because the shut don temperature is set up to be the same as the threshold temperature. Typically, the temperature sensor 26 is located on the insulating portion 18 approximately 10 mm from the conductive portion. A user may adjust the controller such as to vary the size of the ice ball of treated tissues 24 . Another way of adjusting the size of the ice ball of treated tissues 24 is to locate the temperature sensor 26 at different longitudinal positions from the conductive portion 12 . This may be either accomplished by having different models of cryoprobe 10 where the temperature sensor 26 is located at different distances from the conductive portion 12 , or by providing the cryoprobe with many temperature sensors 26 that are located at different longitudinal positions along the insulated portion 24 of the cryoprobe 10 . Then, the controller decides which temperature sensor 26 to monitor. This information may also be provided manually to the controller 36 by a user.
For better reliability, it is possible to equip the insulating portion 18 with more than one temperature sensor 26 at the same distance from the conductive portion 12 . The controller 36 then processes the information gathered by the temperature sensors 26 and takes a decision to shut down or to continue cooling accordingly.
The details of the structure of the cooling system used in the probe are well known in the art and as such will not be described in further details in the present description.
FIG. 3 schematically shows the detail of the controller 36 , which may be a computer. The controller 36 comprises a thermal model storage medium 38 , a size determinator 40 , a comparator 42 and a thermal application module 46 . The thermal model storage medium 38 stores all thermal models. The thermal models are mathematical models of heat transfer in a body based on parameters such as the type of surgery, type of tissue, type of gas used for cooling, probe model, etc. For instance, tissue types vary whether they are intradiscal or interdiscal tissues, flesh surrounding prostate gland, etc. The thermal model includes the size of the ice ball of treated tissues 24 . The thermal model storage medium 38 feeds a desired size signal 48 to the comparator 42 . From a user interface 50 , the surgeon may select a thermal model desired 52 . Optionally, the surgeon may bypass the thermal model storage medium 38 and impose the size of the ice ball of treated tissues 24 with the desired size signal 48 of his own. Optionally, the surgeon may bypass all parameters. The surgeon sends a start command 54 , through the user interface 50 , to the comparator 42 . The size determinator 40 determines the actual size of the ice ball of treated tissues 24 based on the signal 34 received from the temperature sensor or sensors 26 . The comparator 42 compares an actual size signal 56 received from the size determinator 40 with desired size signal 48 received from the thermal model 52 . Whenever the actual size signal 56 indicates a smaller size than the desired size signal 48 , the comparator 42 sends an “ON” signal 58 to the thermal application module 46 . In turns, the thermal application module 46 sends a thermal application command signal 60 to the gas distribution module 28 to send cooling gas to the probe 10 . Preferably, the size determinator 40 is hooked to a display 62 to show the surgeon the actual size of the ice ball of treated tissues 24 .
FIG. 4 shows another embodiment of the invention. In this case, a sleeve 64 having an insulating portion 18 is fitted over a standard cryoprobe 66 which has its body 14 ended by the conductive portion 12 . In the present description, the term “sleeve” is used to describe a device that covers a probe and that may be either open at both its extremities, or closed at one extremity. In the present embodiment, the sleeve 64 is open at both extremities. The sleeve 64 is specially designed to fit over a given model of standard cryoprobe 66 . The sleeve 64 is equipped with the temperature sensor 26 . The sleeve 64 is positioned over the body 14 such that the conductive portion 12 extends from the sleeve 64 . Similarly to the previous embodiment, in use, the ice ball of treated tissues 24 forms at the conductive portion 12 and grows until it reaches the temperature sensor 26 , which continuously sends a signal to the controller 36 (not shown in the Figure). The position of the temperature sensor 26 on the sleeve 64 is adjusted so that the longitudinal position of the temperature sensor 26 with respect to the conductive portion 12 corresponds to the desired size of ice ball of treated tissues 24 . The position of the temperature sensor 26 with respect to the conductive portion 12 may be set by way of locating means 68 . Here, the locating means 68 are depicted as a stopper against which the standard cryoprobe 66 abuts. However, the locating means could be a mark on the standard cryoprobe 66 or simply an edge of the sleeve 64 used to locate the sleeve 64 , and therefore the temperature sensor 26 , with respect to the conductive portion 12 . Optionally, the sleeve 64 may comprise an air chamber 70 , which also thermally insulates the temperature sensor 26 from the standard cryoprobe 66 . For example, the standard cryoprobe 66 may be 4 mm in diameter, the air chamber 70 may be 1 mm thick and the sleeve 64 may be 2 mm thick, including the air chamber 70 . Preferably, Teflon is used as the insulating material of the sleeve 64 . As shown in FIG. 5 , now concurrently referred to, this type of cryoprobe is particularly well adapted for cryosurgery of discs of a spine.
FIG. 6 shows yet another embodiment of the present invention. This design of cryoprobe 10 is adapted for the cryotherapy of facets, as shown in FIG. 7 and now concurrently referred to. In this embodiment, the conductive portion 12 is not located at a tip 72 of the cryoprobe 10 , but rather at a mid-portion of the cryoprobe 10 . The tip 72 is made of the insulating material so as to become the insulating portion 18 . As can be seen, in the case of facet cryotherapy, the insulating portion 18 is placed at the tip 72 to prevent nerve roots in this spine area from being damaged by the cold. The temperature sensor 26 may be placed on either the insulated tip 72 or the body 14 as long as it is on a thermally insulated portion of the cryoprobe 10 and as long as it is at the predetermined distance from the conductive portion 12 such as to detect a condition of the surrounding tissues. However, it might be advantageous to place the temperature sensor 26 on the insulated tip 72 such as to monitor the ice ball growth closer to the freeze sensitive region where major nerve roots are located. The insulating portion 18 may also be used to position the cryoprobe 10 . When the insulating portion 18 abuts a bone or a disc, for example, the conductive portion 12 is in contact with surrounding tissues, such as sensitive nerve cells, where cellular destruction is desired. Positioning the temperature sensor 26 at the insulated tip 72 of the insulating portion 18 enables constant thermal monitoring of the surrounding tissues. Once the temperature sensor 26 detects the front of the ice ball of treated tissues 24 , that is when the temperature sensor 26 reads temperatures close to the freezing point, cryotherapy may be automatically stopped if the threshold temperature corresponds with the shut down temperature.
FIG. 7 depicts a variant of the present embodiment where a sleeve 64 , closed at its distal extremity, is fitted to a standard cryoprobe 66 . The sleeve 64 comprises the insulated tip 72 , the conductive portion 12 and the grabbing portion 16 . Optionally, the grabbing portion 16 may be made of metal. However, in this case, gap is required between the standard cryoprobe 66 and the sleeve 64 in the grabbing portion 16 . As shown in FIG. 8 , now concurrently referred to, this type of cryoprobe is particularly well adapted for cryosurgery of facets joints.
In a particular example, the insulated tip 72 may be 6 mm in diameter and made of an insulating material such as Teflon. An interior air chamber 70 may be provided for added insulation. The temperature sensor 26 is positioned on the insulated tip 72 , approximately 6 mm or more from the distal end of the insulated tip 72 . The conductive portion 12 is made of a conductive metal and is in contact with the standard cryoprobe 66 inside the sleeve 64 . The conductive portion 12 is also 6 mm in outside diameter. The length of the conductive portion 12 depends on the size of the desired treated tissue zone. The standard cryoprobe 66 may be 2 mm in diameter, and the insulated tip 72 may be 1 mm thick, which leaves 1 mm thickness for the air chamber 70 .
FIG. 9 shows yet another embodiment of the present invention. A thermally conductive tip cover 76 is screwed to the insulating portion 18 . The tip cover 76 closely matches the external surface of a probe tip 78 such that heat transfer occurs between the probe tip 78 and the tip cover 76 . The temperature sensor 26 is precisely positioned with respect to the probe tip 78 due to the fact that the probe tip 78 bottoms out in the tip cover 76 .
Now turning to FIGS. 10 a and 10 b , there is depicted yet another embodiment of the present invention where kits 80 are provided that comprise a plurality of sleeves 64 for fitting to a standard cryoprobe. In FIG. 10 a , the kit comprises sleeves 64 having the insulating portions 24 . The sleeves 64 are provided with two opposed openings so that the standard cryoprobe protrudes through each sleeve 64 , such as described previously and shown in FIG. 4 . The only difference between each sleeve 64 of the kit is that the temperature sensor 26 is placed at different longitudinal locations on the insulating portion 18 . Hence, a surgeon may select, prior to cryotherapy, the required sleeve 64 depending on the particular needs of the surgery, or depending on the patient. Similarly, in FIG. 10 b , the kit 80 also comprises sleeves 64 . This time, the sleeves 64 are of a close-ended model where the insulating portion 18 corresponds to the insulating tip 72 . The sleeves 64 are adapted to fit a standard cryoprobe 66 (not shown in this Figure), such as described previously and shown in FIG. 7 . The insulated tips 74 are differentiated from each other by the fact that the temperature sensors 26 are placed at different longitudinal locations from the conductive portion 12 , for the particular needs of a given cryosurgery. For convenience, the kit 80 , or the sleeves 64 themselves may carry an identification of an ice ball size for each sleeve 64 . The ice ball size may be a function of a predetermined body part tissue as the ice ball may grow differently depending on the body part tissue.
Surgery
When operating, the surgeon has to precisely monitor both the placement of the cryoprobe 10 into the patient's body and the growth of the ice ball of treated tissues 24 such as to avoid damaging fragile tissues. With the cryoprobes of prior art, MRI was often used as an imaging system. Advantageously, with the present invention, such costly techniques are not absolutely required since the controller 36 automatically shuts down the gas distribution module 28 , thereby not requiring continuous visual monitoring of the growth of the ice ball of treated tissues 24 by the surgeon. With the thermotherapy system of the present invention, less costly and more readily available imaging techniques such as fluoroscopy, diagnostic ultrasound, etc, can be used. Moreover, when using techniques other than MRI, the composition of the cryoprobe 10 is not restricted to non-ferromagnetic materials, which lowers its cost.
Facet Cryosurgery
Reference is now made to FIG. 8 . For facet cryosurgery, the cryoprobe 10 is inserted under local anaesthesia using a preliminary trocar through a 6 mm incision. For facet cryotherapy, the cryoprobe 10 is positioned on a posterior-inferior portion of foramina close to the nerve root for protection and the conductive portion 12 is placed alongside a lateral facet joint for joint denervation. Position is verified on both antero-posterior and lateral fluoroscopy.
The freezing process is then started: A first step of freezing takes place at −180° C. (temperatures colder than −140° C. are preferred) while monitoring the growth of the ice ball of treated tissues 24 with the temperature sensors 26 . The controller 36 shuts down the gas distribution module 28 when the first temperature threshold is reached, which normally takes approximately 7 minutes. The controller 36 maintains the gas distribution module 28 shut down for 2 minutes for passive thawing to occur. The controller 36 then turns on the gas distribution module 28 once again for a second step of freezing at −180° C. until a second temperature threshold is reached, which takes approximately another 7 minutes. The first and second threshold temperatures may be the same or different, depending on the desired results. To remove the cryoprobes 10 , heating the cryoprobes 10 for a few seconds is sometimes required. Stitches are then applied to the patient. The patient is encouraged to resume his normal activities rapidly and weak to moderate analgesia is necessary for the first week. Cryoprobe tract pain normally disappears after one to two weeks.
Discs Cryosurgery
Reference is now made to FIG. 5 . For discs cryosurgery, 6 mm pointed trocars are inserted through a 6 mm skin puncture. The trocar is inserted bilaterally to postero-lateral corners of the targeted disc 82 at a 45 degrees angle from the skin at 10 cm from a midline under local anaesthesia with AP and lateral fluoroscopy. Through this trocar is inserted a 2 mm drill to perforate the annulus. The drill is then replaced by the cryoprobe 10 which conductive portion 12 penetrates 1-1.5 cm deep into the disc 82 . The insertion into the disc 82 is bottomed by a conic end of the insulating portion 18 . Typically, two cryoprobes 10 are used for disc cryosurgery, one on each side of the disc 82 . Both cryoprobes 10 should nearly meet in the middle of the disc 82 . The freezing process, similar to the one used for facets cryosurgery, is then started while monitoring treated tissues temperatures with the temperature sensors 26 is performed. To remove the cryoprobes 10 and the trocar, heating the cryoprobes 10 for a few seconds is sometimes required. A stitch is then applied to the skin once the cryoprobes 10 are removed and normal activities may be resumed shortly. Mild to moderate analgesia is prescribed for the first week.
While the invention has been described with particular reference to the illustrated embodiment, it will be understood that numerous modifications thereto will appear to those skilled in the art. For example, the assembly of some parts of the probe were depicted as a threaded assembly. However, the person skilled in the art would readily understand that this assembly could also be a snap-fit or other adequate assembly method, for example. Accordingly, the above description and accompanying drawings should be taken as illustrative of the invention and not in a limiting sense. | 1a
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FIELD OF THE INVENTION
[0001] The present invention relates to the pharmaceutical compositions field, in particular it relates to formulations for the oral administration of Mesalazine in multi-particulate, multi-layer form.
BACKGROUND OF THE INVENTION
[0002] Mesalazine, also known as 5-Aminosalicylic Acid, generally abbreviated as 5-ASA, is an Active Substance that is now widely known in that it now is the best medicinal product in the treatment of inflammatory states of the colon, and is the best adjuvant in maintenance and improvement therapies of ulcerative colitis and Crohn's disease. As Acetylsalicylic Acid derivative, it maintains its anti-inflammatory characteristics but has the advantage of acting only at topical intestinal level, avoiding systemic absorption; hence the need to formulate preparations that have a specific release only at the area of action, i.e. the colon.
[0003] Present on the market in different pharmaceutical forms, it is characterised by having high doses (but low concentration of the Active Substance, generally equal to 500-550 mg of Mesalazine per g of formulation), and formulations containing 1-2 g of the Active Substance are frequent. This very often worsens patient compliance in taking the medicinal product, as the total quantity of medicinal product is either too high, or divided into several doses. The object of the present invention is thus to provide a formulation having a high concentration of Mesalazine, to decrease the total quantity to be taken and to improve patient acceptability.
[0004] EP1178781B1 describes a formulation containing Mesalazine that is exclusively released in the colon. It is a multi-layer formulation comprising:
[0005] a core containing the Active Substance, an inner membrane containing a pH-independent retardant polymer and an outer membrane containing a pH-dependent polymer that exclusively releases in the colon.
Core: contains about 50% API; and consists of neutral granules (0.5-0.6 mm) that are coated, by spraying in a Fluid Bed apparatus, with a layer containing API (Mesalazine, Lactose and Aerosil) and a binder (Kallidon 25 and water). Inner Membrane: membrane comprising a polymer or a mixture of methacrylic acid-derived polymers (Eudragit RS, Eudragit RL), with the characteristic of having a dissolution that is slow and independent of the pH. Outer Membrane: membrane comprising a polymer or a mixture of methacrylic acid-derived polymers (Eudragit FS 30 D), with the characteristic of having a dissolution that is pH-dependent, exclusively in of the colon.
[0009] Another problem often found in formulations containing Mesalazine, is ensuring stability of the Active Substance over time; the development of impurities during stability studies is indeed frequent. The impurities are generally due to the oxidation that occurs when the Active Substance remains in contact with water. In fact, the membranes used to confer topical release, are suspended in water, a small part of which remains present in the formulation even after drying. The cause of the degradation of Mesalazine over time is this very water. The object of the present invention is to provide a formulation that can overcome this problem, guaranteeing the stability of Mesalazine over time while ensuring topical intestinal absorption in the colon.
SUMMARY OF THE INVENTION
[0010] The present invention resolves the above-mentioned-mentioned problems by means of granules containing Mesalazine as Active Pharmaceutical Ingredient (API), said granules consisting of API in mixture with a dried gelled composition in a ratio of between 97:3 and 99:1, referring to the dry portion of the composition; said granules being obtained by extrusion, spheronization and drying of a mixture of API with a gelled composition consisting of a mixture of 5-10% Polyvinylpyrrolidone, 20-40% Polysorbate and 45-75% Water, where the % relate to the percentages by weight with respect to the total weight of the gelled composition.
[0011] The granules in question are produced according to the extrusion+spheronization technique; the procedures known to the state of the art include the use of a percentage of plastic matrix, such as microcrystalline Cellulose, ranging between 30% and 50%; this gives the compound a suitable consistency for being extruded and spheronized. From here it can be deduced that the titre of the granules will be low and may not exceed 70%.
[0012] It has however been surprisingly found that by mixing just the API with the gel, in a ratio ranging between 97:3 and 99:1, preferably between 97.5:2.5 and 98.5:1.5, even more preferably 98:2 (relating to the dry weight of the substance), to then extrude and spheronize the compound obtained, compact granules with a high titre are obtained without the need to add plastic material.
[0013] Another surprising finding is that the gelled composition gives the compound a plasticity and malleability such as to be extruded with a very small mesh, so as to be able to obtain granules with a very low granulometry that are generally not obtainable according to traditional state of the art techniques. The density of the granules, which reaches 0.89 g/ml, is thus also increased with the consequent possibility of inserting in a capsule a large amount of Mesalazine per unit volume. Moreover, the gelled composition in the granules according to the invention increases the binding effect and improves the stability of the API, acting as antioxidant over time; in fact, contrary to other formulations that require the addition of anti-oxidants, a formulation comprising the granules according to the invention maintains stability over time without the addition of further ingredients. It is therefore understood that the use of polysorbate in the pellet formulation is not only merely one of the many possible excipients known in the state of the art, but has a fundamental importance, as it serves to create the gelling solution, which not only allows pellets having a very high titre to be produced, but is also responsible for the stability thereof over time.
[0014] It is also surprising that the water used for the gelled composition does not disturb the stability of the API. After extrusion and spheronization, the granules are dried immediately and in a prolonged manner to eliminate all of the water, nonetheless a very small fraction nevertheless remains within them. However, it has been surprisingly noted that the granules maintain an unexpected stability over time, produced by the antioxidant effect of the gelling substance used for granulation. Thus in one aspect, the present invention relates to a pharmaceutical formulation comprising the above-mentioned granules, it in particular relates to multi-layer pellets comprising the afore-mentioned granules as inner core.
[0015] Multi-layer pellets according to the invention comprise:
an inner core consisting of the above-mentioned granules; a first inner coating membrane that surrounds and comes into contact with the core, said first membrane being pH-independent comprising a cellulose-derived polymer, dissolved in a non-aqueous solvent; a second outer coating membrane that surrounds the first membrane, said second membrane being gastroprotective pH-dependent comprising a methacrylic acid derivative.
[0019] To overcome the problem of the development of impurities caused by the residual water deriving from the gastro-resistant coats, the multi-layer pellets of the present invention are characterised by a first protective coat of the cores with a membrane in a non-aqueous solution. The fact that the first coating is applied in a non-aqueous environment combined with the surprising stability of the cores produced by the gelling substance, leads to an even higher final stability, since there is no contact with water during coating.
[0020] The above-mentioned pellets are externally coated with a methacrylic acid derivative (generally Eudragit FS 30 D) to guarantee a release of the API exclusively in the colon; in fact, the chemical structure of the polymer ensures that it only dissolves in environments with a pH greater than 7.2, and this is only found in the last part of the intestine. The multi-layer pellets will pass through both the stomach and the first part of the intestine intact, to then release the medicinal product only in the last section.
[0021] An unexpected synergistic interaction between the two membranes has been surprisingly noted. Indeed, in addition to the protective effect of the first membrane and the gastro-resistant effect of the second membrane, it has been found that the two act together to regulate the release profile.
[0022] Ethyl cellulose being a pH-independent retardant polymer, it also acts here as a retardant in the release of the Active Substance, trapping for a certain period of time most of the Mesalazine within the pellets, for a period which fully or partially coincides with the time it takes the intestine to carry the medicinal product to the colon. The topical release effect in the colon, produced by the Eudragit of the second membrane, is also added to this retarding effect. An exclusive release of Mesalazine in the site of action is thus obtained. In addition thereto, the greatest advantage is that, the medicinal product having already been retarded by the first membrane, the amount of second membrane to be applied will be extremely reduced, thus leading to a greater final titre of the pellets being obtained. This aspect, together with the preceding concept of starting cores having an extremely high titre, leads to a finished product with a surprisingly high amount of Mesalazine, higher than 90%, being obtained.
[0023] Thus in one aspect, the present invention relates to a pharmaceutical formulation comprising the above-mentioned multi-layer pellets; in particular a pharmaceutical formulation comprising the above-mentioned pellets.
DETAILED DESCRIPTION OF THE INVENTION
[0024] For one aspect, the present invention relates to a process for preparing the granules according to the invention, said process comprising preparing the gelled composition by first dissolving Polyvinylpyrrolidone in water and then, on dissolution, adding Polysorbate to achieve the gelification. The gelled composition is indeed a dense composition with viscosity ranging between 4800 mP*s and 5200 mP*s.
[0025] The process for preparing the granules also comprises that the above-mentioned gelled composition be added to and mixed with the Mesalazine, preferably in a Z-arm kneader; the compound is at this point extruded, spheronized and dried. Drying is preferably carried out in a Fluid Bed by means of the inlet of hot air at 80° C. until the product reaches 50° C. The result is a starting core containing Mesalazine in a percentage greater than 97%.
[0026] Extrusion preferably takes place with a net having mesh 400-600 μm mesh.
[0027] The granules obtained according to the invention have an average size ranging between 0.4 mm and 2 mm in diameter, preferably 0.45 mm-1.5 mm, more preferably 0.5 mm-0.8 mm.
[0028] The first protective membrane comprises a polymer, preferably Ethyl cellulose having a viscosity of between 3 and 110 cps, and a solvent, preferably Acetone, Ethanol and mixtures thereof; plasticisers, such as Triethyl citrate, Dibutyl sebacate or Polyethylene glycol and anti-sticking agents, such as Talc, Magnesium stearate, colloidal anhydrous silica or sodium stearyl fumarate, can be optionally present.
[0029] The viscosity of the Ethyl cellulose was calculated on 5% solutions in Toluene/Ethanol (80%:20%) measured at 25° C. in a Ubbelohde viscometer.
[0030] The polymer is present in solution in a percentage ranging between 1% and 10%, preferably between 3% and 8%, more preferably still between 5% and 6%.
[0031] The pellets are coated with the first membrane in a Fluidized Bed or in a Coating Pan until an increase in weight ranging between 0.2% and 2% of the dry weight is achieved with respect to the weight of the cores, preferably 0.5%-1.5%, even more preferably 0.8%-1.2%.
[0032] The second outer, gastroprotective membrane therefore comprises a methacrylic acid derivative, and water; plasticisers, such as Triethyl citrate and Polysorbate, and anti-sticking agents, such as talc and glyceryl monostearate, can be optionally present. The methacrylic acid derivative is selected from anionic polymers with methacrylic acid as functional group such as, for example, Eudragit L100-55, Eudragit L 30 D-55, Eudragit L100, Eudragit L12.5, Eudragit S100, Eudragit S12.5, Eudragit FS 30 or mixtures thereof; they can sometimes also be mixed with Eudragit NE30D and Eudragit NE40D to adjust the gastro-resistance thereof.
[0033] The methacrylic acid derivative is present in suspension in a percentage ranging between 12% and 28%, preferably between 15% and 25%, preferably between 16% and 20%.
[0034] The pellets are coated with the second membrane in a Fluidized Bed or in a Coating Pan until an increase in weight ranging between 5% and 15% of the dry weight is achieved with respect to the weight of the cores, preferably 6%-12%, even more preferably 7%-9%.
[0035] The pellets can at this point be sold in bags or, given the high percentage of Active Substance, even encapsulated or compressed.
[0036] The present invention therefore relates to a pharmaceutical formulation comprising the above-mentioned multi-layer pellets, said formulation in the form of tablets or capsules.
[0037] The pellets of the invention can safely be mixed with Cellulose, and compressed with 400 mg-500 mg-800 mg dosages.
[0038] Particularly advantageous, however, is the possibility of encapsulating in a single dose an amount of Mesalazine equal to 500 mg, which is the generally most common daily dose. Unlike the other formulations present in literature, these pellets, having a medium to high titre (>90%) and a high density (>0.89 g/ml or 900 mg/g), have a very low specific weight per unit of Active Substance and can therefore can be inserted into a 500 mg size 0 Capsule without any problems. This avoids the problem of multi-dose administrations, which would worsen patient compliance.
[0039] A preferred embodiment of the invention provides for the encapsulation of 500 mg of pellets in a single capsule.
[0040] The present invention will be better understood in the light of the following embodiments.
EXPERIMENTS
Example A—Classic Reference Formulation of the State of the Art
[0041] The composition of SALOFALK® GRANU-STIX, also indicated in the patent under the name of CLASSIC FORMULATION, is specified hereunder.
[0000]
SALOFALK RTM GRANU-STIX 3 g
COMPONENT
%
Mesalazine
53.85%
Aspartame
43.15%
Croscarmellose sodium
Citric acid
Colloidal silica
HPMC
Magnesium stearate
Eudragit L100
Methylcellulose
Microcrystalline cellulose
Eudragit NE40D (contains 2% Nonoxynol
100)
Polyvinylpyrrolidone
Simethicone
Ascorbic acid
Talc
Titanium dioxide
Triethyl citrate
Vanilla flavour (contains PEG)
Example 1
[0042] Core
[0043] The following gelled composition is prepared:
[0000] COMPONENT AMOUNT (g) Polyvinylpyrrolidone 100 Polysorbate 320 Water 580 Total 1000
dissolving Polyvinylpyrrolidone in water, to then add Polysorbate on dissolution. Mesalazine raw material is mixed with the above-mentioned gelled composition to then extrude (500 μm net) and spheronize the compound. Immediately following spheronization, the granules obtained are dried in a Fluid Bed with inlet air at 80° C., up to a product temperature of 50° C. Cores having an average diameter of 480 μm-520 μm are obtained with the following dry matter composition:
[0000]
COMPONENT
AMOUNT (g)
Mesalazine
980
Polyvinylpyrrolidone
4.76
Polysorbate
15.24
Total
1000
[0044] First Protective Coating
[0045] A protective membrane is prepared, comprising as follows:
[0000]
COMPONENT
AMOUNT (g)
Ethyl cellulose
50
Triethyl citrate
1
Acetone
949
Total
1000
[0046] Dissolving Ethyl cellulose in Acetone, then adding Talc on dissolution.
[0047] The protective membrane is sprayed onto the previously obtained cores using a Glatt Fluid Bed with Wurster insert, up to a weight increase of 1% with respect to the initial weight of the pellets, thus obtaining a compound with a Mesalazine content of 97.03%.
[0048] Second Gastro-Resistant Coating
[0049] A protective membrane is prepared, comprising as follows:
[0000]
COMPONENT
AMOUNT (g)
Eudragit FS 30 D
180
Polysorbate
3
Triethyl citrate
9
Glyceryl monostearate
7
Water
801
Total
1000
[0050] Homogenising Polysorbate, Triethyl citrate and Glyceryl monostearate in water at 80° C., then adding Eudragit once the compound has cooled.
[0051] The gastro resistant membrane is sprayed onto the previously obtained cores using a Glatt Fluid Bed with Wurster insert, up to a weight increase of 7% with respect to the initial weight of the pellets, thus obtaining a compound with a Mesalazine content of 90.68%.
[0052] The Finished Product has the following characteristics:
[0000]
Titre
90.68%
Average diameter
d(50) = 470 μm
d(90) = 490 μm
Density
0.84 g/ml
[0053] The multilayer pellets thus obtained are analysed in-vitro in HCl 0.1N/750 ml for 2 h, and then adjusted to pH 7.2/1000 ml; the following dissolution profile is obtained:
[0000]
PERCENTAGE
RELEASE of the
PERCENTAGE
DIS-
multi-layer pellets
RELEASE of
SOLUTION
according to the
SALOFALK ®
SPECIFI-
TIMEFRAMES
invention
GRANU-STIX ®
CATIONS
2 h in HCl 0.1N
0%
0.5%
<10%
pH ADJUSTMENT
30′ in pH 7.2
68.1%
61.4%
N.L.T. 60%
60′ in pH 7.2
98.0%
86.9%
N.L.T. 85%
[0054] Stability studies of the pellets according to the present invention are set up, in a climatic chamber with Temperature of 25° C. and Relative Humidity of 60%, to verify the development of impurities. After 3 to 6 months the following results are obtained and are compared with the stability results of a formulation obtained according to traditional composition and production methods:
analysis at 3 months (25° C.-60% RH):
[0000]
FORMULATION
CLASSIC SALOFALK ®
according to
GRANU-STIX ®
IMPURITIES
LIMITS
the invention
FORMULATION
Known
0.5%
0.2%
0.4%
Unknown
1%
0.3%
1.3%
Totals
1.5%
0.5%
1.7%
analysis at 6 months (25° C.-60% RH):
[0000]
FORMULATION
CLASSIC
IMPURITIES
LIMITS
according to the invention
FORMULATION
Known
0.5%
0.4%
0.6%
Unknown
1%
0.6%
1.1%
Totals
1.5%
1.0%
1.8%
Example 2
[0057] Core
[0058] The following gelled composition is prepared:
[0000] COMPONENT AMOUNT (g) Polyvinylpyrrolidone 80 Polysorbate 300 Water 620 Total 1000
dissolving Polyvinylpyrrolidone in water, to then add Polysorbate on dissolution. Mesalazine raw material is mixed with the above-mentioned-mentioned solution, to then extrude (400 μm net) and spheronize the compound. Immediately following spheronization, the granules obtained are dried in a fluid bed with inlet air at 80° C., up to a product temperature of 50° C. Cores having an average diameter of 380 μm-430 μm are obtained with the following dry matter composition:
[0000]
COMPONENT
AMOUNT (g)
Mesalazine
990
Polyvinylpyrrolidone
2.10
Polysorbate
7.90
Total
1000
[0059] First Protective Coating
[0060] A protective membrane is prepared, comprising as follows:
[0000]
COMPONENT
AMOUNT (g)
Ethyl cellulose
50
Talc
2.5
Acetone
947.5
Total
1000
[0061] Dissolving Ethyl cellulose in Acetone, then adding Talc on dissolution.
[0062] The protective membrane is sprayed onto the previously obtained cores using a GS Automatic Coating Pan, up to a 1.2% increase in weight with respect to the initial weight of the pellets, thus obtaining a compound with a 97.83% Mesalazine content.
[0063] Second Gastro-Resistant Coating
[0064] A protective membrane is prepared, comprising as follows:
[0000]
COMPONENT
AMOUNT (g)
Eudragit FS 30 D
160
Polysorbate
3
Triethyl citrate
9
Glyceryl monostearate
7
Water
821
Tot.
1000
[0065] Homogenizing Polysorbate, Triethyl citrate and Glyceryl monostearate in water at 80° C., then adding Eudragit once the compound has cooled.
[0066] The gastro-resistant membrane is sprayed onto the previously obtained cores using a GS Automatic Coating Pan, up to a 7.5% increase in weight with respect to the initial weight of the pellets, thus obtaining a compound with a 91.00% Mesalazine content.
[0067] The Finished Product has the following characteristics:
[0000]
Titre
91.00%
Average diameter
d(50) = 386 μm
d(90) = 429 μm
Density
0.89 g/ml
[0068] The pellets are analysed in-vitro in HCl 0.1N/750 ml for 2 h, and then adjusted to pH 7.2/1000 ml; the following dissolution profile is obtained:
[0000]
PERCENTAGE
RELEASE of the
multi-layer pellets
according to
DISSOLUTION
TIMEFRAMES
the invention
SPECIFICATIONS
2 h in HCl 0.1N
0.3%
<10%
pH ADJUSTMENT
30′ in pH 7.2
79.4%
N.L.T. 60%
60′ in pH 7.2
99.2%
N.L.T. 85%
[0069] Stability studies of the pellets according to the present invention are set up, in a climatic chamber with Temperature of 25° C. and Relative Humidity of 60%, to verify the development of impurities. After 3 to 6 months the following results are obtained and are compared with the stability results of a formulation obtained according to traditional composition and production methods:
analysis at 3 months (25° C.-60% RH):
[0000]
FORMULATION
according to
CLASSIC
IMPURITIES
LIMITS
the invention
FORMULATION
Known
0.5%
0.3%
0.4%
Unknown
1%
0.2%
1.3%
Totals
1.5%
0.5%
1.7%
analysis at 6 months (25° C.-60% RH):
[0000]
FORMULATION
according to
CLASSIC
IMPURITIES
LIMITS
the invention
FORMULATION
Known
0.5%
0.4%
0.6%
Unknown
1%
0.3%
1.1%
Totals
1.5%
0.7%
1.8%
Example 3
[0072] Core
[0073] The following gelled composition is prepared:
[0000] COMPONENT AMOUNT (g) Polyvinylpyrrolidone 90 Polysorbate 400 Water 510 Total 1000
dissolving Polyvinylpyrrolidone in water, to then add Polysorbate on dissolution. Mesalazine raw material is mixed with the above-mentioned-mentioned solution, to then extrude (600 μm net) and spheronize the compound. Immediately following spheronization, the granules obtained are dried in a Fluid Bed with inlet air at 80° C., up to a product temperature of 50° C. Cores having an average diameter of 570 μm-640 μm are obtained with the following dry matter composition:
[0000]
COMPONENT
AMOUNT (g)
Mesalazine
985
Polyvinylpyrrolidone
2.75
Polysorbate
12.25
Total
1000
[0074] First Protective Coating
[0075] A protective membrane is prepared, comprising as follows:
[0000]
COMPONENT
AMOUNT (g)
Ethyl cellulose
50
Acetone
950
Total
1000
[0076] By dissolving Cellulose in Acetone.
[0077] The protective membrane is sprayed onto the previously obtained cores using a Glatt Fluid Bed with Wurster insert, up to a weight increase of 0.8% with respect to the initial weight of the pellets, thus obtaining a compound with a Mesalazine content of 97.72%.
[0078] Second Gastro-Resistant Coating
[0079] A protective membrane is prepared, comprising as follows:
[0000]
COMPONENT
AMOUNT (g)
Eudragit FS 30 D
180
Talc
18
Triethyl citrate
36
Water
766
Total
1000
[0080] Homogenising Triethyl citrate and Talc in water, then adding Eudragit to the compound.
[0081] The gastro resistant membrane is sprayed onto the previously obtained cores using a Glatt Fluid Bed with Wurster insert, up to a weight increase of 7% with respect to the initial weight of the pellets, thus obtaining a compound with a Mesalazine content of 91.33%.
[0082] The Finished Product has the following characteristics:
[0000]
Titre
91.33%
Average diameter
d(50) = 586 μm
d(90) = 624 μm
Density
0.81 g/ml
[0083] The pellets are analysed in-vitro in HCl 0.1N/750 ml for 2 h, and then adjusted to pH 7.2/1000 ml; the following dissolution profile is obtained:
[0000]
PERCENTAGE
RELEASE of the
multi-layer pellets
according to
DISSOLUTION
TIMEFRAMES
the invention
SPECIFICATIONS
2 h in HCl 0.1N
1.4%
<10%
pH ADJUSTMENT
30′ in pH 7.2
66.4%
N.L.T. 60%
60′ in pH 7.2
95.2%
N.L.T. 85%
[0084] Stability studies of the pellets according to the present invention are set up, in a climatic chamber with Temperature of 25° C. and Relative Humidity of 60%, to verify the development of impurities. After 3 to 6 months the following results are obtained and are compared with the stability results of a formulation obtained according to traditional composition and production methods:
analysis at 3 months (25° C.-60% RH):
[0000]
FORMULATION
according to
CLASSIC
IMPURITIES
LIMITS
the invention
FORMULATION
Known
0.5%
0.2%
0.4%
Unknown
1%
0.6%
1.3%
Totals
1.5%
0.8%
1.7%
analysis at 6 months (25° C.-60% RH):
[0000]
FORMULATION
according to
CLASSIC
IMPURITIES
LIMITS
the invention
FORMULATION
Known
0.5%
0.3%
0.6%
Unknown
1%
0.6%
1.1%
Totals
1.5%
0.9%
1.8% | 1a
|
RELATED APPLICATIONS
[0001] The present application claims priority under 35 U.S.C. §119(e) to U.S. provisional application No. 61/355,948 filed Jun. 17, 2010.
FIELD
[0002] Methods are provided herein relating to the field of bioprosthetic implants, and more particularly to the treatment of bioprosthetic tissues to decrease post-implantation antigenicity and calcification in host subjects.
BACKGROUND
[0003] A primary limitation of bioprosthetic implants made from animal tissues is the occurrence of hyperacute rejection reactions in transplant recipients. Such reactions are driven largely by the presence of antigenic carbohydrate epitopes within implanted tissues, the most common of which is the α-GAL glycoprotein epitope: D Galactose (α 1-3) Galactose (β1-4) N acetyl Glucosamine-R-motif (α-GAL) is found on vascular endothelial tissues of all species with the exception of old world monkeys, great apes, and humans. The presence of α-GAL on harvested animal donor tissues elicits an immediate and powerful immune response after transplantation into humans that can quickly destroy surrounding tissues and/or organs. The rapidity of the rejection response is due to very high levels of preformed anti-α-GAL antibodies in human subjects (nearly 1% of all antibodies in human blood are anti-α-GAL antibodies). The high levels of anti-α-GAL are an adaptive response to the ubiquitous presence of bacteria bearing α-GAL epitopes in the human digestive tract.
[0004] The most common tissue sources for xenographic bioprosthetic tissues are equine (horse), ovine (sheep), porcine (pig) and bovine (cow) tissues, all of which bear α-GAL epitopes and are potentially antigenic. One approach for limiting the antigenicity of bioprosthetic tissues is to chemically modify antigenic epitopes so that they are no longer recognized by host antibodies. This is typically accomplished by chemical fixation, which involves exposing a bioprosthetic tissue to a fixative agent (or tanning agent) that forms cross-linkages within (intramolecular cross-linkages) and/or between (intermolecular cross-linkages) polypeptides of the tissue. Examples of fixative agents used for treating bioprosthetic tissues include formaldehyde, glutaraldehyde, dialdehyde starch, hexamethylene diisocyanate and polyepoxy compounds. Glutaraldehyde is the most widely used fixative agent and glutaraldehyde treatment is currently the standard approach for stabilizing clinically useful bioprosthetic tissues. Examples of glutaraldehyde fixed bioprosthetic heart valves include the Carpentier-Edwards® Stented Porcine Bioprosthesis, the Carpentier-Edwards® PERIMOUNT® Pericardial Bioprosthesis, and the Edwards PRIMA Plus™ Stentless Aortic Bioprosthesis, all available from Edwards Lifesciences, Irvine, Calif. 92614.
[0005] Although chemical fixation can considerably limit the antigenicity of bioprosthetic tissues, fixed tissues, particularly glutaraldehyde-fixed tissue, suffer from several drawbacks. For example, the protective effects of glutaraldehyde fixation tend to deteriorate over the lifespan of bioprosthetic implants due to the labile Schiff Base cross-links, resulting in increased immunogenicity and impaired long-term stability and performance. In addition, glutaraldehyde treatment renders bioprosthetic tissues more susceptible to calcification, particularly when an implant remains in place for an extended period of time (e.g., more than ten years) due to their high levels of residual aldehyde groups. Structural valve deterioration (SVD) is the most common cause for early valve explanation, with tissue calcification the leading cause of failure in bioprosthetic implants. These glutaraldehyde-derived aldehydes are associated with high levels of calcium mineralization.
[0006] U.S. Pat. No. 6,861,211 to Levy and Vyavahare describes methods of stabilizing a bioprosthetic tissue through chemical cross-linking affected by treating the tissue with an agent, such as periodate, that oxidizes carbohydrate moieties of glycosaminoglycans (GAG) to generate aldehydes, and then treating the tissue with a bifunctional agent that reacts with the carbohydrate aldehydes as well as reactive groups on adjacent proteins to cross-link the GAG to the surrounding tissue matrix. Like conventional glutaraldehyde fixation, the methods result in residual reactive aldehyde groups, which serve as potential calcium binding sites and thus destabilize the tissue by ultimately compromising the biomechanical properties of the material.
[0007] U.S. Pat. No. 6,383,732 (Stone) describes an alternative to chemical modification for limiting the antigenicity of bioprosthetic tissues using the enzyme alpha-galactosiadase to destroy α-GAL epitopes. Enzymatic approaches suffer from the general high cost of enzyme preparations and the fact that the large size of alpha-galactosiadase and other enzymes prevents these protein structures from penetrating deeply into tissues, such as the extracellular matrix of pericardial bioprosthetic tissues. Thus, enzyme-based treatments do not eliminate all of the epitopes targeted by an enzyme, particularly in the interior of a bioprosthetic implant. In addition, alpha-galactosiadase and other enzymes are specific for particular epitopes (e.g., α-GAL in the case of alpha galactosiadase), making it highly difficult to limit the antigenicity of tissues containing multiple and/or unknown epitopes. The enzymatic removal of cellular components and tissue structures can also degrade the biomechanical properties of the tissue. Moreover, these enzyme treatments cannot be used with glutaraldehyde-fixed tissue since the enzyme's protein structure will react with the residual aldehydes and become covalently bound to the material. The result is an increase in foreign proteins and further degradation in tissue performance.
[0008] Accordingly, there remains a need in the art for the development of new and improved methods for reducing antigenicity and limiting calcification of xenographic tissues, thereby enhancing the durability, stability, and performance of the tissues. These enhanced characteristics are consistent with the demands of bioprosthetic tissues in vivo, including maintaining the structural, mechanical, and biocompatible properties of, for example, heart valves.
BRIEF SUMMARY
[0009] Methods are provided herein for improving the stability, durability, and/or performance of a xenographic bioprosthetic tissue implant by chemically modifying antigenic carbohydrates within the bioprosthetic tissue.
[0010] In some aspects, the methods comprise the steps of: treating the bioprosthetic tissue with an oxidizing agent which oxidizes vicinal diol moieties of antigenic carbohydrates to form aldehydes or acids and treating the bioprosthetic tissue with a capping agent, the capping agent comprising a primary amine or alcohol which combines with the aldehydes or acids to form imines, amides or esters.
[0011] In some aspects, the methods comprise the steps of: treating the bioprosthetic tissue with a capping agent, the capping agent comprising a primary amine or alcohol which combines with aldehydes or acids to form imines, amides or esters, and treating the bioprosthetic tissue with a stabilizing agent, the stabilizing agent converting the imines to secondary amines or the esters to amides.
[0012] In some aspects, the methods comprise the steps of: treating the bioprosthetic tissue with an oxidizing agent which oxidizes vicinal diol moieties of antigenic carbohydrates to form aldehydes or acids; treating the bioprosthetic tissue with a capping agent, the capping agent comprising a primary amine or alcohol which combines with the aldehydes or acids to form imines, amides or esters; and treating the bioprosthetic tissue with a stabilizing agent, the stabilizing agent converting the imines to secondary amines or the esters to amides.
[0013] In some aspects, the antigenic carbohydrate is N-glycolylneuraminic acid (Neu5Gc) in some aspects the antigenic carbohydrate is the Forssman antigen (GalNAc alpha1,3GalNAc beta1,3Gal alpha1,4Gal beta1,4Glc-Cer). In further aspects, the antigenic carbohydrate comprises an α-galactosyl (α-Gal) epitope.
[0014] In some aspects, the oxidizing agent is a periodate. In some aspects, the periodate selectively oxidizes vicinal diols of antigenic carbohydrates relative to β-aminoalcohol and/or vicinal diketone groups comprising the bioprosthetic tissue.
[0015] In some aspects, the capping agent is a primary amine. In further aspects, the primary amine reacts with aldehydes on the bioprosthetic tissue to form imines.
[0016] In some aspects, the capping agent is an alcohol. In further aspects, the alcohol reacts with acids on the bioprosthetic tissue to form esters.
[0017] In some aspects, the stabilizing agent is a reducing agent. In further aspects, the reducing agent converts bioprosthetic tissue imines to secondary amines and esters to amides.
[0018] In some aspects, the bioprosthetic tissue is treated with the oxidizing agent in the presence of the capping agent. In further aspects, the bioprosthetic tissue is washed sufficiently to remove the oxidizing agent prior to treatment with the reducing agent.
[0019] In some aspects, the bioprosthetic tissue is treated with the stabilizing agent in the presence of the primary amine or alcohol capping agent. In further aspects, the bioprosthetic tissue is treated with the capping agent and the stabilizing agent concurrently. In yet further aspects, the bioprosthetic tissue is washed to remove the oxidizing agent prior to treatment with the capping agent and/or the stabilizing agent.
[0020] In some aspects, the bioprosthetic tissue has been treated with one or more of a surfactant and/or a fixative agent. In various aspects, the fixative agent is selected from the group consisting of an aldehyde, a dialdehyde, a polyaldehyde, a diisocyanate, a carbodiimide, a photooxidation agent, and a polyepoxy compound and the surfactant is selected from the group consisting of an anionic surfactant, an alkyl sulfonic acid salt, a polyoxyethylene ether, a pluronic or tetronic surfactant, and an alkylated phenoxypolyethoxy alcohol.
[0021] In some preferred aspects, the bioprosthetic tissue has been treated with glutaraldehyde.
[0022] In some preferred aspects, the bioprosthetic implant is a heart valve. In further aspects, the bioprosthetic tissue is bovine pericardium or porcine aortic valve. In yet further aspects, the bioprosthetic implant is a pediatric heart valve.
[0023] In some aspects, the oxidized bioprosthetic tissue is substantially non-immunogenic in a human host. In further aspects, the antigenic carbohydrate of the treated bioprosthetic tissue is substantially non-antigenic in a human host. In yet further aspects, the treated bioprosthetic tissue is substantially non-calcifying in a human host. In some aspects, the human host is a pediatric patient.
[0024] In some aspects, the oxidizing agent is a periodate. In further aspects, the periodate is sodium periodate. In some aspects, the sodium periodate is used at a concentration of 20 mM. In some aspects, the bioprosthetic tissue is treated with sodium periodate for about 3 hours at about 25° C.
[0025] In some aspects, the method further comprises treating the bioprosthetic tissue with one or more of a surfactant and a fixative agent. In further aspects, the method comprises treating the bioprosthetic tissue with an aldehyde fixative agent. In yet further aspects, the method comprises treating the bioprosthetic tissue with glutaraldehyde. In some aspects, the fixative agent is carbodiimide (such as EDC). In some aspects, the fixative agent is diepoxy.
[0026] In some aspects, the bioprosthetic tissue is a fresh tissue.
[0027] In some aspects, the method further includes treating the bioprosthetic tissue with a bioburden reduction solution including formaldehyde, ethanol, and a Tween® solution. In some aspects, the method further includes drying the bioprosthetic tissue with ethanol and glycerol. In some aspects, the method further includes sterilizing the bioprosthetic tissue with ethylene oxide.
[0028] In some aspects, the method further includes decellularizing the bioprosthetic tissue with a decellularization method including treating the tissue with 0.1% SDS, rinsing the tissue, and treating the tissue with DNAse. In some aspects, the method further includes drying and electrophoretically cleaning the bioprosthetic tissue. In some aspects, the method further includes sterilizing the bioprosthetic tissue with glutaraldehyde.
[0029] In some aspects, the method further includes treating the bioprosthetic tissue with a bioburden reduction solution comprising ethanol and a Tween® solution.
[0030] Other aspects are described in co-owned U.S. Pub. No. 2009/0164005, filed Dec. 18, 2008, herein incorporated by reference in its entirety, for all purposes.
BRIEF DESCRIPTION OF THE DRAWINGS
[0031] FIG. 1 shows various aspects of the tissue treatment process as provided in the present disclosure. As shown in FIG. 1 , the process generally includes vicinal diol (i.e., vic Diol) oxidation, treatment with a capping agent, and/or treatment with a stabilizing agent.
[0032] FIG. 2 shows immunohistochemistry for α-Gal expression following treatments of un-fixed tissues. Blue is DNA (DAPI staining) and Green is α-Gal (Isolectin IB4 staining). FIG. 2A shows minimal staining in fresh, un-fixed tissue treated with the process described herein (vic Diol oxidation, capping agent, and reducing agent). FIG. 2B shows a lighter area of intense α-Gal (Isolectin IB4 staining) in fresh, un-fixed tissue treated with periodate only.
[0033] FIG. 3 shows immunohistochemistry for α-Gal expression on un-fixed tissues treated with various types of periodate. Stained areas are shown as lighter areas compared to the darker background. Blue is DNA (DAPI staining) and Green is α-Gal (Isolectin IB4 staining). FIG. 3A shows un-fixed tissue treated with a 1% SDS/DNAse decellularization procedure. FIG. 3B shows un-fixed tissue treated with a commercially available decellularized collagen tissue. FIG. 3C shows un-fixed tissue treated with another commercially available decellularized collagen tissue.
[0034] FIG. 4 shows that tissue fixed with glutaraldehyde has severe autofluorescence.
[0035] FIG. 5 shows α-Gal and DNA expression as darker areas on fixed tissue treated with ThermaFix (TFX) only. Brown is α-Gal (Isolectin-IB4, DAB) and Blue is nuclei (Hematoxylin staining). FIG. 5 also shows a flow-diagram of the process used for this experiment.
[0036] FIG. 6 shows α-Gal and DNA expression as darker areas on fixed tissue treated with the combined treatment of fixed tissue with TFX and the process described herein. The upper panels show tissue treated with ethanolamine. The lower panels show tissue treated with taurine. Brown is α-Gal (Isolectin-IB4, DAB) and Blue is nuclei (Hematoxylin staining).
[0037] FIG. 7 shows α-Gal and DNA expression as darker areas on fixed tissue treated with a capping, reduction, and drying process. FIG. 7 also shows a flow-diagram of the process used for this experiment. Brown is α-Gal (Isolectin-IB4, DAB) and Blue is nuclei (Hematoxylin staining).
[0038] FIG. 8 shows α-Gal and DNA expression as darker areas on fixed tissue treated with the combined treatment e with TFX and vicinal diol (i.e., vic Diol) oxidation, treatment with a capping agent, treatment with a reducing/stabilizing agent, and drying as described herein. The upper panels show tissue treated with ethanolamine. The lower panels show tissue treated with taurine. Brown is α-Gal (Isolectin-IB4, DAB) and Blue is nuclei (Hematoxylin staining).
[0039] FIG. 9 shows the percent of total isolectin-B4-α-Gal binding inhibition as induced by various tissue treatments and as compared to a control.
[0040] FIG. 10 shows the anti-α-Gal response for the following treatments: glutaraldehyde; TFX; vic Diol oxidation, treatment with a capping agent, and treatment with a stabilizing agent; and a capping, reduction and drying treatment in primate subjects. Data is given as a percent increase or decrease in absorbance compared to an original value.
DETAILED DESCRIPTION
[0041] Descriptions of the invention are presented herein for purposes of describing various aspects, and are not intended to be exhaustive or limiting, as the scope of the invention will be limited only by the appended claims. Persons skilled in the relevant art can appreciate that many modifications and variations are possible in light of the aspect teachings.
[0042] Unless defined otherwise, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art. While exemplary methods and materials are described herein, it is understood that methods and materials similar or equivalent to those described can be used. All publications mentioned herein are incorporated by reference to disclose and describe the methods and/or materials in connection with which they are cited.
[0043] It must be noted that, as used in the specification, the singular forms “a”, “an” and “the” include plural referents unless the context clearly dictates otherwise.
[0044] Methods are provided herein for mitigating the immunogenicity of a xenographic bioprosthetic tissue by chemically modifying one or more antigenic carbohydrates within the tissue while leaving the overall tissue structure substantially unmodified.
[0045] In some aspects, the methods comprise the steps of: treating the bioprosthetic tissue with an oxidizing agent which oxidizes vicinal diol moieties of antigenic carbohydrates to form aldehydes or acids and treating the bioprosthetic tissue with a capping agent, the capping agent comprising a primary amine or alcohol which combines with the aldehydes or acids to form imines, amides or esters.
[0046] In some aspects, the methods comprise the steps of: treating the bioprosthetic tissue with a capping agent, the capping agent comprising a primary amine or alcohol which combines with aldehydes or acids to form imines or esters, and treating the bioprosthetic tissue with a stabilizing agent, the stabilizing agent converting the imines to secondary amines or the esters to amides.
[0047] In some aspects, the methods comprise the steps of: treating the bioprosthetic tissue with an oxidizing agent which oxidizes vicinal diol moieties of antigenic carbohydrates to form aldehydes or acids; treating the bioprosthetic tissue with a capping agent, the capping agent comprising a primary amine or alcohol which combines with the aldehydes or acids to form imines or esters; and treating the bioprosthetic tissue with a stabilizing agent, the stabilizing agent converting the imines to secondary amines or the esters to amides.
[0048] Without being limited by a particular theory, it is believed that glutaraldehyde fixation and other established methods for stabilizing xenographic tissues suffer from several limitations that are associated with antigenicity, calcification, and long-term failure of bioprosthetic implants. Glutaraldehyde and other fixative agents stabilize tissues by forming cross-linkages between certain reactive moieties within the tissues without necessarily altering or eliminating antigenic epitopes. Glutaraldehyde fixation reduces antigenicity in a largely indirect manner due to the adsorption of host immune cells, antibodies, and serum proteins to concentrated aldehyde groups on the surfaces of glutaraldehyde fixed tissues, forming a coating of native molecules that isolates the tissue from host immune factors. However, such protein coatings deteriorate over time, exposing the tissue to the host immune system. In addition, the interior of glutaraldehyde fixed tissues often contains high levels of “latent antigens” due to the slow rate of penetration and diffusion of glutaraldehyde throughout treated tissues. As a result, glutaraldehyde fixed bioprosthetic tissues can become increasingly antigenic over time, leading to calcification, tissue fatigue, and eventually failure of the bioprosthetic implant.
[0049] Advantageously, methods provided herein reduce the antigenicity and/or calcification of bioprosthetic tissues by addressing one or more limitations associated with glutaraldehyde fixation and/or other established methods. Treating bioprosthetic tissues with periodate according to the instant methods selectively oxidizes antigenic carbohydrates, resulting in the covalent modification of xenographic antigens. In addition, periodate and other chemical agents are small molecules that readily diffuse throughout bioprosthetic tissues, including chemically fixed tissues, to eliminate latent antigens throughout the tissues. Methods provided herein use a capping agent to convert aldehyde groups produced by periodate oxidation and/or glutaraldehyde fixation to imines, and a reducing agent to convert the hydrolytically unstable imines to stable and substantially non-antigenic secondary amines. The methods thus eliminate reactive and toxic aldehydes and prevent further oxidation of aldehydes to acids that serve as potential calcium-binding sites. Moreover, calcification is further reduced by the modification of latent antigens and the resulting decreased immunogenicity of bioprosthetic tissues. Advantageously, methods provided herein improve the stability, durability, and/or performance of bioprosthetic tissue implants.
[0050] In some aspects, the “antigenic carbohydrate” targeted for modification by the instant methods is a glycosaminoglycan (GAG) polysaccharide that is found on glycoproteins and/or glycolipids of a xenographic tissue and is recognized as foreign by the immune system of a human subject. Antigenic carbohydrates within bioprosthetic tissues can trigger varying levels of immune responses that can decrease the performance, durability, and/or lifespan of the implant and potentially require immediate medical intervention to replace the implant. In some aspects, antigenic carbohydrates modified according to methods provided herein are “periodate labile” in that they comprise one or more exposed vicinal diol (R 1 —CH(OH)CH(OH)—R 2 ) moieties capable of being oxidized by a periodate to produce a pendant aldehyde (R 1 CHO). Advantageously, periodate oxidation of an antigenic carbohydrate modifies its structure so that it is no longer recognized by circulating antibodies. In some preferred aspects, treating a glutaraldehyde fixed tissue with periodate according to a method provided herein substantially eliminates periodate labile antigenic carbohydrate epitopes. In further aspects, treating a glutaraldehyde fixed tissue with periodate according to a method provided herein renders the tissue substantially non-antigenic.
[0051] In some aspects, an antigenic carbohydrate modified according to the instant methods is the α-GAL epitope (Galα 1-3 Galβ 1-4 GlcNAc—R). Treating an α-GAL-expressing xenographic tissue with periodate according to the methods provided herein results in oxidation of the vicinal diol of the α-GAL terminal galactose, producing two pendant aldehydes. The pendant aldehydes are preferably converted to imines by a primary amine-containing “capping agent”, and the imines are converted to stable secondary amines by a reducing agent. Advantageously, periodate oxidation of the terminal galactose unit modifies the α-GAL epitope such that it is no longer recognized by human anti-α-GAL (“anti-GAL”) antibodies, thus substantially reducing the antigenicity of the bioprosthetic tissue.
[0052] In further aspects, an antigenic carbohydrate modified according to the instant methods is the sialic acid N-glycolylneuraminic acid (Neu5Gc), the so called Hanganutziu-Deicher (HD) antigen, which comprises a nine-carbon sugar with a periodate labile vicinal diol. Neu5Gc is common in mammalian tissues, especially porcine tissues, but is not synthesized endogenously by humans. Nevertheless, Neu5Gc is sometimes detected at relatively stable levels in humans due to dietary intake and possible metabolic incorporation of small amounts of Neu5Gc in human glycoproteins. Human subjects have varying levels of circulating antibodies against Neu5Gc, with the highest levels comparable to those of anti-GAL antibodies. Advantageously, periodate oxidation of Neu5Gc sialic acid residues within a xenographic tissue modifies the Neu5Gc epitope so that it is no longer antigenic to human subjects.
[0053] In further aspects, the antigenic carbohydrate is the Forssman antigen (GalNAc alpha1,3GalNAc beta1,3Gal alpha1,4Gal beta1,4Glc-Cer). M. Ezzelarab, et al Immunology and Cell Biology 83, 396-404 (2005).
[0054] In some preferred aspects, treating a bioprosthetic tissue according to a method provided herein significantly reduces the antigenicity of the tissue in a human subject. In further aspects, treating a bioprosthetic tissue according to a method provided herein renders the tissue substantially non-antigenic in a human subject. In yet further aspects, methods provided herein significantly reduce antigenicity and/or render the tissue substantially non-antigenic in a human pediatric subject.
[0055] In some aspects, bioprosthetic tissues treated according to the instant methods have been treated with a fixative agent. As used herein, the terms “fixed” or “fixation” refer generally to the process of treating biological tissue with a chemical agent (a fixative agent) that forms intermolecular and intramolecular cross-linkages within and between structures in order to stabilize the tissue structure and prevent degradation. For example, fixation reduces the susceptibility of tissues to proteolytic cleavage by preventing the unfolding and denaturation required for proteases to access potential substrate proteins. Glutaraldehyde, formaldehyde, dialdehyde starch, and other aldehyde cross-linking agents are the most commonly used fixative agents for treating bioprosthetic tissues in preparation for surgical implantation. While fixation with fixative agents is desirable for stabilizing the tissue, fixation can also generate reactive chemical moieties in the tissue that are capable of binding calcium, phosphate, immunogenic factors, or other precursors to calcification. For example, glutaraldehyde fixation produces a high concentration of free aldehydes which are intrinsically toxic and can be further oxidized to form negatively charged carboxylic acid groups that serve as potential binding sites for positively charged calcium ions.
[0056] The term “calcification” as used herein, means deposition of one or more calcium compounds, such as calcium phosphate, calcium hydroxyapatite, and/or calcium carbonate, within a bioprosthetic tissue, which can lead to undesirable stiffening and/or degradation of the bioprosthesis. Although the precise mechanisms underlying calcification are unclear, calcification is generally known to arise in bioprosthetic tissues out of the interaction of plasma calcium ions with free aldehydes, phospholipids, and other tissue components. In addition, bioprosthetic tissues are particularly prone to calcification in pediatric subjects. Calcification can be intrinsic or extrinsic with respect to a bioprosthetic tissue. Intrinsic calcification is characterized by the precipitation of calcium and phosphate ions at sites within a bioprosthetic tissue, such as the extracellular matrix and remnant cells. Extrinsic calcification is characterized by the precipitation of calcium and phosphate ions on external sites on a bioprosthetic tissue by, e.g., thrombus formation or the development of surface plaques. Advantageously, methods provided herein reduce both intrinsic and extrinsic forms of calcification.
[0057] In some preferred aspects, treating a bioprosthetic tissue according to a method provided herein significantly reduces the level of calcification in the tissue and/or the propensity of the tissue for calcification in a human subject. In further preferred aspects, treating a bioprosthetic tissue according to a method provided herein renders the tissue substantially non-calcifying in a human subject. In yet further aspects, methods provided herein significantly reduce the level of and/or the propensity for calcification of a tissue and/or render a tissue substantially non-calcifying in a human pediatric subject.
[0058] The effects of the instant methods on reducing and/or eliminating xenographic antigens, free aldehydes, and/or calcification (or the propensity for calcification) can be detected using a variety of methods known to those skilled in the art. The mitigation of antigenic carbohydrates can be monitored by, e.g., direct galactose assays (α-GAL epitopes), immunohistochemical staining (e.g., using anti-α-GAL and/or anti-Neu5Gc antibodies), and conventional histology. The level of free aldehydes in a tissue can be measured spectrophotometrically using a colorimetric reagent, such as 4-amino-3-hydrazino-5-mercato-1,2,4-triazole (available under the tradename PURPALD), which reacts specifically with aldehydes to yield colored 6-mercapto-striazolo-(4,3-b)-s-tetrazines detectable at 550 nm, as described, e.g., in Dickinson and Jacobsen, Cem. Commun., 1719 (1970). A reduction in the concentration of free aldehydes in a bioprosthetic tissue can also be measured as a reduction in the toxicity of the tissue. For example, a bioprosthetic tissue (or sample thereof) can be used as a substrate for seeding cultured endothelial cells, and the growth of the endothelial cell monolayer on the bioprosthetic tissue substrate can provide a sensitive biological indicator of the number and concentration of residual aldehydes in the tissue.
[0059] The extent of calcification of a bioprosthetic tissue can be measured using a variety of methods known in the art, such as spectrophotometric methods (e.g., as described by Mirzaie et al., Ann Thorac. Cardiovasc. Surg., 13:2 (2007)) and spectroscopic methods (e.g., inductively-coupled plasma mass spectroscopy (ICP-MS) after nitric acid ashing). Calcification of tissues may also be assayed by histological staining (e.g., Von Kossa staining) or by using a calcification indicator (e.g., eriochrome black T, murexide, or o-cresolphthalein, as described, e.g., in Sarkar et al., Anal Biochem, 20:155-166 (1967)). In addition, calcification of heart valve bioprosthetic implants can be detected by associated changes in the mechanical properties of the tissue, such as increased stiffening, which can be detected visually and/or measured using various methods known in the art. Those skilled in the art will be familiar with these and other methods.
[0060] As used herein, the term “bioprosthetic” refers to any prosthesis which is implanted in a mammalian subject, preferably a human subject, and derived in whole or in part from animal or other organic tissue(s). Bioprosthetic implants used in methods provided herein include tissue “patches,” heart valves and other heart components, heart replacements, vascular replacements or grafts, urinary tract and bladder replacements, bowel and tissue resections, and the like.
[0061] Bioprosthetic implants treated according to methods provided herein can be derived from any biological tissue, including but not limited to, heart valves, blood vessels, skin, dura mater, pericardium, cartilage, ligaments and tendons. In some aspects, the tissue used to prepare a bioprosthetic implant is selected according to the degree of pliability or rigidity, which varies with the relative amounts of collagen and elastin present within the tissue, the structure and conformation of the tissue's connective tissue framework (e.g., arrangement of collagen and elastin fibers), and/or other factors known to those skilled in the art. Bioprosthetic tissues having relatively high levels of collagen, such as heart valve tissue and pericardial tissue, have been found to be particularly suitable for human bioprosthetic heart valve implant. However, those skilled in the art will realize that the instant methods can be used to treat bioprosthetic implants made from any suitable tissue.
[0062] In some preferred aspects, the bioprosthetic implant is a heart valve implant that is derived from a xenographic mammalian donor tissue and intended for use in a human subject. In further preferred aspects, the bioprosthetic implant is derived from a xenographic mammalian donor other than a great ape or an old world monkey, such as but not limited to, an equine donor, an ovine donor, a porcine donor or a bovine donor.
[0063] Those skilled in the art will recognize that the instant methods are particularly beneficial in treating those prostheses for which post-implantation degeneration and/or calcification poses a significant a clinical problem. For example, in some aspects, the bioprosthetic implant is a heart valve formed from bovine pericardium or porcine aortic valve and designed for implantation in a human subject. In yet further preferred aspects, the bioprosthetic implant is derived from a xenographic mammalian donor tissue and is designed for implantation in a human pediatric subject.
[0064] An “oxidizing agent” according to the present methods includes any mild oxidizing agent that is suitable for the selective oxidation of antigenic carbohydrates having vicinal diols to produce free aldehyde or acid moieties. Oxidizing agents according to the present disclosure can be halogen series oxidizing agents or peroxide series oxidizing agents or the like. Examples of oxidizing agents include, but are not limited to, periodic acid, salts of periodic acid such as sodium periodate, lead tetraaceatate, hydrogen peroxide, sodium chlorite, sodium hypochlorite, potassium permanganate, oxygen, halogens such as bromine and others known to those skilled in the art.
[0065] In some aspects, the oxidizing agent is a periodate. A “periodate” according to methods provided herein is a compound comprising a periodate ion (IO 4 − ) that is capable of reacting, as shown in the reaction scheme below, with vicinal diol moieties (1) of antigenic carbohydrates to yield two pendant aldehyde moieties (2) along with formic acid and H 2 O.
[0000]
[0066] In some aspects, oxidation of vicinal diols is carried out in an aqueous solution, preferably an aqueous buffered solution, under conditions suitable for maintaining the structure and biological properties of the bioprosthetic tissue. In some aspects, a periodate is used for oxidation of vicinal diols. Typically, a stoichiometric amount of periodate is used to oxidize vicinal diol moieties, which amount can be determined empirically for a particular volume of tissue and/or for a particular type of tissue. Alternatively, a stoichiometric excess or periodate can be used. Solutions are generally buffered to have a pH between about 4 and about 9, with a pH between about 6 and about 8 desired for certain pH sensitive biomolecules. Periodate oxidation is generally carried out at a temperature between about 0 and about 50 degrees Celsius, and preferably at a temperature between about 4 and about 37 degrees Celsius. Depending on the antigenic carbohydrate(s) targeted for modification, the size and geometry of the bioprosthetic tissue and/or other considerations, periodate oxidation can be carried out for a period of between a few minutes to as long as many days. Preferably, periodate oxidation is carried out for a period between about several hours and about 24 hours. Long-term oxidation reactions are preferably performed under conditions that prevent over-oxidation. Treatment times and temperatures for periodate oxidation tend to be inversely related, in that higher treatment temperatures require relatively shorter treatment times. Those skilled in the art will recognize that the precise reaction conditions for a particular bioprosthetic tissue can be determined by routine experimentation, using methods known in the art.
[0067] In various aspects, the oxidizing agent is capable of oxidizing vicinal diols within antigenic carbohydrates targeted for modification, forming either pendant aldehyde moieties, which are converted to imines and then to more stable secondary amines by methods provided herein, or acids, which are converted directly to amides, or alternatively, converted to esters and then to more stable amides by methods provided herein. In some aspects, the size, charge, and/or other characteristics of the oxidizing agent allow it to readily penetrate and diffuse throughout the bioprosthetic tissue and be washed out of the tissue after a desired duration of treatment. In some aspects, the oxidizing agent is a periodate that is a periodic acid or a salt thereof, such as sodium periodate, potassium periodate, or another alkali metal periodate salt. In some preferred aspects, the oxidizing agent is sodium periodate. In some aspects the oxidizing agent is an acetate, such as lead acetate.
[0068] In some aspects, treating a bioprosthetic tissue with a periodate according to a method provided herein results in selective oxidation of vicinal diols relative to other reactive functionalities, including but not limited to, 2-aminoalcohols (e.g., on N-terminal serine, N-terminal threonine or 5-hydroxylysine residues), 1,2-aminothiols (e.g., on N-terminal cysteine residues), and vicinal diketones. In some preferred aspects, treating a bioprosthetic tissue with an oxidizing agent according to methods provided herein selectively oxidizes vicinal diols within one or more antigenic carbohydrates while leaving non-targeted structures substantially unmodified.
[0069] Without being limited to a particular theory, it is believed that potentially reactive moieties within bioprosthetic tissues vary in their susceptibility to oxidation with the following general order of reactivity (from most to least labile): vicinal diols, 2-aminoalcohols, 1,2-aminothiols, and vicinal diketones. In addition, the selectivity of an oxidizing agent for vicinal diols can be further enhanced by treating tissues with the oxidizing agent under mildly oxidizing conditions. Skilled artisans will recognize that mildly oxidizing conditions can be determined empirically using various methods known in the art, such as carrying out oxidation reactions under varying conditions with a mixture of carbohydrate substrates and monitoring the rate of production of reaction products. For example, the stringency of oxidation can be modulated by adjusting various reaction conditions, such as oxidizing agent concentration, treatment duration, temperature, solution chemistry, and the like.
[0070] In some aspects, a bioprosthetic tissue is treated with an oxidizing agent under conditions that favor oxidation of a particular antigenic carbohydrate. For example, antigenic carbohydrates having a sialic acid terminal sugar, such as Neu5Gc, are generally more susceptible to periodate oxidation than those having other terminal sugars, such as galactose (e.g., α-GAL).
[0071] In some aspects, the oxidizing agent selectively oxidizes vicinal diols of antigenic carbohydrates targeted for modification relative to other potentially labile moieties on biomolecules comprising the bioprosthetic tissue.
[0072] A “capping agent” according to the present methods includes any capping agent capable of reacting with free aldehyde or acid moieties. The capping agent can be a primary amine or an alcohol. In various aspects, the capping agent is R 4 -M-NH 2 , wherein: R 4 is H, C 1-6 alkyl, S(═O) 2 OR 5 , C 1-6 alkoxy, or hydroxyl; M is a linker, wherein the linker is C 1-6 alkylene; and R 5 is H or C 1-6 alkyl. In further aspects, R 4 is H. In yet further aspects, R 4 is S(═O) 2 OR 5 and R 5 is H. In certain aspects, the capping agent is an amine, alkyl amine, hydroxylamine, aminoether, amino sulfonate, or a combination thereof.
[0073] Examples of capping agents include, but are not limited to, ethanolamine; taurine; amino acids such as glycine and lysine; alkoxy alkyl amines, such as 2-methoxyethylamine; n-alkyl amines such as ethylamine, and propylamine, N-Hydroxysuccinamide (NHS), N-Hydroxysulfosuccinamide (NHSS), and others known to those skilled in the art.
[0074] Chemical moieties referred to as univalent chemical moieties (e.g., alkyl, alkoxy, etc.) also encompass structurally permissible multivalent moieties, as understood by those skilled in the art. For example, while an “alkyl” moiety generally refers to a monovalent radical (e.g., CH 3 CH 2 —), in appropriate circumstances an “alkyl” moiety can also refer to a divalent radical (e.g., —CH 2 CH 2 —, which is equivalent to an “alkylene” group).
[0075] All atoms are understood to have their normal number of valences for bond formation (e.g., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, depending on the atom's oxidation state). On occasion a moiety can be defined, for example, as (A) a B, wherein a is 0 or 1. In such instances, when a is 0 the moiety is B and when a is 1 the moiety is AB.
[0076] Where a substituent can vary in the number of atoms or groups of the same kind (e.g., alkyl groups can be C 1 , C 2 , C 3 , etc.), the number of repeated atoms or groups can be represented by a range (e.g., C 1 -C 6 alkyl) which includes each and every number in the range and any and all sub ranges. For example, C 1 -C 3 alkyl includes C 1 , C 2 , C 3 , C 1-2 , C 1-3 , and C 2 -3 alkyl.
[0077] “Alkoxy” refers to an O-atom substituted by an alkyl group as defined herein, for example, methoxy (—OCH 3 , a C 1 alkoxy). The term “C 1-6 alkoxy” encompasses C 1 alkoxy, C 2 alkoxy, C 3 alkoxy, C 4 alkoxy, C 5 alkoxy, C 6 alkoxy, and any sub-range thereof.
[0078] “Alkyl” refer to straight and branched chain aliphatic groups having from 1 to 30 carbon atoms, or preferably from 1 to 15 carbon atoms, or more preferably from 1 to 6 carbon atoms, each optionally substituted with one, two or three substituents depending on valency. “Alkyl” includes unsaturated hydrocarbons such as “alkenyl” and “alkynyl,” which comprise one or more double or triple bonds, respectively. The term “C 1-6 alkyl” encompasses C 1 alkyl, C 2 alkyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, C 6 alkyl, and any sub-range thereof. Examples of such groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, vinyl, allyl, isobutenyl, ethynyl, and propynyl.
[0079] “Alkylene” refers to a divalent radical that is a branched or unbranched hydrocarbon fragment containing the specified number of carbon atoms, and having two points of attachment. An example is propylene (—CH 2 CH 2 CH 2 —, a C 3 alkylene). The term “C 1-6 alkylene” encompasses C 1 alkylene, C 2 alkylene, C 3 alkylene, C 4 alkylene, C 5 alkylene, C 6 alkylene, and any sub-range thereof.
[0080] “Amine” refers to a —N(R*)R** group, wherein R and R′ are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, heterocyclyl, or heteroaryl as defined herein. In the case of a primary amine, R* and R** are each H.
[0081] A “substituted” moiety is a moiety in which one or more hydrogen atoms have been independently replaced with another chemical substituent. As a non limiting example, substituted phenyl groups include 2-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluorophenyl, and 2-fluoro-3-propylphenyl. In some instances, a methylene group (—CH 2 —) is substituted with oxygen to form a carbonyl group (—CO).
[0082] An “optionally substituted” group can be substituted with from one to four, or preferably from one to three, or more preferably one or two non-hydrogen substituents. Examples of suitable substituents include, without limitation, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aroyl, halo, hydroxy, oxo, nitro, alkoxy, amino, imino, azido, mercapto, acyl, carbamoyl, carboxy, carboxamido, amidino, guanidino, sulfonyl, sulfinyl, sulfonamido, formyl, cyano, and ureido groups.
[0083] Carboxylic acid groups like those in glutamic acid or gamma carboxy glutamic acid are known to bind calcium atoms. Calcium binding proteins such as bone sialoprotein contain carboxylic acid-rich domains designed to attract and bind calcium, leading to hydroxyapatite formation (calcification). The overall level and location of acid groups in these proteins determines the ability of the protein to efficiently bind calcium and form hydroxyapatite. The term “acid potential” of the tissue refers to the level of these chemical functional groups within the fixed tissue which may eventually form acid groups or “binding sites” by oxidation, dehydration, hydration, or similar processes.
[0084] Calcium binding causes significant post-implant damage in bioprosthetic materials, especially tissues used for heart valve leaflets. For example, the oxidative damage that occurs during storage and handling of dehydrated or “dry” tissue can create carboxylic acid groups that will bind calcium and lead to tissue failure. This progressive leaflet damage process can create new binding sites or potential binding sites that are precursors to calcification and immunogenic related pathways. The present disclosure provides for a method for capping these newly formed binding sites prior to implantation of the tissue for tissue-based bioprosthetic into the body. Bioprosthetic tissue exposed to oxidation from the atmosphere when not submersed in a glutaraldehyde solution or during sterilization is likely to contain more acid groups that contribute to calcification and inflammation. In dry storage, the dehydrated tissue is sterilized and stored “dry” without the protective effect of the glutaraldehyde solution. The ease of handling and storage of this new product is greatly facilitated due to the absence of the glutaraldehyde storage solution. This technology can be improved by treating such bioprosthetic tissue with a capping agent and/or adding a chemical protectant during the dehydration phase.
[0085] As shown in the reaction scheme below, a “capping agent” according to methods provided herein is in some aspects a primary amine (R′NH 2 )-containing agent (3) capable of reacting with free aldehydes (R 1 CHO) (2) to form imines (R 3 N═CHR 1 ) (4).
[0086] Aldehyde Capping (Schiff base reaction):
[0000]
[0087] In some aspects, the capping reaction is carried out independently of oxidation in a neutral or slightly basic solution, at a temperature between about 0 and about 50 degrees Celsius, for a period of several minutes to many hours. Preferably, the reaction is carried out at a pH between about 6 and about 10, at a temperature between about 4 and about 37 degrees Celsius, and for a period of about 1 to about 3 hours. Those skilled in the art will recognize that the precise reaction conditions for a particular bioprosthetic tissue can be determined by routine experimentation, using methods known in the art.
[0088] One chemical target within the invention is the permanent “capping” of the acid groups which dramatically reduces their ability to attract calcium, phosphate, immunogenic factors, or other groups. The term “capping” refers to the blocking, removal, or alteration of a functional group that would have an adverse effect on the bioprosthesis properties. For example, the addition of 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDC), N-hydroxysulfosuccinimide (sulfo-NHS) and ethanolamine will effectively cap the acid groups with a non-reactive esters.
[0089] Preferably, the capping agent is capable of reacting with aldehydes or acids produced by oxidation of vicinal diols and/or by chemical fixation with an aldehyde fixative agent (e.g., glutaraldehyde) to form imines or esters under conditions suitable for maintaining the structure and function of the bioprosthetic implant. In various aspects, the capping agent can be an amine, an alkyl amine (e.g., ethylamine or isopropylamine), a hydroxyl amine (e.g., ethanolamine), an aminoether (e.g., 2-methoxyethylamine), an amino sulfonate (e.g., taurine, amino sulfates, dextran sulfate, or chondroitin sulfate), an amino acid (e.g., lysine or beta-alanine), a hydrophilic multifunctional polymer (e.g., polyvinyl alcohol or polyethyleneimine), hydrophobic multifunctional polymer (α-dicarbonyls, methylglyoxal, 3-deoxyflucosone, or glyoxal), a hydrazine (e.g., adipic hydrazide), mono-, di- or polyepoxy alkanes, or combinations thereof.
[0090] In some aspects, the capping agent is a monoamine. Without being limited by a particular theory, it is believed that certain agents comprising two or more primary amine groups can mediate cross-linking and other non-specific reactions within the bioprosthetic tissue. In some preferred aspects, the capping agent is selected from ethanaolamine, taurine (2-aminoethanesulfonic acid), 2-methoxyethylamine, and ethylamine. Advantageously, using a monoamine capping agent converts free aldehydes within a bioprosthetic tissue into stable secondary amines without forming residual reactive groups and/or altering the basic structural and/or mechanical properties of the tissue. Advantageously, using an alcohol capping agent such as ethanolamine, acids produced by oxidation of vicinal diols can be converted into stable esters without forming residual reactive groups and/or altering the basic structural and/or mechanical properties of the tissue.
[0091] In some aspects, the capping reaction is performed concurrently with vicinal diol oxidation to prevent sequential oxidation of aldehydes to carboxylic acids. The reaction can be carried out under essentially similar conditions as described above for oxidation. In further aspects, the bioprosthetic tissue is washed to remove the oxidation agent prior to treatment with the reducing agent.
[0092] In some preferred aspects, the bioprosthetic tissue is pre-treated with a chemical fixative agent, such as glutaraldehyde. Fixation limits potential cross-reactivity between aldehydes formed by oxidation and other reactive moieties within the tissue by extensively cross-linking the tissue and/or modifying reactive functionalities. For example, primary amines found on lysine and hydroxylysine residues of collagens and other proteins comprising the extracellular matrix can potentially compete with the capping agent in reactions with aldehydes formed by oxidation of vicinal diols and such competing reactions can have a negative impact on the structure and/or stability of the tissue. Chemical fixation with an aldehyde fixative agent, such as glutaraldehyde, substantially eliminates such competing reactions by cross-linking reactive amines within the tissue and stabilizing the overall tissue structure.
[0093] In some aspects, a bioprosthetic tissue is pre-treated with a protecting agent that couples to reactive moieties within the tissue and prevents undesired cross-linking and/or other reactions. For example, lysine amino acid residues may be protected or blocked by a number of methods known in the art, including but not limited to, the use of tert butyloxycarbonyl (Boc), benzyloxycarbonyl (Z), biphenylisopropyloxycarbonyl (Bpoc), triphenylmethyl (trityl), 9-fluoroenylmethyloxycarbonyl (Fmoc) protecting groups. Protecting groups may be preferred in cases where a bioprosthetic tissue is incompatible with chemical fixation, for example because of a need to preserve the native biological structure and/or activity of the tissue.
[0094] Advantageously, treating a fixed and/or oxidized bioprosthetic tissue with a capping agent according to the instant methods eliminates potential binding sites for calcium, phosphate, immune factors, and/or other undesirable factors. In further aspects, treating a bioprosthetic tissue with a capping agent according to the instant methods replaces aldehydes and/or acids within the tissue with a chemical moiety that imparts one or more beneficial properties to the tissue, such as a reduction in local and/or overall net charge, improved hemocompatibility, increased hydration, or improved mechanical flexibility. For example, treating a bioprosthetic tissue with the capping agent taurine replaces aldehydes with a sulfonate group which can be beneficial for tissue hydration, flexibility, and/or compatibility with host tissues. Furthermore, treating a bioprosthetic tissue with the capping agent ethanolamine replaces acids with ester moieties, thereby improving the biocompatibility of the tissue.
[0095] A “stabilizing agent” according to the present methods includes any chemical agent capable of reacting with free aldehyde or acid moieties. In various aspects, the stabilizing agents are reducing agents. The stabilizing agents are selected from the group consisting of sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, direct atmospheric or high pressure hydrogenation, carbodiimides such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), pyridines such as 2-chloro 1-methylpyridinium iodide (CMPI) and similar Mukaiyama's condensation reagents, and others known to those skilled in the art.
[0096] In some aspects, the present capping process can include chemical reduction of the tissue, which, when applied to the tissue in the presence of a capping agent, will permanently connect the capping agent to the target group. For example, the addition of ethanolamine to the tissue will cap the aldehyde groups, while the reducing agent (e.g., sodium borohydride) reduces any Schiff base created by reaction of the aldehyde with the amine group of ethanolamine. Thus an aldehyde is ultimately replaced by a stable chemical moiety, which may be beneficial for tissue hydration, flexibility, and cell interactions. Of course, other capping agents can be used instead of ethanolamine and other reducing agents other than sodium borohydride and are known by those skilled in the art and which are included in the scope of this patent. Another strategy provided by the present methods is to oxidize the tissue aldehydes to acids, and then cap the acid groups. This may involve the addition of 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride (EDC), N-hydroxysulfosuccinimide (sulfo-NHS), or ethanolamine. These new “capped” groups will reduce the attraction of calcium, phosphate, immunogenic factors, or other similar agents.
[0097] In some aspects, the stabilizing agent is a reducing agent. A “reducing agent” according to methods provided herein is any agent capable of converting esters to amides or imines to secondary amines. In various aspects, the stabilizing agent is a reducing agent and can convert imines to secondary amines as shown in the reaction scheme below. As shown below, imines (4) produced by reaction of the capping agent with aldehydes (2) are reduced to form secondary amines (5) by using a suitable reducing agent.
[0098] Imine Reduction:
[0000]
[0099] Imine reduction may be carried out under essentially the same conditions described above for the periodate oxidation and capping agent steps. In some aspects, imine reduction is carried out in a neutral or slightly basic solution, at a temperature between about 0 and about 50 degrees Celsius, and for a period of about a few minutes to many hours. Preferably, the pH is between about 6 and about 10, the temperature is between about 4 and about 37 degrees Celsius, and the reaction period is between about 3 to about 8 hours. In some aspects, the complete sequence of reactions is complete within about 24 hours.
[0100] The reaction of an aldehyde moiety (R 1 CHO) with the primary amine moiety (R 3 NH 2 ) of a capping agent produces a hemiaminal intermediate which forms the imine in a reversible manner through the loss of H 2 O. In some aspects, the bioprosthetic tissue is treated with the capping agent separately from treatment with the reducing agent. The isolated imine reaction product is then converted to a secondary amine with a suitable reducing agent, such as but not limited to, sodium borohydride.
[0101] In some preferred aspects, the bioprosthetic tissue is treated with the reducing agent concurrently with the capping agent, such that imine formation and reduction of the hydrolytically unstable imine occur concurrently to form a secondary amine. In some preferred aspects, the bioprosthetic tissue is treated concurrently with the capping agent and a reducing agent that is selective for imines relative to aldehydes and/or ketones, such as but not limited to, sodium cyanoborohydride (NaBH 3 CN), sodium triacetoxyborohydride (NaBH(OCOCH 3 ) 3 ), or a combination thereof.
[0102] In some aspects, aldehydes produced by oxidation and/or chemical fixation are reductively aminated directly, without formation of the intermediate imine, by treating a periodate oxidized bioprosthetic tissue with a reducing agent in an aqueous environment, e.g., as described in Dunsmore et al., J. Am. Chem. Soc., 128(7): 2224-2225 (2006).
[0103] In a particular aspect, an oxidation/capping and stabilization scheme is used involving the treatment of the tissue with a periodic acid salt to selectively cleave the vicinal diols of the carbohydrates, followed by treatment of the tissue with a secondary mild oxidizing agent such as sodium chlorite or hydrogen peroxide to convert the aldehydes to acids; then capping the acids with a capping agent selected from the group consisting of N-hydroxysuccinamide and N-hydroxysulfosuccinamide to form an ester; and then stabilizing the cap by converting the ester to an amide by the action of a carbodiimide stabilizing agent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC).
[0104] Also provided herein is a method for improving the performance of a bioprosthetic implant, the method including: obtaining the bioprosthetic tissue, wherein the bioprosthetic tissue is a fresh tissue; decellularizing the bioprosthetic tissue; fixing the bioprosthetic tissue with a fixation agent comprising glutaraldehyde; exposing the tissue to an initial bioburden reduction solution; at least partially fabricating a bioprosthetic product or device; treating the at least partially fabricated bioprosthetic tissue product or device with a second bioburden reduction solution comprising formaldehyde, ethanol, and a Tween® solution; treating the at least partially fabricating bioprosthetic product or device with a periodate, wherein the tissue expresses an antigenic carbohydrate including a vicinal diol, and wherein the vicinal diol is oxidized by the periodate to form an aldehyde; treating the bioprosthetic tissue with a capping agent, wherein the capping agent comprises a primary amine, and wherein the primary amine reacts with the aldehyde to form an imine; treating the bioprosthetic tissue with a reducing agent, wherein the reducing agent reacts with the imine to form a secondary amine; drying the bioprosthetic tissue; and sterilizing the at least partially fabricated bioprosthetic product or device with ethylene oxide.
[0105] Also provided herein is a method for improving the performance of a bioprosthetic implant, the method including: obtaining the bioprosthetic tissue, wherein the bioprosthetic tissue is a fresh tissue; decellularizing the bioprosthetic tissue; fixing the bioprosthetic tissue with a fixation agent including glutaraldehyde; exposing the tissue to an initial bioburden reduction solution, at least partially fabricating a bioprosthetic tissue product or device; treating the at least partially fabricated bioprosthetic tissue product or device with a second bioburden reduction solution including formaldehyde, ethanol, and a Tween® solution; treating the at least partially fabricated bioprosthetic product or device with a periodate, the tissue expressing an antigenic carbohydrate including a vicinal diol, wherein the vicinal diol is oxidized by the periodate to form an aldehyde; treating the bioprosthetic tissue with a capping agent, wherein the capping agent includes a primary amine, wherein the primary amine interacts with the aldehyde to form an imine; treating the bioprosthetic tissue with a reducing agent, wherein the reducing agent interacts with the imine to form a secondary amine; drying and electrophoretically cleaning the bioprosthetic tissue; and sterilizing the at least partially fabricated bioprosthetic product or device with ethylene oxide.
[0106] Also provided herein is a method for improving the performance of a bioprosthetic implant, the method including: obtaining the bioprosthetic tissue, wherein the bioprosthetic tissue is a fresh tissue; decellularizing the bioprosthetic tissue; fixing the bioprosthetic tissue with a fixation agent including glutaraldehyde; exposing the tissue to an initial bioburden reduction solution; at least partially fabricating a bioprosthetic product or device; treating the at least partially fabricated bioprosthetic tissue product or device with a second bioburden reduction solution including formaldehyde, ethanol, and a Tween® solution; treating the at least partially fabricated bioprosthetic product or device with a periodate, the tissue expressing an antigenic carbohydrate including a vicinal diol, wherein the vicinal diol is oxidized by the periodate to form an aldehyde; treating the bioprosthetic tissue with a capping agent, wherein the capping agent includes a primary amine, wherein the primary amine interacts with the aldehyde to form an imine; treating the bioprosthetic tissue with a reducing agent, wherein the reducing agent interacts with the imine to form a secondary amine; drying and electrophoretically cleaning the bioprosthetic tissue; and sterilizing the at least partially fabricated bioprosthetic product or device glutaraldehyde.
[0107] Also provided herein is a method for improving the performance of a bioprosthetic implant, the method including: obtaining the bioprosthetic tissue, wherein the bioprosthetic tissue is a fresh tissue; decellularizing the bioprosthetic tissue; fixing the bioprosthetic tissue with a fixation agent including glutaraldehyde; exposing the tissue to an initial bioburden reduction solution; at least partially fabricating a bioprosthetic product or device; treating the at least partially fabricated bioprosthetic tissue product or device with a second bioburden reduction solution including formaldehyde, ethanol, and a Tween® solution; treating the at least partially fabricated bioprosthetic product or device with a periodate, the tissue expressing an antigenic carbohydrate including a vicinal diol, wherein the vicinal diol is oxidized by the periodate to form an aldehyde; treating the bioprosthetic tissue with a capping agent, wherein the capping agent includes a primary amine, wherein the primary amine interacts with the aldehyde to form an imine; treating the bioprosthetic tissue with a reducing agent, wherein the reducing agent interacts with the imine to form a secondary amine; drying and electrophoretically cleaning the bioprosthetic tissue; and sterilizing the at least partially fabricated bioprosthetic product or device drying and electrophoretically cleaning the bioprosthetic tissue; and sterilizing the bioprosthetic tissue with ethylene oxide.
[0108] In various aspects, bioprosthetic tissues subject to methods provided herein may be pre-treated with one or more secondary stabilizing agents, including but not limited to, a fixative agent and/or a skinning agent.
[0109] The instant methods are compatible with fresh, partially and fully fixed bioprosthetic tissues. Fixative agents useful for pre-treating bioprosthetic tissues used in methods provided herein include, but are not limited to, aldehydes (e.g., formaldehyde, glutaraldehyde, dialdehyde starch, acrolein, glyoxal acetaldehyde), polyglycidyl ethers (e.g., Denacol 810), diisocyanates (e.g., hexamethylene diisocyanate), carbodiimide(s), and epoxides (e.g., any of the various Denacols and their individual reactive species, including mono, di, tri, and multi-functionalized epoxides). In some preferred aspects, the bioprosthetic tissue has been previously fixed with glutaraldehyde, which has proven to be relatively physiologically inert and suitable for fixing a variety of biological tissues for subsequent surgical implantation (Carpentier, A., J. Thorac. Cardiovasc. Surg. 58:467-68 (1969)). An exemplary protocol for glutaraldehyde pre-treatment is set forth in Example 1. Fixation with glutaraldehyde or another fixative agent can provide a variety of benefits, including increased stability, increased durability, improved preservation, increased resistance to proteolytic cleavage.
[0110] In some aspects, the bioprosthetic implant is a commercially available bioprosthetic heart valve, such as the Carpentier-Edwards® stented porcine bioprosthesis, Edwards Lifesciences, Irvine, Calif., the Carpentier-Edwards® Pericardial Bioprosthesis, Edwards Lifesciences, Irvine, Calif., or the Edwards® PRIMA Stentless Aortic Bioprosthesis, Edwards Lifesciences AG, Switzerland, which has been treated according to a method provided herein.
[0111] In further aspects, the bioprosthetic tissue is a fresh, non-fixed xenographic tissue harvested from a mammalian host, which is treated according to methods provided herein and implanted into a host subject.
[0112] The tissue to be treated can be freshly harvested from an abattoir, it can be washed and pre-treated with various decellurizing agents, and/or it can be at least partially fixed with fixative agents. After the stabilization step, the tissue can also be treated by decelluarization methods, various fixation methods, bioburden reduction, drying and glycerolization, and final sterilization steps. It is understood that in general some or all of the sequential steps can be combined into simultaneous steps e.g., the oxidation and capping step, the capping and stabilization steps, or all three steps can react in concert. Likewise some or all of the pre- and post-carbohydrate antigen mitigation steps can be combined into a smaller set of various simultaneous steps.
[0113] A number of surfactants may be used in accordance with the present methods, including but not limited to, anionic surfactants (e.g., esters of lauric acid, including but not limited to, sodium dodecyl sulfate), alkyl sulfonic acid salts (e.g., 1-decanesulfonic acid sodium salt), non-ionic surfactants (e.g., compounds based on the polyoxyethylene ether structures, including Triton X-100, 114, 405, and N-101 available commercially from Sigma Chemical, St. Louis, Mo., and related structures, and pluronic and tetronic surfactants, available commercially from BASF Chemicals, Mount Olive, N.J.), alkylated phenoxypolyethoxy alcohols (e.g., NP40, Nonidet P40, Igepal, CA630, hydrolyzed/functionalized animal and plant compounds including, Tween® 80, Tween® 20, octyl-derivatives, octyl b-glucoside, octyl b-thioglucopyranoside, deoxycholate and derivatives thereof, zwitterionic compounds, 3-([cholamidopropyl]-dimethyl ammonio-1-propanesulfonate (CHAPS), 3-([cholamidopropyl]-dimethyl ammonio)-2-hydroxy-1-propanesulfonate (CHAPSO)), and mixtures thereof (e.g., deoxycholate/Triton, Micro-80/90).
[0114] In some aspects a tissue is treated with a cell disrupting agent. Cell disrupting agents can include a hypotonic saline of 0% to 0.5% NaCl, non-ionic, anionic, and/or cationic detergents, and surfactants, e.g., Tweens, sodium dodecyl sulfate (SDS), sodium deoxycholate, tetradecyl ammonium chloride, and benzalkonium chloride. In one aspect, CHAPSO in the range of 0% to 5% can be used as a cell disrupting agent.
[0115] In some aspects a tissue is treated with a proteolytic inhibitor including, e.g., Protinin or EDTA.
[0116] In some aspects a tissue is treated with a lipid, phospholipid, cell membrane, and/or cell remnant extracting agent. Such extracting agents can include alcohols (e.g., ethanol, 2-propanol, or n-decanol in the concentration range of 1% to 100%); ketones (e.g., acetone, methyl ethyl ketone); ethers (e.g., diethyl ether, tetrahydrofurane, 2-methoxy ethanol); surfactants and detergents (e.g., Tweens®, sodium dodecyl sulfate (SDS), sodium deoxycholate, tetradecyl ammonium chloride, benzalkonium chloride); CHAPSO; or Supercritical fluids (e.g., CO 2 , NO).
[0117] In some aspects a tissue is treated with an anti-antigenic enzyme (e.g., DNAse, RNAse).
[0118] In some aspects a tissue is treated with a bioburden reducing agent, including: antibiotics (e.g., penicillin, streptomycin); alcohols (e.g., ethanol, 2-propanol, n-decanol in the concentration range of 1% to 100%); aldehydes (e.g., formaldehyde, acetaldehyde, glutaraldehyde in the range of 0% to 5%).
[0119] In one aspect, a tissue is treated with a bioburden reducing solution that is a combination of formaldehyde, ethanol, and tween-80 (FETs) in a concentration of about 1%/22.5%/0.1%, respectively.
[0120] In some aspects, a fabrication device is used for at least partially fabricating a bioprosthetic product or device. The fabrication device can be any device that is suitable for the assembly of a bioprosthetic product or device.
[0121] Those skilled in the art will appreciate that various alternative agents suitable for pre-treating bioprosthetic tissues are known in the art and may be substituted for those indicated herein.
[0122] Having now generally described the invention, the same will be more readily understood through reference to the following examples which are provided by way of illustration, and are not intended to be limiting of the disclosed invention, unless specified.
EXEMPLARY ASPECTS
Example 1
Tissue Pre-Treatment
[0123] Prior to chemically modifying the antigenic carbohydrates in a xenographic bioprosthetic tissue, the tissue may optionally be pre-treated by exposure to cross-linking agents and/or surfactants. The following non-limiting procedure sets forth one potential tissue pre-treatment protocol that produces fixed tissues. Those skilled in the art will appreciate that various alternative methods, chemical compounds, or solutions may be substituted for those indicated.
Step 1: Harvest/Prepare Biological Tissue
[0124] A desired biological tissue is harvested (surgically removed or cut away from a host animal) at a slaughterhouse, placed on ice, and transported to the location at which the bioprosthesis will be manufactured. Thereafter, the tissue is typically trimmed and washed with a suitable washing solution, such as a saline solution, sterile water, or a basic salt solution. For example, harvested tissues can be rinsed, washed, and/or stored in a phosphate or non-phosphate buffered saline solution that includes an organic buffering agent suitable for maintaining the solutions at a physiologically compatible pH without deleterious effects to the tissue. Both phosphate and non-phosphate buffering agents are suitable for tissue processing. The following buffering agents, at a concentration of about 10 mM to about 30 mM, are generally suitable for non-phosphate buffered saline solutions used herein: acetate, borate, citrate, HEPES (N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid), BES (N,N-bis[2-hydroxyethyl]-2-amino-ethanesulfonic acid), TES (N-tris[hydroxymethyl]methyl-2-aminoethanesulfonic acid), MOPS (morpholine propanesulfonic acid), PIPES (piperazine-N,N′-bis[2-ethane-sulfonic acid]), or MES (2-morpholino ethanesulfonic acid). The buffering agent HEPES, which has a pKa of about 7.4, is well-suited for tissue processing. Advantageously, the use of a non-phosphate buffered organic saline solution typically decreases the likelihood of calcium precipitation on a bioprosthetic tissue.
[0125] Buffered saline solutions used in the instant methods may also comprise a chelating agent, which preferably binds divalent cations, such as calcium, magnesium, zinc, and manganese. Examples of suitable chelating agents include EDTA (ethylenediaminetetraacetic acid), EGTA (ethylenebis(oxyethylenenitrilo)tetraacetic acid), ethylenebis(oxyethylenenitrilo)tetraacetic acid, citric acid or salts thereof, and sodium citrate, at concentrations of about 20 mM to about 30 mM. Advantageously, the removal of divalent cations by the chelating agent renders the tissue less susceptible to spontaneous precipitation of the divalent ions with phosphate ions that may be present in the tissue.
[0126] In one aspect, the non-phosphate buffered organic saline solution is isotonic and comprises about 0.9 wt-% saline, about 10 mM to about 30 mM HEPES buffer, pH 7.4, and about 20 mM to about 30 mM of EDTA.
Step 2: Glutaraldehyde Fixation of Biological Tissue
[0127] The harvested, trimmed and washed tissue is disposed within a container filled with a 0.625% solution of glutaraldehyde comprising approximately 26 ml/l glutaraldehyde (25%); approximately 4.863 g/l HEPES buffer; approximately 2.65 g/l MgCl 2 .6H 2 O; and approximately 4.71 g/l NaCl. The balance of the solution comprises double filtered H 2 O, NaOH is added to adjust the pH to approximately 7.4. The glutaraldehyde solution can optionally contain a sterilant (e.g., 2% (w/w) ethanol) and/or a skinning agent (e.g., 1% (w/w) Tween® 80). Where the glutaraldehyde solution contains a sterilant and/or skinning agent, the tissue is incubated at a controlled temperature (e.g., between about 20 to 37° C.) with continuous circulation of the solution for a period of between about 2 to 24 hours, typically about 9 hours. The tissue is then washed and incubated in glutaraldehyde solution without sterilant or skinning agent at a controlled temperature (e.g., 50+/−5° C.) with continuous circulation for a period of between about 7 to 14 days to complete glutaraldehyde fixation. Room air is allowed to blanket or cover the glutaraldehyde solution throughout the process. Glutaraldehyde fixed tissues prepared according to the instant methods are preferably fixed under conditions that allow the tissues to be immersed in 6N hydrochloric acid at 110° C. for 5 days with minimal degradation.
Step 3: Assembly/Fabrication of Prosthesis
[0128] After completion of Steps 1 and 2, the tissue is rinsed with a suitable rinsing solution such as buffered saline or 0.625% glutaraldehyde. Thereafter, the tissue may be transported into a clean room or aseptic environment, further trimmed or shaped (if necessary) and assembled with any non-biological components (e.g., stents, frames, suture rings, conduits, segments of polyester mesh to prevent suture tear-through, etc.) to form the desired implantable bioprosthetic device.
Example 2
Selective Chemical Modification of Antigenic Carbohydrates
[0129] Chemical modification of antigenic carbohydrates in a xenographic bioprosthetic tissue, as described herein, may be performed whether or not the tissue is pre-treated. The following non-limiting procedure sets forth methods for chemically modifying select antigenic carbohydrates in either scenario.
[0130] After the bioprosthetic tissue has been rinsed and stored, the tissue is preferably immersed in isotonic buffered saline solution containing a periodate oxidizing agent, such as sodium periodate, at a concentration of about 20 mM for a period of about 20 minutes at room temperature with constant agitation.
[0131] After treatment with the periodate oxidizing agent, the tissue is rinsed extensively in 20% ethanol to completely remove the periodate, preferably in a vessel allowing a large solution to tissue volume ratio to create a favorable gradient for solute diffusion.
[0132] The tissue is then immersed in a solution containing a primary amine capping agent and a reducing agent suitable for converting any free aldehydes within the tissue to secondary amines. In one method, the tissue is immersed in isotonic buffered saline solution with a pH of 8.5 containing a capping/reducing solution comprised of taurine and isoproplyamine 50%/50% 20 mM and 10 mM sodium borohyride at room temperature for a period of about 10 minutes with constant agitation. The tissue is then washed and treatment with the capping/reducing solution is repeated for a total of three 10 minute treatments with the capping/reducing solution.
[0133] The bioprosthetic tissue is removed from the capping/reducing agent solution, rinsed in 20% ethanol, and transferred to a container and fully immersed in a phosphate-buffered storage solution comprising 0.25% glutaraldehyde, formaldehyde, ethanol, and Tween® (pH adjusted to 7.4 with HCl and NaOH). Thereafter, the container is sealed and placed in an oven where it is heated to a terminal sterilization temperature of 37.5+/−2.5° C. for 25 to 27 hours. The container is then cooled to room temperature and stored until the time of implantation.
Example 3
Treatment of Un-Fixed Tissue with Periodate
Tissue Treatment
[0134] Bovine pericardial tissue (National Beef, Item # 192769001, WO# 58745266) was treated to mask antigens by the following procedure. Tissue was soaked in a phosphate buffer containing 10 mM ethanolamine (Alfa Aesar, #36260) with pH 7.0±0.5 or 10 mM taurine with 7.0±0.5 pH (Sigma, #T0625). In both treatment groups, sodium periodate (Sigma, #311448) was added to yield a 20 mM solution with 7.0±0.5 pH. Tissue from the two groups was incubated in one of three ways: 1) shaking at 4° C. for 18 hours (New Brunswick Scientific, Innova 4230, refrigerated incubator/shaker) 2) shaking at room temperature for 3 hours (VWR, Model 1000, orbital shaker) and 3) shaking at 37° C. for 30 min. (VWR, Model 1570, orbital shaker/incubator). After treatment the tissue was rinsed thoroughly in 0.9% saline (Baxter, #2F7124). The tissue was then incubated in ethanolamine and sodium borohydride (Sigma, #452882) for 1 hour at room temperature while shaking. Once again tissue was rinsed thoroughly in saline. One piece of tissue was placed in 10% Neutral Buffered Formalin (Lazer Scientific, NBF-4G) the remaining tissue was frozen in liquid nitrogen and stored at −80° C. for future analysis.
Histochemical Procedure
[0135] Tissue samples from each group were processed according to standard paraffin embedding procedure. Tissue was fixed overnight in neutral buffered formalin. Tissue was then dehydrated through a series of graded alcohol (Harleco, #65347); 70%, 80%, 95% and 100% and cleared in xylene (EMD Sciences, #XX0060-4) before being embedded in paraffin wax (McCormick Scientific, Para-Plast Plus #502004) using histology tissue processor (Sakura, Tissue-Tek VIP-1000). Each sample was then embedded into a wax block (Miles Scientific embedding station) and sectioned at ˜5 μm using a rotary microtome (Reichert, HistoStat). The resulting slides (Fisher, #15-188-51) were heat-fixed overnight before staining.
[0136] Tissue from each slide was stained with standard H&E procedure and immunohistochemistry, for the presence of α-galactose. Paraffin was removed by incubating in Xylene and rehydrated through a series of graded alcohol; 100%, 95% 80% and water. For H&E, slides were stained with Gill modified hematoxylin (Harleco, #65065), followed by staining in Eosin Phloxine (ENG Scientific, #8923). After staining, slides were dehydrated and mounted (Fisher permount, # SP-15). Slides for immunohistochemistry were incubated in isolectin-GS IB 4 conjugated to Alexa Fluor 488 (1:500, Invitrogen, I21411) in PBS, for 2 hrs at 37° C.
Results
[0137] Fresh, unfixed tissue was subjected to periodate treatments, with or without treatment according to the methods described herein (oxidizing agent such as periodate, capping agent, and reducing agent). FIG. 2 shows immunohistochemistry for α-Gal expression following NexGen treatments of un-fixed tissues. FIG. 2A shows fresh, un-fixed tissue treated according to the methods described herein. FIG. 2B shows fresh, un-fixed tissue treated with periodate only. The combined treatment of fresh, unfixed tissues according to the methods described herein completely inhibits the binding of α-Gal antibody to the tissue compared to control tissue treated with periodate only.
[0138] FIG. 3 shows immunohistochemistry for α-Gal expression on un-fixed tissues treated with various types of periodate solutions. FIG. 3A shows un-fixed tissue treated with an in-house decell periodate. FIG. 3B shows un-fixed tissue treated with a Lifenet decell periodate. FIG. 3C shows un-fixed tissue treated with another commercial decell periodate.
Example 4
Treatment of Fixed Tissue with Periodate
Tissue Treatment
[0139] Thermafix (tissue fixation followed by heat treatment; TFX) treated pericardial tissue was obtained from isolation. Tissue was rinsed in three changes of 0.9% saline (Baxter, #2F7124) before being soaked in a phosphate buffer containing 10 mM ethanolamine (Alfa Aesar, #36260) and 20 mM sodium periodate (Sigma 311448) or 10 mM taurine (Sigma, #T0625) with 20 mM sodium periodate. Tissue from the both groups was incubated at room temperature for 3 hours while shaking (VWR, Model 1000, orbital shaker). After treatment the tissue was rinsed thoroughly in 0.9% saline. The tissue was then incubated in 0.06% ethanolamine and 0.25% sodium borohydride (Sigma, #452882) for 1 hour at room temperature while shaking. Once again tissue was rinsed thoroughly in saline. Tissue from each group was stored in 0.625% glutaraldehyde (EW # 400611) and the remaining tissue was incubated in 75% glycerol (JT Baker, #4043-01)/25% ethanol (EMD, #EX0276-3) for one hour at room temperature. Tissue was then laid out on absorbent pads to remove excess glycerol solution. One piece from each group was placed in 10% Neutral Buffered Formalin (Lazer Scientific, NBF-4G).
Histochemical Procedure
[0140] Tissue samples from each group were processed according to standard paraffin embedding procedure. Tissue was fixed overnight in neutral buffered formalin. Tissue was then dehydrated through a series of graded alcohol (Harleco, #65347); 70%, 80%, 95% and 100% and cleared in xylene (EMD Sciences, #XX0060-4) before being embedded in paraffin wax (McCormick Scientific, Para-Plast Plus #502004) using histology tissue processor (Sakura, Tissue-Tek VIP-1000). Each sample was then embedded into a wax block (Miles Scientific embedding station) and sectioned at ˜5 μm using a rotary microtome (Reichert, HistoStat). The resulting slides (Fisher, #15-188-51) were heat-fixed overnight before staining.
[0141] Tissue from each slide was stained with standard H&E procedure and immunohistochemistry, for the presence of a-galactose. Paraffin was removed by incubating in Xylene and rehydrated through a series of graded alcohol; 100%, 95% 80% and water. For H&E, slides were stained with Gill modified hematoxylin (Harleco, #65065), followed by staining in Eosin Phloxine (ENG Scientific, #8923). After staining, slides were dehydrated and mounted (Fisher permount, # SP-15). Slides for immunohistochemistry were incubated in solutions according to typical immunohistochemical staining with PBS (GBiosciences, #R028) rinses in between each step; 3% hydrogen peroxide (Sigma, #216763) in methanol (EMD, #MX0475P-1) for 15 minutes, 1% albumin, bovine serum (BSA, Sigma #A7030) in PBS with Tween® 20 (VWR, BDH4210) for 30 minutes, isolectin-GS IB 4 conjugated to biotin (1:2000, Invitrogen, 121414) in PBS for 1 hr at room temperature, Vectastain ABC reagent (Vector Laboratories, PK-1600) for 30 minutes and diamino-benzidine (DAB) reagent kit (KPL #54-10-00) for less than 3 minutes. Tissue was counterstained with Hematoxylin (Harleco, #65065) for 1 minute and dehydrated in alcohol series before mounting in permount (Fisher, SP-15).
Results
[0142] Fixed tissue was subjected to TFX, with or without treatment with periodate and/or capping with sodium borohydride and either ethanolamine or taurine.
[0143] FIG. 4 shows that tissue fixed with glutaraldehyde has severe autofluorescence. The tissue shown was treated with TFX and periodate. Isolectin dye was used for staining.
[0144] TFX tissue was treated with formaldehyde bioburden reduction process (fBReP), then terminal liquid sterilization (TLS), and then stored in glutaraldehyde. FIG. 5 shows α-Gal and DNA expression on fixed tissue treated with TFX only. FIG. 5 also shows a flow-diagram of the process used for this experiment, also described above. The presence of brown staining demonstrates the inability of TFX treatment alone to block the binding of α-Gal antibody to the fixed tissue.
[0145] TFX/fBReP tissue was subjected to periodate treatment followed by capping and then stored in glutaraldehyde. FIG. 6 shows the combined treatment of fixed tissue with TFX and periodate, a capping agent, and a reducing agent. The upper panels show tissue treated with ethanolamine as the capping agent. The lower panels show tissue treated with taurine as the capping agent. The absence of brown staining demonstrates the inability of α-Gal antibody to bind the fixed tissue following the combined treatment.
[0146] TFX tissue was subjected to capping and ethanol/glycerol drying followed by ethylene oxide terminal gas sterilization. FIG. 7 shows the results of this treatment, and also shows a flow-diagram of the process used for this experiment, also described above. The presence of staining demonstrates the inability of TFX treatment combined with capping to block the binding of α-Gal antibody to the tissue.
[0147] TFX tissue was subjected to treatment with periodate, a capping agent, a reducing agent, and drying. FIG. 8 shows the results of fixed tissue having received such combined treatment. The upper panels show tissue treated with ethanolamine as the capping agent. The lower panels show tissue treated with taurine as the capping agent. The absence of dark staining demonstrates the inability of α-Gal antibody to bind the fixed tissue following the combined treatment.
Example 5
Comparative Analysis of Tissue Treatments
[0148] Relative levels of free α-Gal in variously treated tissues were compared by an ELISA assay. Six tissue samples were treated by distinct combinations of fixation/non-fixation; treatment according to the methods described herein (vic Diol oxidation, treatment with a capping agent and treatment with a stabilizing agent); TFX treatment; capping, reduction and drying; and glutaraldehyde treatment alone. The six tissue treatments compared are as follows: (1) unfixed bovine pericardium; (2) Treatment A: unfixed, bovine pericardium treated with a vic Diol oxidizing agent, a capping agent and a stabilizing agent; (3) Treatment B: TFX-treated bovine pericardium; (4) Treatment C: bovine pericardium treated with a combination of TFX treatment and a vic Diol oxidizing agent, a capping agent and a stabilizing agent; (5) Treatment D: bovine pericardium treated with a capping agent, a reducing agent, and then dried; (6) Treatment E: bovine pericardium treated with a combined treatment of a vic Diol oxidizing agent, a capping agent and a reducing/stabilizing agent and drying; and (7) glutaraldehyde-fixed primate pericardium.
[0149] Following tissue treatment as specified above and in FIG. 9 , each sample was incubated with isolectin-B4, which is known to specifically bind to α-Gal. After overnight incubation, the isolectin-B4 remaining in solution was measured using a standard ELISA assay. Specifically, the tissue samples were cut into small pieces, frozen in liquid nitrogen and ground into a powder. A solution of biotin conjugated, IB 4 -isolectin (Invitrogen #121414) and 1% BSA (Albumin, bovine serum; Sigma # A7030) were added to the ground tissue and incubated @ 37° C. overnight. The samples were then centrifuged to pellet tissue pieces to the bottom of the tube and the supernatant was transferred to a new tube. Samples were diluted before adding to the plate for IB 4 -isolectin quantification.
[0150] As ELISA assay was performed using Isolectin-B4 in 1% BSA as a standard. Plates were coated with synthetic α-Gal-BSA (V-Labs, Ca t #NGP1334) in carbonate buffer overnight at 4° C. The plate was washed three times with PBS containing Tween (0.01%) and then blocked in 1% BSA for 2 hours at 37° C. A standard curve using Isolectin was added to the plate and the diluted samples from above were added to the plate in triplicate. These were incubated for 1 hr at 37° C. The plate was washed 3 times with PBS-Tween. Vectastain substrate (Vector Labs, cat# PK-6100) was added to the plate and incubated for 30 minutes at room temperature. The plate was washed 3 times with PBS-Tween and once with PBS only. Residual PBS was carefully removed using an aspirator. Quantablu fluorescent substrate (Pierce, Cat#15169) was added and the plate was incubated for 20 minutes. Stop solution was then added and the plate was read on a plate reader (Excitation: 320 nm, Emission: 420 nm).
[0151] The concentration of isolectin-B4 remaining in solution was used to calculate the percent of total isolectin that is inhibited by the treated tissue relative to a control. FIG. 9 shows the results of the in vitro α-Gal ELISA assay for the variously treated tissues. As demonstrated in FIG. 9 , the tissues treated with the methods described herein exhibited a significant reduction in binding between α-Gal and isolectin-B4. These results indicate that the presently claimed tissue treatment methods significantly reduce the quantity of free α-Gal epitopes and thus reduce the antigenicity of treated tissues.
Example 6
Anti-α-Gal IgG Primate Study
[0152] A series of comparative analyses were conducting characterizing the anti-α-Gal IgG response in a group of five primates. Animal implantation was performed at MPI Research. Five macaques were used for this study. Different combinations of test groups were implanted in the animals as described below in order to see the immune response to tissue treatments with or without α-Gal. Six 6 mm tissue discs were implanted intramuscularly in the back of each animal. Three discs were implanted on one side and three discs were implanted on the other side. Blood samples (2 ml per time point) were collected before implant (baseline) and at 5, 10, 20, 45, 60, 75, 90, and 125 days after implant. The study was terminated at 135 days. The blood was stored on dry ice and allowed to clot. Each sample was centrifuged and the serum was transferred to a pre-labeled tube and stored in a −70° C. freezer.
[0153] The plate was coated with synthetic α-Gal-BSA (V-Labs, Cat# NGP1334) in carbonate buffer overnight at 4° C. The plate was washed three times with PBS containing Tween (0.01%) and then blocked in 1% BSA for 2 hours at 37° C. The serum from different monkeys and different time points was plated at different dilutions on the plate in duplicate. The serum was incubated for one hour at 37° C. The plate was then washed 3 times in PBS-Tween. The secondary antibody, HRP conjugated, mouse anti-human IgG (Invitrogen, Cat# 05-4220; 1:1000 in 1% BSA) was added to the plate and incubated for 1 hour at room temperature. The plate was washed 3 times with PBS-Tween and once with PBS only. The residual PBS was removed by aspirator and o-phenylenediamine dihydrochloride substrate (Sigma, Cat# P8806) was added and incubated for 20 minutes at room temperature. 3M sulfuric acid was added to stop the solution and the absorbance of the plate is read using a plate reader (@492 nm).
[0154] The first monkey received three glutaraldehyde-treated tissue samples and three TFX-treated tissue samples. Both sample types produced an anti-α-Gal response in the monkey. Previous experiments have demonstrated high calcification for glutaraldehyde and TFX-treated tissues (data not shown). Monkeys two and three each received three capped/reduced/dried tissue samples and three tissue samples treated according to the method described herein. An anti-α-Gal response was observed. Previous experiments have demonstrated low calcification for both of these types of treated tissue samples (data not shown). The fourth monkey received four samples of tissue treated according to the method described herein and two primate tissue samples. Neither the treated tissue samples nor the control produced an anti-α-Gal response. The fifth monkey received six samples of primate pericardium as a control. The primate pericardium did not produce an anti-α-Gal response.
[0155] FIG. 10 shows the percent increase from baseline in the anti-α-Gal IgG response assay for each of the various tissue treatments as described in detail above. As demonstrated in FIG. 10 , the presently claimed tissue treatment significantly suppressed the anti-α-Gal response in xenographic tissue samples.
[0156] The invention being thus described, it will be obvious that the same can be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention, and all such modifications as would be obvious to one skilled in the art are intended to be included within the scope of the following claims. | 1a
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RELATED APPLICATION
The present application claims the benefit under title 35, United States Code, Section ii 9(e) of U.S. provisional application No. 60/362,862, filed Mar. 8, 2002 entitled “SELF LUBRICATING SEX AIDS”.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to self lubricating sex aids for use in avoiding irritation or pain during sexual activities or during auto erotic sex activities, while concomitantly increasing the pleasure of the users or user.
2. Description of the Prior
The use of sex aids of known designs and configurations is well known in the prior art. More specifically, sex aids of known designs and configurations heretofore devised and utilized for the purpose of increasing sexual stimulation through known methods and apparatuses are known to consist basically of familiar, expected, and obvious structural configurations.
Among the large number of prior art sex aids of known designs and configurations are, by way of example, those taught in U.S. Pat. No. 5,690,603 which discloses a sexual stimulator that contains a vibrator and can include a fluid chamber that allows the flow of the fluid from part to part within the sealed chamber; U.S. Pat. No. 6,280,403 which discloses a massage device that includes a sealable chamber to include, for example, warm water, but from which chamber no fluid is allowed to flow to the skin or internal private parts of the user; and U.S. Pat. No. 6,322,493 which teaches a clitoral stimulator that directly dispenses a stimulating compound. None of these prior art systems include normally open through-holes from their chambers to the surfaces of the devices. In fact, as noted, U.S. Pat. Nos. 5,690,603 and 6,280,403 are rigorously designed to avoid allowing any fluid to exit from their chambers during use. It is also noted that during the use of many sex toys it is not unusual to apply moisturizing fluid by hand or by other mean to the skin or internal private parts of the user, thereby requiring unwanted interruptions before or distractions during such activity.
Therefore, it can be appreciated that there exists a previously unappreciated need for a new and improved sex aid that allows a lubricating fluid to exit from normally open through-holes from chambers associated with the device to the surface of the device during use for the purpose of avoiding irritation or pain during sexual activities or during auto erotic sex activities, while concomitantly serving the purpose of increasing the pleasure of the users or user during such activities.
SUMMARY OF THE INVENTION
In this respect, the sex aids according to the present invention substantially depart from the conventional concepts and designs of the prior art, and in so doing has as an object to provide various apparatus primarily developed for the purpose of avoiding irritation or pain during sexual activities or during auto erotic sex activities, while concomitantly increasing the pleasure of the users or user during sexual activity by intentionally having fluid exit through normally open through-holes from chambers associated with the device during use. In this regard, the present invention substantially fulfills a previously unappreciated need.
In view of the limitations inherent in the sex aids of known designs and configurations now known in the prior art, the present invention provides new and improved self-lubricating sex aids that allow the users or user to avoid irritation or pain during sexual activities, or during auto erotic sex activities, while concomitantly increasing the pleasure of the users or user. As such, the general purpose of the present invention, which is described in greater detail below, is to provide a new and improved self lubricating sex aids and methods which have all the advantages of the prior art and none of the disadvantages.
To attain such results, the present invention essentially comprises modifications to sex aid systems to provide new and improved systems for use in avoiding irritation or pain during sexual activities or during self stimulated sex activities, while concomitantly increasing the pleasure of the users or user. The new and improved sex aid systems uniformly comprise the modification of or addition to art known sex aid systems which provides for the self lubrication of the sex aids for the users or user, especially at the surface or surfaces of the sex aid that contact and stimulate the external or internal erotic surfaces of the users or user.
In one format, where the volume and the shape of the sex aid will allow, each new and improved sex aid system is modified to include a hollow chamber associated with the sex aid, either internal or external to the sex aid. Such new and improved sex aids, in accordance with the present invention, are further modified to include at least one or more normally open through-hole extending from the added chamber to the surface portions of each sex aid, and especially to the surface portions of each sex aid that are intended to contact and stimulate the external or internal erotic surfaces of the users or user.
In the operation of the present invention, an off the shelf water-soluble moisturizing fluid, or sterile water or other non-irritating fluid is poured into the hollow chamber. In each instance the moisturizing fluid is preferably inert to both plastic and to rubber. Each such new and improved sex aid system may be manipulated for its desired purpose by the users or user, or may include or be attached to a vibrator device or other energizing apparatus. In operation, external air pressure and the motion or vibration of each new and improved sex aid system causes the fluid present in the hollow chamber to exit through the through-hole or holes to lubricate any external or internal body parts with which the hole or holes are placed in contact.
In another format, where the volume and the shape of the sex aid will not allow it to be modified to include an internal chamber, a fluid reservoir may be provided that is either attached directly to the sex aid or remotely connected, say through a tube, but in either case to normally open through-holes to lubricate any external or internal body parts with which the hole or holes are placed in contact with the device. In such modifications in accordance with the present invention, the attached or remote reservoir is in fluid contact with the new and improved sex aids of the present invention, which sex aids are also modified to include at least one or more hole extending from connection with the reservoir to the surface portions of each such sex aid, and especially to the surface portions of each such sex aid that are intended to contact the external or internal surfaces of the users or user. Those modifications with an added external reservoir also operate in response to external air pressure and the motion or vibration of each new and improved sex aid system, to cause the fluid present in the reservoir to exit through the hole or holes to lubricate any external or internal body parts with which the hole or holes are placed in contact.
It has been determined that the preferred diameter of the through-holes added to the sex aids of the present invention for use with lubricating fluids is in the size range of from about 1.5 mm to about 3.5 mm, although smaller or larger diameter holes, say in the range of from about 0.5 mm to about 5 mm may work, depending on the viscosity of the fluid and the energy output of any associated vibrator or other associated stimulation. The sex aids with which the present invention can be used may be of any hard, soft or pliable material, say plastic, plastic-jelly, simulated skin, rubber, silicone and the like. The sex aids may be active or passive, say vibrating or non-vibrating. Non-limiting examples of the sex aids that may be improved by the present invention are dongs, dongs with simulated testicles, dildos, double dildos, attachable prosthetic penises, strap-on penises with or without an opposed extension, male masturbator tubes, simulated vaginas, blow-up dolls with orifices, activated simulated tongues, anal plugs, anal probes, G-spot vibrators, double dongs, penis rings with clitoral stimulators, female stimulators, and the like, all as are well known in the art. It is also apparent that any and all new sex aids may be modified for the practice of the present invention.
In one specific embodiment, a state of the art hand-held reciprocating vibrator base is connected to a stimulating element. The stimulating element is modified to have an added hollow internal chamber. At least one or more hole extends from the added hollow internal chamber in open fluid contact with the surface of the stimulating element. In operation, an off the shelf water soluble moisturizing fluid is poured into the added hollow internal chamber. When used, vibration and external air pressure causes the moisturizing fluid to egress from the chamber through the holes to lubricate the body parts with which the stimulating element is placed in contact to thereby avoid irritation or pain during sexual activities or during auto erotic sex activities, while concomitantly increasing the pleasure of the users or user and thereby meeting one of the objects of the present invention.
These and other objects of the present invention will become apparent to those skilled in the art from the following detailed description and accompanying drawings, showing the contemplated novel construction, combination, and elements as herein described, and more particularly defined by the appended claims, it being understood that changes in the precise embodiments to the herein disclosed invention are meant to be included as coming within the scope of the claims, except insofar as they may be precluded by the prior art.
BRIEF DESCRIPTION OF THE DRAWINGS
The accompanying drawings, which are incorporated in and form a part of this specification, illustrate complete preferred embodiments of the present invention according to the best modes presently devised for the practical application of the principles thereof, and in which:
FIG. 1 shows an exploded isometric view of one preferred embodiment of a sex toy in accordance with the present invention including a hand held reciprocating vibrator base and a connecting stimulating element sex aid modified in accordance with the present invention;
FIG. 2 shows an inverted isometric view of the stimulating element sex aid portion of FIG. 1 modified in accordance with the present invention,
FIG. 3 shows a cross-sectional view taken along line 3 — 3 of FIG. 1, but including the hand held reciprocating vibrator base connected to stimulating element of a sex aid modified in accordance with the present invention;
FIG. 4 shows an isometric view of another preferred embodiment in the form of a simulated vagina sex toy, to which a male masturbator tube is attached, and including an imbedded vibrating element in accordance with the present invention;
FIG. 5 shows a cross-sectional view taken along line 5 — 5 of FIG. 4 of the simulated vagina sex toy, but with the male masturbator tube not in cross-section in accordance with the present invention;
FIG. 6 shows an explode isometric view of another preferred embodiment, in this embodiment of a double dildo; and
FIG. 7 shows a cross-sectional view taken along line 7 — 7 of FIG. 6 of the double dildo sex toy in accordance with the present invention.
DETAILED DESCRIPTION OF THE INVENTION
Referring now to FIGS. 1-3, one preferred embodiment of the present invention, generally 10 , a state of the art hand-held reciprocating vibrator base 12 , including a standard threaded male extension 14 for connection to a stimulating element 16 , is shown. Stimulating element 16 is shown to be modified to define a hollow internal chamber 18 , FIG. 3, along with a standard threaded internal female receiver 20 . Stimulating element 16 also includes a plurality of through-holes 22 extending in open contact with added hollow internal chamber 18 to provide open fluid contact to the surface of the stimulating element 16 . Holes 22 have a diameter in the size range of from about 1.5 mm to about 3.5 mm. In operation, an off the shelf water-soluble moisturizing fluid 24 is poured from container 26 into internal chamber 18 within stimulating element 16 . The size of through-holes 22 and the viscosity and surface tension of moisturizing fluid 24 is such that the moisturizing fluid 24 tends to stay within internal chamber 18 within stimulating element 16 . As best shown in FIG. 3, hand-held reciprocating vibrator base 12 carries an imbedded electrically powered vibrator motor 28 that may be energized by dry cell batteries 32 removably carried within hand-held reciprocating vibrator base 12 . Base cap 34 is removable to allow access to batteries 32 , and also serves as a rotatable switch to turn electrically powered vibrator motor 28 on and off, and in preferred embodiments to vary the amplitude and speed of electrically powered vibrator motor 28 . In their current embodiment, the exterior of both reciprocating vibrator base 12 and stimulating element 16 are constructed of rigid plastic, although modification of stimulating element 16 to soft rubber or silicone rubber is contemplated as being within the teaching of the present invention.
In operation, after moisturizing fluid 24 has been placed within internal chamber 18 of stimulating element 22 , movement, vibration and external air pressure causes moisturizing fluid 24 to egress from chamber 18 through-holes 22 to lubricate the body parts with which the stimulating element 16 is placed in contact. The presence of moisturizing fluid 24 assists in avoiding irritation or pain during sexual activities or during autoerotic sex activities, while concomitantly increasing the pleasure of the users or user, and without requiring interruptions before or distractions during such activity to apply moisturizing fluid by hand or by other means.
Now referring to FIGS. 4 and 5, another embodiment the present invention is shown. In this embodiment a simulated vagina sex toy, generally 40 , is shown. In the embodiment shown a flaccid soft plastic male masturbator tube 42 , including internal stimulator knobs 43 is attached. Simulated vagina portion 44 is generally toroidal in shape, and, in the embodiment illustrated, includes simulated vaginal lips 46 . As best shown in FIG. 5, included in vagina portion 44 is an electrically powered imbedded reciprocating vibrating element 28 connected by wires 48 to an external battery 32 powered multi-speed battery pack 52 . Also carried by vagina portion 44 is a reservoir 54 including a closure cap 56 . A plurality of internal tubes 58 each extends from hollow reservoir 54 to provide open fluid contact to holes 62 at the surface of simulated vagina portion 44 . As with the previous embodiment, holes 62 have a diameter in the size range of from about 1.5 mm to about 3.5 mm.
In operation, closure cap 56 is opened and an off the shelf water-soluble moisturizing fluid, not shown, is poured into reservoir 54 carried by vagina portion 44 . Once again the size of through-holes 62 and the viscosity and surface tension of the moisturizing fluid is such that the moisturizing fluid tends to stay within through-holes 62 within vagina portion 44 . A rotatable switch 64 integrated with multi-speed battery pack 52 is capable of turning electrically powered vibrator element 28 on and off, and in preferred embodiments, to vary the amplitude and speed of electrically powered vibrator motor 28 . In operation, after moisturizing fluid has been placed within reservoir 54 of vagina portion 44 , after which movement, vibration and external air pressure causes moisturizing fluid to egress from reservoir 54 through-holes 62 to lubricate the body parts with which the vagina portion 44 is placed in contact. The moisturizing fluid assists in avoiding irritation or pain during sexual activities or during autoerotic sex activities, while concomitantly increasing the pleasure of the user, and without requiring interruptions before or distractions during such activity to apply moisturizing fluid by hand or by other means.
In preferred embodiments, vagina portion 44 is composed of a jelly form of silicone plastic, and, where desired may be scented to enhance the pleasure of using the system. While reservoir 54 is shown to be connected to vagina portion 44 , it may be readily seen that such a reservoir may be separate and connected, for example by tubes, to vagina portion 44 .
Finally, referring to FIGS. 6 and 7 yet another embodiment of the present invention is shown. In this embodiment a double dildo, generally 70 , is shown in an explode view. In the embodiment shown first and second dildo elements, generally 72 and 74 respectively, are shown. As best shown in FIG. 7, included in both dildo portions 72 and 74 is a hollow reservoir 76 including a plurality of tubes 78 , each extending from each hollow reservoir 76 to provide open fluid contact to holes 80 at the surfaces of first and second dildo elements 72 and 74 . Holes 80 have a diameter in the size range of from about 2 mm to about 5 mm.
As shown, a dildo portion 72 includes a standard threaded female internal receiver 82 . Threaded female internal receiver 82 defines an annular opening leading to its hollow reservoir 76 for ease of filling its reservoir 76 with moisturizing fluid. Similarly, dildo portion 74 includes a standard threaded external male element 84 . Threaded male element 84 also defines an annular opening leading to its respective hollow reservoir 76 for ease of filling that reservoir 76 with moisturizing fluid. Dildo portions 72 and 74 are preferably constructed of semi-rigid, bendable soft rubber or plastic. Unlike the previous two embodiments, double dildo 70 includes no vibrator element.
In operation, after moisturizing fluid is placed within reservoirs 76 , movement and external air pressure causes moisturizing fluid to egress from reservoirs 76 through the plurality of tubes 78 , to holes 80 at the surfaces of first and second dildo elements 72 and 74 to thereby lubricate the body parts with which dildo portions 72 and 74 are placed in contact. In such use, once again the moisturizing fluid assists in avoiding irritation or pain during sexual activities or during autoerotic sex activities, while concomitantly increasing the pleasure of the users or user, and without requiring interruptions before, or distractions during, such activity to apply moisturizing fluid by hand or by other means. While not shown, a central plug element may be placed in use between dildo portions 72 and 74 . For use with the embodiment shown in FIGS. 6 and 7 the plug would have appropriate threaded male and female elements for use in connecting dildo portions 72 and 74 together. In the alternative, dildo portions 72 and 74 could be modified to both carry threaded female elements and the plug have appropriate threaded male elements for use in connecting dildo portions 72 and 74 together. Similarly, dildo portions 72 and 74 could be modified to both carry threaded male elements and the plug has appropriate threaded female elements for use in connecting dildo portions 72 and 74 together. The benefit of using such plugs is that they will allow one reservoir 76 in one dildo portion portions 72 or 74 to be filled and then closed with such a plug, after which the remaining dildo portion 72 or 74 to be filled and then easily connected to the already plugged dildo portion.
It is possible for the devices of the present invention to be used for other purposes, such as massage of any part of the body. Regardless of how the devices are used, they are best used if they are cleaned before and after each use.
As noted in the summary, the concept of the present invention as shown i can be easily applied to many other forms of sex aid, as listed in the summary.
The foregoing exemplary descriptions and the illustrative preferred embodiments of the present invention have been explained in the drawings and described in detail, with varying modifications and alternative embodiments being taught. While the invention has been so shown, described and illustrated, it should be understood by those skilled in the art that equivalent changes in form and detail may be made therein without departing from the true spirit and scope of the invention, and that the scope of the present invention is to be limited only to the claims except as precluded by the prior art. Moreover, the invention as disclosed herein, may be suitably practiced in the absence of the specific elements that are disclosed herein. | 1a
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CROSS REFERENCE TO RELATED APPLICATIONS
This application claims priority to co-pending U.S. provisional application Ser. No. 60/761,526, filed Jan. 24, 2006.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH
Not Applicable.
BACKGROUND OF THE INVENTION
The present invention relates to a blood perfusion system used during surgery such as cardiovascular surgery wherein air emboli present in the perfusion circuit is efficiently removed by an air removal device before returning the embolus-free blood back to circulation in the patient.
During cardiac bypass surgery, the heart is stopped in order to allow repair of defects, such as the replacement of defective heart valves, or the placement of bypass grafts. The patient's blood is redirected through an extracorporeal perfusion circuit typically including various items such as a venous cannula, PVC tubing, a reservoir, a pump, an oxygenator, an arterial filter, and an arterial cannula. During extraction of blood from the patient and/or at various stages of flow within the perfusion circuit, air emboli may form within the circulating blood. If these emboli are not removed from the circulating blood and are instead introduced back to the patient's bloodstream, there may be serious complications.
Air or other gaseous emboli can be removed (i.e., filtered) from blood that is flowing in a perfusion circuit by passing it through an air removal system. A screen or mesh filter can be employed for this purpose. Other examples of air removal devices that can be used include those shown in co-pending U.S. application Ser. No. 11/118,726, filed Apr. 29, 2005, entitled “Air Removal Device with Float Valve for Blood Perfusion System”, co-pending U.S. application Ser. No. 11/136,047, filed May 24, 2005, entitled “Vortex-Flow Air Removal in a Blood Perfusion System”, co-pending U.S. application Ser. No. 11/245,751, filed Oct. 7, 2005, entitled “Float-Driven Lever Arm for Blood Perfusion Air Removal Device”, and co-pending U.S. application Ser. No. 11/245,752, filed Oct. 7, 2005, entitled “Blood Perfusion Air Removal Device with Arcuate Manifold”, all of which are incorporated herein by reference in their entirety.
Some currently available perfusion systems monitor the fluid level in the perfusion circuit reservoir using a level sensor in order to infer that air emboli are present when the level in the reservoir is too low. It is known to display or sound an alert signal when the level in the reservoir drops below a predetermined threshold limit (or when emboli are otherwise detected, such as with an ultrasonic sensor). In response to the alarm, the circulation is manually stopped by a health care professional (such as a perfusionist) as quickly as manually possible. Special steps must then be taken to remove the air emboli before restoring the circulation back to the patient.
The perfusionist has many tasks to perform in the operating room during cardiac surgery and the corresponding distractions can lengthen the response time for stopping circulation when an alarm is triggered. Therefore, there is a need in the art for a means of automatically stopping the emboli before it reaches the patient without having to wait for action from the perfusionist.
Besides the need to quickly divert any emboli from reaching the patient, it is very important to clear the emboli from the blood in the perfusion circuit so that circulation to the patient can be restored as soon as possible. Once circulation is stopped in the perfusion circuit, it is time consuming for the perfusionist to isolate the quantity of blood containing the emboli and remove the emboli. Therefore, there is also a need in the art for a means of quickly purging emboli in order to safely restore blood circulation to the patient.
SUMMARY OF THE INVENTION
The present invention protects the patient from emboli in blood by automatically diverting emboli-containing blood away from the patient and then quickly removing the emboli by recirculating the blood through an air removal device. When the excess air has been removed from the blood, then circulation to the patient can be manually or automatically restored.
In one aspect of the invention, a perfusion system is provided for treating blood of a patient during a surgical procedure. A venous line carries blood removed from the patient. A flow control valve has first and second inlets and first and second outlets, wherein the venous line is coupled to the first inlet. An air removal system is provided for removing emboli from the blood flowing in the perfusion system. A first intermediate line couples the first outlet of the flow control valve to the air removal system. A second intermediate line couples blood having passed through the air removal system to the second inlet of the flow control valve. An arterial line couples to the second outlet of the flow control valve for carrying treated blood back to the patient. The flow control valve is selectably placed in an open position or a recirculate position, wherein the first inlet is coupled to the first outlet when the flow control valve is in either the open position or the recirculate position. The second inlet is coupled to the second outlet and blocked from the first outlet when the flow control valve is in the open position. The second inlet is coupled to the first outlet and blocked from the second outlet when the flow control valve is in the recirculate position.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic view of a perfusion system according to one embodiment of the present invention.
FIG. 2 is a diagram showing blood flow during a normal operating mode of the perfusion system.
FIG. 3 is a diagram showing blood flow during a recirculating mode of the perfusion system.
FIG. 4 is a flowchart showing a preferred method for controlling the flow control valve of FIG. 1 .
FIG. 5 is an exploded view of a plug valve used in one embodiment of the present invention.
FIG. 6 is a cross-sectional view of the plug valve in its open position.
FIG. 7 is a cross-sectional view of the plug valve in its recirculate position.
FIG. 8 is an isometric view of the plug valve showing the extension of the valve stem.
FIG. 9 is an exploded view of a piston valve used in another embodiment of the invention.
FIG. 10 is a cross-sectional view of the piston valve of FIG. 9 .
FIG. 11 is an exploded view of an alternate embodiment of a plug valve having magnetic coupling.
FIG. 12 is a perspective view of the plug valve of FIG. 11 with the top cover removed.
FIG. 13 is a perspective view of the bottom of the plug valve of FIG. 11 with the bottom cover removed.
FIG. 14 is a perspective view of the plug valve and a combined automatic/manual actuator.
FIG. 15 is an exploded view of a gate valve used in another embodiment of the invention adapted for automatic actuation.
FIG. 16 is an exploded view of a gate valve used in another embodiment of the invention adapted for manual actuation.
FIG. 17 is a perspective view of the gate valve of FIG. 16 with the top cover removed.
FIG. 18 is a top, perspective view of the gate valve of FIG. 16 .
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
Referring now to FIG. 1 , a perfusion system supporting a patient 10 includes a venous cannula 11 supplying the patient's blood to a venous line 12 is connected to an inlet of a flow control valve 13 . An intermediate line 14 passes the blood flow to an air removal system 15 and then to a blood pump 16 . Another intermediate line 17 provides blood flow from pump 16 to a second inlet of flow control valve 13 .
In a normal operating mode, blood from pump 16 is passed from valve 13 through an oxygenator 18 to an arterial line 19 and to an arterial cannula 20 for return to the patient. Thus, flow control valve 13 is shown in an open position such that substantially all emboli are removed from the flowing blood by air removal system 15 and the blood is passed through oxygenator 18 back to the patient.
In order to detect and react to emboli that may be entrained in the blood, a controller 21 is used to detect the presence of excessive air emboli and to prevent emboli-containing blood from reaching the patient. Thus, controller 21 is connected to a gas sensor 22 and/or a level detector 23 . Gas sensor 22 may comprise an ultrasonic detector disposed in contact with intermediate line 17 for measuring an overall volume of emboli present in predetermined volumes of blood, as is known in the art. Level sensor 23 is contained on or within air removal system 15 . Air removal system 15 utilizes a reservoir of blood upon which it acts to remove gas bubbles. A condition wherein the volume of blood present in the reservoir is less than a predetermined volume of blood results in a reduction of the ability to remove emboli from the blood. In response to either type of sensor indicating that excessive emboli are present, controller 21 actuates a mechanical actuator 24 on flow control valve 13 to move it from the open position shown in FIG. 1 to a recirculation position which redirects blood from intermediate line 17 back to air removal system 15 . Simultaneously, controller 21 supplies an alert signal to an annunciator 25 such as a loudspeaker or a visual display. Sensor 22 and 23 may be used alone or together depending upon the specific air removal system being used, for example.
FIG. 2 represents the normal operation mode with flow control valve 13 in the open position. Blood from the patient is drawn through valve 13 and air separator 15 by pump 16 . The blood flows past sensor 22 , through the second set of ports on valve 15 , to oxygenator 18 , and finally back to the patient. FIG. 3 shows the perfusion system in a recirculate mode with blood from the patient being drawn through valve 13 and through air separator 15 by pump 16 . Blood pumped by pump 16 past sensor 22 containing excessive emboli is coupled by valve 13 back to the flow going to air separator 15 . Importantly, both the recirculated blood from pump 16 and newly extracted blood from the patient are supplied by flow control valve 13 to air separator 15 simultaneously. Thus, if the introduction of emboli is related to a low level of blood in air separator 15 , additional volumes of blood from the patient can be added while the existing blood flow having the emboli continues to recirculate through air separator 15 until safe, emboli-free blood is detected by sensor 22 and the system can then be restored to the normal operating mode with the valve moving from the recirculate position to the open position.
A preferred method for operating the perfusion system is shown in FIG. 4 . In step 30 , the perfusion system is initialized in the normal mode with the flow control valve in the open position (e.g., after system priming as is known in the art). A check is made in step 31 to determine whether excess air emboli are detected. If they are, then a check is made in step 32 to determine whether the valve is already in the recirculate position. If it is, then a return is made to step 31 for continuously checking the presence of excess air emboli. If the valve is not already in the recirculate position, then the valve is moved to the recirculate position in step 33 and a return is made to step 31 .
In step 31 , if excess air emboli are not detected then a check is performed step 34 to determine whether the flow control valve is already in the open position. If it is, then a return is made to step 31 . Otherwise, the flow control valve is moved to the open position in step 35 and then a return is made to step 31 .
In the preferred embodiment, the flow control valve for diverting emboli-containing blood starts out in the normal or open position when operation of the perfusion system is initiated. When emboli or any excess air is detected by a sensor in the blood flow path, the controller or computer moves the flow control valve to the recirculate position so that suspect blood is sent back to the air removal system. Once the air embolism event passes, the flow control valve is returned to the open position thereby permitting blood to be sent to the oxygenator and then the patient. Preferably, the control of the valve is performed electronically by the controller. However, the perfusionist may choose to bypass the controller and activate the valve manually. In particular, the perfusionist may wish to restore the normal circulation mode only after they can verify that the problem leading to the presence of emboli has been corrected. Various types of flow control valve constructions will now be described which can be adapted to both automatic and manual control.
FIG. 5 shows a rotating plug valve 40 including a main body 41 having a cylindrical chamber 42 for receiving a disk-shaped valve element 43 . A first inlet is formed by a nozzle 44 joined to a passageway 45 that extends through body 41 to a nozzle 46 for providing the first outlet port. A second inlet port comprises nozzle 47 mounted in communication with a passage 48 leading to chamber 42 . A second outlet port comprises a nozzle 50 joined to a passage 51 likewise leading to chamber 42 . Passage 45 also communicates with chamber 42 . Valve element 43 is received in chamber 42 and has an internal passage 52 for selectively coupling the second inlet nozzle 47 with either second outlet nozzle 50 or first outlet nozzle 46 when element 43 is rotated within cylindrical chamber 42 .
Valve element 43 has a control stem 53 extending out through a mating aperture in main body 41 to an actuator 54 which is mounted to the side of main body 41 by a plurality of screws 55 . Actuator 54 preferably includes an electrically controlled motor (such as a DC stepper motor) for selectably controlling the rotational position of valve element 43 in response to control signals from the controller. Valve stem 53 and actuator 54 are sealed in order to retain blood within plug valve 40 . Likewise, valve element 43 is sealed within cylindrical chamber 42 by a bottom cover 56 mounted to main body 41 using a plurality of screws 57 . Main body 41 , the nozzles, and cover 56 are preferably comprised of a clear, biocompatible plastic so that blood within the valve can be seen during perfusion.
FIG. 6 illustrates a cross sectional view with valve element 43 rotated to the open position with blood flow proceeding from the first inlet to the first outlet and from the second inlet to the second outlet. FIG. 7 is a cross sectional view with valve element 43 rotated to the recirculate position wherein blood flows from the first inlet to the first outlet and from the second inlet to the first outlet so that emboli-containing blood returns to the air removal system. Simultaneously, fresh blood from the patient can enter the system while the outlet to the oxygenator is isolated so that no flow occurs to the patient.
FIG. 8 shows the actuator side of plug valve 40 with control stem 53 extending through actuator 54 . If manual control is desired, a handle can be attached to control stem 53 and the handle and/or valve body labeled to indicate the proper movement of the handle to obtain the open and recirculate positions, respectively.
FIG. 9 shows an exploded view of an alternative embodiment for the control valve wherein a piston-type valve is employed. A main valve body 60 has longitudinal bores 61 and 62 extending therethrough. A movable valve element 63 is received in bore 61 . A nozzle 64 is attached to body 61 at one end of bore 62 to form a first inlet as shown in FIG. 10 . A nozzle 65 is connected with the other end of bore 62 to provide a first outlet which is coaxial with first inlet nozzle 64 . A nozzle 66 is connected to valve body 60 at one end of bore 61 via a connection ring 67 to form a second inlet. A nozzle 68 is connected to an aperture 69 in main body 60 to provide a second outlet. A passageway 70 is provided between bores 61 and 62 . It may be formed by drilling through main body 60 and then plugging the exterior hole as shown at 71 .
Valve element 63 has an internal passageway 72 that connects one end of valve element 63 to an intermediate exit hole 73 and to a flow recess 74 around the circumference of the valve element. Thus, depending upon the longitudinal position of valve element 63 , flow from second inlet 66 is recirculated to first outlet 65 through hole 70 as shown in FIG. 10 or is directed through second outlet 68 when passage 73 and recess 74 are extended to a position aligned with second outlet 68 . In order to control the position of valve element 63 , a control end 75 is coupled to an actuator 76 . Actuator 76 may include a magnetic solenoid, for example.
As shown in FIG. 11 , an alternate embodiment employing a plug-type valve includes an outer housing wall 81 for receiving a valve element 82 . Sealed bottom and top covers 83 and 84 retain valve element 82 in housing 81 . A nozzle 85 provides a first inlet port through housing 81 and a nozzle 86 provides a first outlet port through top cover 84 . A nozzle 87 provides a second inlet port through housing 81 and a nozzle 88 provides a second outlet port through housing 81 .
As shown in FIG. 12 , valve element 82 includes a channel 90 and a channel 91 for interconnecting the various ports to provide the open and recirculate positions of the valve. FIG. 12 is shown with cover 84 removed so that channels 90 and 91 can be seen. Valve element 82 is in the recirculate position wherein channel 90 is aligned with second outlet nozzle 88 at one end and is blocked at its opposite end and wherein channel 91 interconnects first inlet nozzle 85 with first outlet nozzle 86 and second inlet nozzle 87 . By rotating element 82 clockwise by 90°, the first inlet and outlet ports are interconnected and the second inlet and outlet ports are interconnected, thereby configuring the valve in the open position.
FIG. 13 shows that a bottom surface of valve element 82 includes a plurality of disk shaped recesses 92 for receiving disk-shaped magnets 93 for providing a magnetic coupling to valve element 82 . Pins 94 and 95 extend from housing 81 in order to receive the bottom cover and to facilitate mounting of the valve to an actuator 96 as shown in FIG. 14 . A motor 97 is controlled by the controller and drives a magnet disk 98 configured to have magnetic poles for magnetically linking with the magnetic disks 93 on the valve element so that rotation of the valve element matches the rotation of motor 97 . A handle 99 is coupled to disk 98 via motor 97 for manually adjusting the position of the valve element.
FIGS. 15-18 illustrate the use of a gate-type valve for the flow control valve of the present invention. As shown in FIG. 15 , a valve body 100 has parallel flow channels 101 and 102 separated by an opening 103 . A rotatable gate 104 is received in opening 103 and may be oriented parallel to the flow channels in order to separate the flow channels and provide the open position of the valve wherein the inlet ports are connected just to their respective output ports. A shaft 105 is connected to gate 104 and has a control wheel 106 adapted to be coupled with an actuator in order to provide an automatically controlled version of the valve. As shown in FIG. 16 , a manual version utilizes a handle 107 coupled with shaft 105 for controlling gate 104 . FIG. 17 shows handle 107 and gate 104 in a recirculate position so that both inlet ports are coupled to the first outlet port and the second outlet port is isolated. As shown in FIG. 18 , handle 107 may include a pointer 111 for aligning with labeling on a cover 112 to show when the valve is in the open or recirculate position. | 1a
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a vacuum cleaner, and more particularly, to a passage system of a vacuum cleaner in which an air passage system is modified to increase an amount and speed of air drawn into a vacuum cleaner without having to increase a capacity of a motor so that the performance of a vacuum cleaner is enhanced.
2. Description of the Related Art
Conventional vacuum cleaners are classified, depending upon a use and a shape, into a cylindrical vacuum cleaner which is generally employed at home, a pot-type vacuum cleaner, which is generally known as a canister vacuum cleaner, for a large places such as a place of business that requires a large capacity, and a portable vacuum cleaner which is easily carried around and employed for a specified purpose (such as a vehicle).
Among various kinds of vacuum cleaners, in case of a rechargeable vacuum cleaner such as the portable vacuum cleaner equipped with a rechargeable battery, it is difficult to produce an output of a sufficient level when using the vacuum cleaner due to the limitation of a capacity of a battery.
FIG. 1 is a schematic cross-sectional view illustrating a construction of a passage system of the conventional vacuum cleaner.
Referring to FIG. 1, the passage system of the conventional vacuum cleaner comprises a suction motor 10 which is installed on an upper end of the vacuum cleaner to provide a suction force for sucking the outside air into the vacuum cleaner, a suction fan 20 which is placed below the suction motor 10 and blades for sucking the outside air using rotating force of the suction motor 10 , a dust filter 30 which is placed below the suction fan 20 to filter dust contained in the outside air sucked by the suction fan 20 , a dust-collecting bucket 40 which is positioned below the dust filter 30 to collect dust and the like filtered by the dust filter 30 , and a suction nozzle 50 which is arranged below the dust collecting bucket 40 to elevate the speed of flow of the outside air sucked from the outside by the suction fan 20 , up to a predetermined value.
Operations of the passage system of the conventional vacuum cleaner according to the aforementioned configuration is described hereinafter. When a user turns on the vacuum cleaner to perform a cleaning work, the suction motor 10 is initiated. The Rotating force of the suction motor 10 is transferred to the suction fan 20 which is rotatably attached to a lower end of the suction motor 10 . Thereafter, as the suction fan 20 rotates, a low-pressure space is formed below the suction motor 10 to draw in the air from the outside into the vacuum cleaner.
As the air is sucked in from the outside toward the low-pressure space, dust and other particles are also sucked into the vacuum cleaner along with the outside air through the suction nozzle 50 .
The outside air is then directed to the dust filter 30 . In the dust filter 30 , while air can freely pass through the dust filter 30 , dust and the particles having a size larger than that of meshes of the dust filter 30 , are filtered by the dust filter 30 .
Dust and other particles which did not pass through the dust filter 30 , drop down to be collected in the dust collecting bucket 40 , whereby one cycle of operations of the vacuum cleaner is completed.
Also, the air which passed through the dust filter 30 , is exhausted to the outside after sequentially passing through the suction fan 20 and the suction motor 10 . While the air passes through the suction motor 10 , heat generated by the suction motor 10 is cooled.
While undergoing time serial sequences as described above, dust and other particles contained in the outside air, are filtered by the dust filter 30 . If dust and the particles are collected in the dust-collecting bucket 40 built up to the point in which in flow of the air is effected and degrade an efficiency of the vacuum cleaner, a user of the vacuum cleaner should empty out the dust-collecting bucket 40 .
Since the air, which is discharged to the outside after passing through the suction motor 10 , flows at a high speed, the air retains a substantial amount of kinetic energy which could be utilized to improve the efficiency. However, the passage system of the conventional vacuum cleaner dose not employ any means to reuse the air having kinetic energy.
SUMMARY OF THE INVENTION
Accordingly, the present invention has been made in an effort to solve the problems occurring in the related art, and an object of the present invention is to provide a passage system of a vacuum cleaner, which enables the air to be exhausted is utilized again to provide an additional source of energy for the vacuum cleaner. And, in the case of a rechargeable vacuum cleaner wherein an output cannot be raised beyond a predetermined level due to the limitation within its own configuration, the passage system of the vacuum cleaner in accordance with the present invention allows a cleaning work to be performed in more efficient manner with the same power supply source.
In order to achieve the above object, the present invention provides a passage system of a vacuum cleaner, comprising: an ejector suction passage which is connected to one end of an outer surface of a motor case to reutilize air which has been exhausted from a suction motor; an ejector formed at the end of the ejector suction passage for accumulating air that has passed through the ejector suction passage; an ejector nozzle formed at one end of the ejector for exhausting the air at a high speed and under a low pressure; a second suction passage having one end placed at a predetermined distance from the ejector nozzle and the other end connected to a dust collecting bucket, such that the air discharged from the ejector nozzle and the air existing in an ejector chamber are simultaneously drawn in together into an ejector chamber and thereafter flows in the direction of a suction motor, an ejector chamber which is formed in the inside of the ejector nozzle, and one end of the second suction passage is connected in the ejector chamber so that an inside of the ejector chamber remains under low pressure; a second suction nozzle formed at a predetermined position in the ejector chamber to draw in the outside air at a high speed; a first suction nozzle placed at a predetermined position of the vacuum cleaner to draw the air in at a high velocity by a suction force generated by the suction motor; and a first suction passage having one end which is fastened to the first suction nozzle and the other end is connected to a predetermined part of the dust collecting bucket, in a manner such that outside air which is drawn in via the first suction nozzle, is guided toward the suction motor.
By the feature of the present invention, the passage system of a vacuum cleaner according to the present invention provides advantages in that, since energy, which is contained in air discharged through a suction motor, is utilized again, cleaning performance of the vacuum cleaner can be improved.
BRIEF DESCRIPTION OF THE DRAWINGS
The above objects, and other features and advantages of the present invention will become more apparent after a reading of the following detailed description when taken in conjunction with the drawings, in which:
FIG. 1 is a schematic cross-sectional view illustrating a construction of a passage system of a conventional vacuum cleaner;
FIG. 2 is a schematic cross-sectional view illustrating a construction of a passage system of a vacuum cleaner in accordance with an embodiment of the present invention; and
FIG. 3 is a schematic cross-sectional view illustrating a construction of a passage system of a vacuum cleaner in accordance with another embodiment of the present invention.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
Reference will now be made in greater detail to a preferred embodiment of the invention, an example of which is illustrated in the accompanying drawings. Wherever possible, the same reference numerals will be used throughout the drawings and the description to refer to the same or like parts.
FIG. 2 is a schematic cross-sectional view illustrating a construction of a passage system of a vacuum cleaner in accordance with an embodiment of the present invention.
Referring to FIG. 2, in the present invention, in order to allow the outside air to be sucked into the vacuum cleaner, two suction paths are included as described below.
First, the passage system of a vacuum cleaner according to the present invention comprises a suction motor 10 , a suction fan 20 , a dust filter 31 , a dust collecting bucket 41 , a fan suction passage 42 , a motor case 11 , a plurality of discharging holes 11 a , an ejector suction passage 62 , an ejector 60 , an ejector nozzle 61 , an ejector chamber 63 , a second suction nozzle 64 and a second suction passage 65 .
The suction motor 10 is installed adjacent to an upper end of the vacuum cleaner to provide the suction force for draw the outside air into the vacuum cleaner. The suction fan 20 is located on an upper end of the suction motor 10 and has blades which receive the suction force from the suction motor 10 and thereby suck the outside air. The dust filter 31 is arranged above the suction fan 20 to filter out dust and other particles contained in the outside air drawn in by the suction fan 20 . The dust filter 31 has a doughnut-shaped configuration. The dust-collecting bucket 41 is positioned below the dust filter 31 to collect dust and other particles filtered by the dust filter 31 . The dust collecting bucket 41 has a hollow configuration. The fan suction passage 42 is placed at the center portion of the dust collecting bucket 41 in a manner such that outside air that has been through the filtering process to remove the dust and the like by the dust filter 31 , flows through the fan suction passage 42 toward the suction fan 20 . The fan suction passage 42 has a cylindrical shaped which is opened at an upper end thereof. The motor case 11 is formed to have a cylindrical shape to accommodate the suction motor 10 . The plurality of discharging holes 11 a are formed on a circumferential outer surface of the motor case 11 at predetermined places in a manner to exhaust the air that has been pressurized while passing through the suction fan 20 to the outside. The ejector suction passage 62 serves as an exhausting passage and is connected at one end thereof to the circumferential outer surface of the motor case 11 at a predetermined place in a manner such that the air which has been passed through the suction fan 20 , can be reutilized.
The ejector 60 is formed at the other end of the ejector suction passage 62 to exhaust the air which passed through the ejector suction passage 62 . The ejector nozzle 61 is placed at the lower end of the ejector 60 to further pressurize the air which has been already pressurized while passing through the suction fan 20 , and then exhaust the air at a high velocity. The ejector chamber 63 is defined in a manner such that an inside of the ejector chamber 63 remains under a low pressure by the air which is ejected from the ejector nozzle 61 at a high speed. The second suction nozzle 64 is formed at a lower end of the ejector chamber 63 in a manner such that outside air can be sucked therein. The second suction passage 65 is connected at one end thereof to the duct collecting bucket 41 in a manner such that air which is ejected therein from the ejector nozzle 61 and sucked therein from the ejector chamber 63 , is guided toward the suction fan 20 .
A second suction path operates in the same manner as a suction path of the conventional vacuum cleaner. The second suction path according to the present invention is formed with a first suction nozzle 71 and a first suction passage 72 . The first nozzle 71 directly receives the suction force generated by the suction motor 10 to draw in the outside air containing dust and other particles with intensive force. One end of the first suction passage 72 is connected to the dust-collecting bucket 41 and the other end is connected to the first suction nozzle 71 , so that the outside air, which is drawn into the vacuum cleaner by the first suction nozzle 71 , can pass through the first suction passage 72 .
It is preferred that the first suction nozzle 71 and the second suction nozzle 64 are formed at the lowermost end of the entire vacuum cleaner structure to allow dust and the like existing on a floor to be easily drawn in along with outside air.
Hereinafter, operations of the passage system of a vacuum cleaner according to the present invention, constructed as mentioned above, will be described in detail.
When a user turns on the vacuum cleaner to perform a cleaning work, the suction motor 10 rotates, and at the same time, the suction fan 20 which is connected to the suction motor 10 also rotates.
If the suction fan 20 is rotated, the outside air is drawn in and passes through the first suction nozzle 71 , the first suction passage 72 , the dust collecting bucket 41 , the dust filter 31 and the fan suction passage 42 in order. Upon reaching the suction fan 20 and the suction motor 10 after passing through the fan suction passage 42 , air cools the suction motor 10 and at the same time is pressurized by the suction motor 10 .
In the course of the suction process, dust and the like which are contained in the outside air, are filtered by the dust filter 31 . As dust and other particles are piled up in the dust-collecting bucket 41 , a cycle of the second outside air suction path is completed.
Hereinafter, the operation of the first outside air suction path is described in detail. The motor case 11 which accommodates the suction motor 10 , is attached with the plurality of discharging holes 11 a in which predetermined amount of air that has been pressurized while passing through the suction fan 20 , is discharged to the outside, and the remaining predetermined amount of the air which has been pressurized while passing through the suction fan 20 flows into the ejector 60 through the ejector suction passage 62 . A ratio between the preselected amount which is discharged to the outside through the plurality of discharging holes 11 a and the predetermined amount which flows out through the ejector suction passage 62 , can be adjusted according to the needs by adjusting the size and the number of the discharging holes 11 a.
The air, which flows into the ejector 60 , is exhausted through the ejector nozzle 61 formed at the free end of the ejector 60 . Since the air is exhausted under a high pressure, it is to be readily understood that the surrounding area near the ejector nozzle 61 is maintained under a remarkably low pressure as explained in the Bernoulli's theorem, and the inside of the ejector chamber 63 which includes the discharging end of the ejector 60 , also remains in a significantly low pressure.
Due to the low pressure environment which has been created in the inside the ejector chamber 63 as described above, the outside air is drawn into the vacuum cleaner through the second suction nozzle 64 which is formed at a predetermined position in the ejector chamber 63 , as in the case of the first suction nozzle 71 .
This function will be described hereafter in further detail using the Bernoulli's theorem.
The Bernoulli's theorem is expressed as given below:
H=P/γ+V 2 /2 g+Z= constant,
where H is a total head, P is a pressure at a corresponding point, γ is a specific weight of fluid, V is a flow velocity, g is an acceleration of gravity, and Z is a height of fluid on a reference plane. The Bernoulli's theorem applies to all incompressible fluid. According to the Bernoulli's theorem, water heads are divided into a pressure head (P/γ) due to a pressure of fluid, a velocity head (V 2 /2g) due to a flow velocity of the fluid, and a position head (Z) due to a height of the fluid. The Bernoulli's theorem shows that the total sum of the three heads is always held equal at any point in the fluid.
Describing again operations of the passage system of a vacuum cleaner according to the present invention on the basis of the Bernoulli's theorem as deliberated above, since the air existing in the ejector 60 has a low flowing velocity, a high pressure and a constant height, the air in the surrounding area near the ejector nozzle 61 , more particularly the outlet end of the ejector 60 having a high velocity at a constant height, has a low pressure when considering the Bernoulli's theorem.
As a result, a low pressure space of a sufficient level is created in between the ejector nozzle 61 and the second suction passage 65 , thereby the low pressure environment is created in the inside the ejector chamber 63 that includes the low pressure space.
The second suction nozzle 64 is placed below the ejector chamber 63 to intake the outside air which then gets mixed up with the air exhausted from the ejector nozzle 61 before passing through the second suction passage 65 . Consequently, in the passage system of a vacuum cleaner according to the present invention includes two suction nozzles that are formed at the outside air suction paths through which dust and the like can be sucked into the vacuum cleaner. Particularly, since the predetermined amount of air that has passed through the suction motor 10 is utilized to draw in the outside air, an efficiency of the vacuum cleaner is increased.
As described above, in the passage. system of a vacuum cleaner in accordance with the embodiment of the present invention, since the plurality of suction nozzles are formed, a cleaning capability of the vacuum cleaner for sucking the outside air has been substantially increased without using an additional source of energy, but by only modifying a passage system of the conventional vacuum cleaner.
FIG. 3 is a schematic cross-sectional view illustrating a construction of a passage system of a vacuum cleaner in accordance with another embodiment of the present invention. In the above-described first embodiment of the present invention, although it is possible to place the first suction passage 72 and the second suction passage 65 separately and connect to the dust collecting bucket 41 at different positions, this passage construction makes not only the passage system of a vacuum cleaner more complex but also a manufacturing procedure thereof complicated. In order to resolve this problem, in the second embodiment of the present invention, an outside air passage 70 in which the first suction passage 72 and the second suction passage 65 merge is independently formed. The passage system of a vacuum cleaner in accordance with the present invention allows the outside air containing dust and other particles to flow into the dust-collecting bucket 41 via the outside air passage 70 .
As a result, the passage system of a vacuum cleaner according to the present invention provides more powerful suction force for sucking the outside air through two sucking passages in the passage system, thus the cleaning process can be performed more quickly. Also, when compared with the conventional vacuum cleaner, less amount of input power is required for sucking the same amount of outside air thereby substantially saving energy. Moreover, in the case a rechargeable vacuum cleaner wherein the output of a motor cannot be raised beyond a predetermined level due to limitation within its own specification, greater cleaning capability can be accomplished when the passage system in accordance with the present invention is applied.
In the drawings and specification, there have been disclosed typical preferred embodiments of the invention and, although specific terms are employed, they are used in a generic and descriptive sense only and not for purposes of limitation, the scope of the invention being set forth in the following claims. | 1a
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present patent application is related to and claims the priority benefit of U.S. Provisional Patent Application Ser. No. 62/126,028, filed Feb. 27, 2015, the contents of which is hereby incorporated by reference in its entirety into this disclosure.
TECHNICAL FIELD
[0002] The present disclosure generally relates to syringes, and in particular to a syringe with a solid core, allowing fluid to fill an area around the perimeter of the syringe barrel, enabling a wider diameter for the barrel thus increasing the visibility of the markings and ease of handling by the patient.
BACKGROUND
[0003] This section introduces aspects that may help facilitate a better understanding of the disclosure. Accordingly, these statements are to be read in this light and are not to be understood as admissions about what is or is not prior art.
[0004] Health care providers administering medications to patients must exercise great care in determining the amount medication to inject into the patient's body. Similarly, for example, diabetic patients must likewise take great care to ensure the amount of insulin injected into their bodies is of the appropriate dosage. Unfortunately, however, many patients suffer ailments (e.g., failing eyesight) that make it difficult, and often dangerous, to adequately administer the required dosage of medication into their bodies. Such consequences can be extended to all drugs that must be administered via a syringe. Given that an improper dosage can result in serious consequences, it is critical that both health care providers and patients themselves be able to clearly and accurately determine the amount of medications loaded in a syringe prior to injection.
[0005] Additionally, health care providers and patients themselves who must administer a drug via a syringe continually face the risk of accidental needle sticks. Even when cautious, there is always a chance that the person administering the drug via a needle syringe will slip and accidentally stick himself or another person. Every year in the United States, 44,000 to 98,000 people die as a result of medical error. Medication errors are a leading form of medical harm with over 1.5 million adverse drug events associated with medication use occurring every year. The medication use process is complex and difficult to navigate, even for trained professionals. Some medications are more prone to error than others for patients and professionals alike, and these medications earn the title high risk medications. Every year without fail, more errors associated with injectable insulin are reported than any other medication. This is exceptionally troubling given the nature of the medication insulin. It is an endogenous hormone in the human body that we supplement for patients with diabetes who do not synthesize sufficient quantities or for those who have developed an insensitivity to insulin in their body. Small volumes of insulin, measured and dosed to patients in terms of units of insulin, can have profound effects on our bodies. Volumes as small as 10 units or less can be enough to send someone into a state of hypoglycemia, a condition that if uncorrected can have dramatic effects and in some instances, if not reversed, be fatal. This range between where the medication is useful to patients and the point at which it becomes toxic is known as a therapeutic window. Insulin has one of the narrowest therapeutic windows but one of the widest ranges of dosing as patients can require as little as 2 units and some could require over 100 units.
[0006] Combined with the narrow therapeutic window of insulin, we additionally complicate this process by manufacturing more than one concentration of insulin. Currently, 100 unit/mL and 500 unit/mL concentrations are readily available with a 200 unit/mL concentration available in the EU that may someday soon be available in the United States. Administering these doses requires drawing insulin up into an insulin syringe, which is a device specifically designed and marked for volumes of 100 unit/mL insulin. Therefore, a patient needing to administer 16 units could draw up precisely this amount into their syringe from a multi-dose vial and administer it to themselves. Patients that receive more than 200 units of insulin per day may elect to be placed on U500 (500 unit/mL insulin) to minimize the volume of fluid injected daily. In order to perform this process, these patients still must use a U100 (100 unit/mL) insulin syringe to accomplish this task.
[0007] Thus, there remains an unmet need for syringes that enable safe, reliable administration of a drug to protect against both improper dosage and inadvertent needle sticks.
SUMMARY
[0008] In one aspect, a perimeter fill syringe is presented. The perimeter fill syringe includes a top end, wherein the top end is configured to be coupled to a syringe needle, and a bottom end, wherein the bottom end is configured to be coupled to a plunger. The plunger is configured to be slidably coupled to the perimeter fill syringe. The perimeter fill syringe also includes an outer shell that is along the length between the top and the bottom end of the perimeter fill syringe. The perimeter fill syringe also includes a core that is encased within the outer shell.
[0009] In another aspect, a method for reliably administering medication and dosage to a patient is presented. The method includes utilizing the presented perimeter fill syringe of a particular design to administer the medication.
BRIEF DESCRIPTION OF THE FIGURES
[0010] FIG. 1 is an image of an insulin syringe in common use.
[0011] FIG. 2A is an image of one embodiment of the perimeter fill syringe that is cylindrical in shape.
[0012] FIG. 2B is an image of an embodiment of the top end of the outer shell of the perimeter fill syringe.
[0013] FIG. 3A is an image of one embodiment of the perimeter fill syringe that is rectangular in shape.
[0014] FIG. 3B is an image of the embodiment shown in FIG. 3A but also includes a cross-sectional view of the interior of the perimeter fill syringe.
[0015] FIG. 4 is a cross-sectional view of an intermediate portion along the length of the perimeter fill syringe.
[0016] FIG. 5A shows an embodiment of the plunger that is configured to be inserted into a perimeter fill syringe that has a rectangular shape.
[0017] FIG. 5B is an image of the embodiment shown in FIG. 5A but also includes a cross-sectional view of the interior of the plunger.
[0018] FIG. 6 is an image of an embodiment of the plunger that is configured to be inserted in to a perimeter fill syringe that has a cylindrical shape, such as that in FIG. 2A .
[0019] FIG. 7 shows separate images of the core and of the outer shell of an embodiment of the perimeter fill syringe.
[0020] FIG. 8 shows an alternate embodiment of the perimeter fill syringe shown in FIG. 7 , but in FIG. 8 , the shape of the perimeter fill syringe is rectangular.
[0021] FIG. 9A shows an embodiment of the fully assembled perimeter fill syringe, wherein the core is partially slidably inserted into the outer shell.
[0022] FIG. 9B shows an image of an embodiment of a fully assembled perimeter fill syringe.
DETAILED DESCRIPTION
[0023] For the purposes of promoting an understanding of the principles of the present disclosure, reference will now be made to the embodiments illustrated in the drawings, and specific language will be used to describe the same. It will nevertheless be understood that no limitation of the scope of this disclosure is thereby intended.
[0024] In response to the unmet need for a syringe design that enable safe, reliable administration of a drug to protect against both improper dosage and inadvertent needle sticks, such a novel syringe design is disclosed herein. For demonstration purposes, the herein described novel syringe design is an insulin syringe. However, it should be appreciated that the applications for the herein described novel syringe extends beyond insulin syringes and can apply to medications of all types that are to be administered via a syringe.
[0025] Referring to FIG. 1 , which is an image of an insulin syringe in common use, current syringes comprise a hollow barrel and a solid plunger used to push fluid out of a nozzle at the tip. There are numerous shortcomings in the current insulin syringe designs. First, the size of the syringe is quite small. It has a narrow diameter cylinder with markings that wrap almost completely around the barrel of the syringe. This small size can be difficult to handle for both health care providers and patients of all ages. Notably, complications of diabetes, specifically in those patients who may already have high insulin demand (in excess of 200 units per day), include blurred vision and neuropathy, or pain and loss of sensation in their fingers and toes. These patient conditions make the current syringe design far less than optimal for the safe, ergonomic handling of a device that is intended to inject a drug with a narrow therapeutic window.
[0026] Second, these syringes can be used for both U100 and U500 concentrations. For example, if a health care provider drew up 100 units of U500 in one syringe and 20 units of U100 into separate syringes (same volumes of clear liquid) and walked away to attend to another task (e.g., answer a ringing phone), the syringes would be indistinguishable upon the health care provider's return. If the health care provider did not remember which was which, one represents a lethal dose for one patient while the other represents a dose far too low to combat the conditions of the other patient. Without any visual cues or “forcing functions” to indicate differently concentrated insulin doses is a formula for catastrophe. A forcing function would be any discernable difference between syringes such as shape, size, color, structure, or any other means of immediately noticing a difference beyond having to remember.
[0027] Third, the current U100 syringes require computations to be made in order to achieve the correct dose. In order for a health care provider or a patient to achieve a 100 unit dose of U500 insulin, they would need 0.2 mL of insulin at this concentration to achieve this. However, 0.2 mL in a U100 syringe is labeled on the barrel as only being 20 units. Such requirements are accompanied by risk that errors can be made in the computations and can thus lead to disastrous results, should an error be made.
[0028] To address the above concerns, a novel design for a syringe, hereinafter referred to as a “perimeter fill syringe” is disclosed. Referring to FIGS. 2A and 2B , in one embodiment, the perimeter fill syringe 100 is cylindrical in shape. In another embodiment, referring to FIGS. 3A and 3B , the perimeter fill syringe 100 is of a rectangular shape. It should be appreciated that although for demonstration purposes of this disclosure a cylindrical and rectangular shape for the perimeter fill syringe 100 are described, such descriptions are not intended to be limiting, and rather, any shape can be used. Referring to FIG. 4 , which is a cross-sectional view of an intermediate portion 200 along the length of the perimeter fill syringe 100 , the perimeter fill syringe 100 and has a core 201 . Still referring to FIG. 4 , an outer shell 203 encases the core 201 . In between the outer shell 203 and the core 201 is a fluid space 205 for the medication or fluid to be placed. Referring to FIGS. 5A and 5B , a plunger 301 is configured to be inserted into the fluid space 205 . FIGS. 5A and 5B show an embodiment of the plunger 301 that is configured to be inserted into a perimeter fill syringe 100 that has a rectangular shape. FIG. 6 shows an embodiment of the plunger 301 that is configured to be inserted in to a perimeter fill syringe 100 that has a cylindrical shape.
[0029] Referring to FIG. 2B , an image of an embodiment of the top end 204 of the outer shell 203 of the perimeter fill syringe 100 is shown, of which the plunger 301 shown in FIG. 6 can be inserted. The fluid space 205 is no longer along the shape of a ring at the top end 204 of the outer shell 203 to allow for minimal waste of the medication or fluid traveling through the fluid space 205 .
[0030] Referring to FIG. 7 , which shows separate images of the core 201 and of the outer shell 203 of an embodiment in which the perimeter fill syringe 100 is in cylindrical in shape, the top end 204 of the outer shell 203 can be configured to have a syringe needle inserted thereon. Still referring to FIG. 7 , the core 201 can have a bottom end 207 that is configured to be coupled to a plunger that can facilitate the core 201 being inserted into the outer shell 203 to thereby administer the medication through the fluid space 205 . A space for the plunger needs to be configured into the design of the perimeter fill syringe 100 , an example of which is shown at the top of FIGS. 3A and 3B . FIG. 8 similarly shows an alternate embodiment of the perimeter fill syringe 100 shown in FIG. 7 , but in FIG. 8 , the shape of the perimeter fill syringe 100 is rectangular. FIG. 4 shows an alternate view of the embodiment of the perimeter fill syringe 100 of FIG. 8 . Referring to FIG. 4 , the fluid can be inserted into the fluid space 205 can be seen to form the shape of a ring along a bottom portion 209 of the perimeter fill syringe 100 . Still referring to FIG. 4 , the top end 211 of the core 201 is configured to be inserted into the bottom portion 209 to fill the fluid space 205 .
[0031] FIGS. 9A and 9B show an embodiment of the fully assembled perimeter fill syringe 100 , wherein the core 201 is partially slidably inserted into the outer shell 203 . Referring to FIG. 9B , drawing back the core 201 allows the fluid space 205 to fill with fluid medication. Such a thin perimeter geometry enables a wider syringe design that is easier to grasp for patients and health care providers, especially those with lessening of motor function or dexterity. The wider diameter on the perimeter fill syringes 100 also enables markings to appear more clearly on a single face of the perimeter fill syringe 100 , thus eliminating the need to roll or rotate the syringe in a user's hand while drawing up a dosage of medication.
[0032] As described above, the perimeter fill syringes 100 can take on a plurality of shapes and geometries. For instance, the perimeter fill syringe 100 can be of a cylindrical shape. Alternatively, a rectangular prism-like shape can be used. Yet another embodiment features a triangular prism-like shape for the perimeter fill syringe 100 .
[0033] Table 1 shows an example of the calculations for a 500 unit syringe and various inner width dimensions, specifically for estimating a desired fluid space 205 for a perimeter fill syringe 100 that is rectangular in shape and the core 201 and outer shell 203 each have widths that are the same (i.e., their top and bottom ends are squares), given the dimensions of the outer shell 203 and the core 201 , for a desired height of the perimeter fill syringe, and an inner width core 201 diameter. Such calculations are conducted using volume dimensions and the exact calculations can vary depending on the geometry of the perimeter fill syringe 100 (e.g., volumetric calculations for a cylinder can be used if the perimeter fill syringe 100 is cylindrical; volumetric calculations for a triangle will be used if the perimeter fill syringe 100 is triangular). The fluid space 205 needs to be calculated such that the plunger will not cripple with the force of drawing the fluid in and out of the perimeter fill syringe 100 .
[0000]
TABLE 1
Sample Fluid Space and Dimension Calculations for a 500 unit syringe
Outer Width (i.e., the
Inner Width
radius square that is
Height of
(i.e., radius of the square
the outer perimeter of
intermediate space
that forms the inner
the fluid space (i.e.,
between the top and
perimeter of the fluid
the inner cutout
bottom of the outer
space) (i.e., the width
portion of the outer
shell
of the core)
shell))
Fluid Space
4
0.1
0.367423
2.67435
4
0.15
0.384057
2.340573
4
0.2
0.40620192
2.062019
4
0.25
0.433013
1.830127
4
0.3
0.463681
1.636809
4
0.35
0.497494
1.474937
4
0.4
0.533854
1.338539
4
0.45
0.572276
1.222762
4
0.5
0.612372
1.123724
[0034] The exact dimensions can vary depending on a variety of factors, including the desired ease of flow of the particular medication to be administered and the age and physical abilities of individual administering the medication. For example, a patient with weak hands and poor dexterity may need a perimeter fill syringe 100 that is capable of having a sliding motion that has less resistance than what is considered normal in the field. Similarly, if the user of the perimeter fill syringe 100 is a child, the sliding motion may have to be altered accordingly to ensure ease of use for the patient. Alternate colors and shapes can also be used to help identify and alert the user as to which medication and dosage is being administered.
[0035] Such configurations can revolutionize the way in which medications are administered by patient and health care providers. Such designs address the issue of drawing up different concentrations of insulin into a single type of syringe. In the example given above where a health care provider walks away from two identical volumes of different concentrations of insulin, it was previously impossible to discern between the two. Now, with this disclosure, the rectangular shape of the U500 insulin syringe acts as a physical alert and a forcing function to warn both patients and nurses alike that this syringe contains highly concentrated insulin. Using this new invention, a new standard will be set for administration of insulin. The cylindrical shape will be retained for U100 insulin while the rectangular shape will become the new standard by which all 500 unit/mL insulin will be dispensed and administered. Changing the shape of the syringe is a human factors strategy that will reduce the cognitive load on nurses and patients when they need to be focused on other matters. Now, rather than having to be extremely diligent to avoid mixing concentrations, they can consistently rely upon syringe geometry as a forcing function to prompt safe dispensing and administration techniques.
[0036] In addition to the differing syringe geometries, each syringe can have markings on the barrel or outer shell 203 that precisely correlate to the concentration of the corresponding insulin being administered. Therefore, in a U100 syringe, 0.2 mL will be 20 units every time and no dose of U500 should ever be drawn up in these syringes ever again. A U500 syringe will have 100 units marked at the corresponding 0.2 mL line on the barrel because only 500 unit/mL insulin shall ever be used in this shape of syringe. Keeping the markings distinct eliminates the need for additional math and calculations or incorrect labeling on the barrel after drawing up insulin.
[0037] Those skilled in the art will recognize that numerous modifications can be made to the specific implementations described above. The implementations should not be limited to the particular limitations described. Other implementations may be possible. | 1a
|
FIELD OF THE INVENTION
This invention relates to the use of certain zwitterionic compounds and their N-halo derivatives in the treatment of related clinical conditions.
BACKGROUND AND PRIOR ART
Prostaglandins and leukotrienes are products of arachidonic acid metabolism via the cyclooxygenase pathway and the lipoxygenase pathway, respectively. Leukotriene B 4 is one of the most potent naturally occurring mediators of inflammation and is a potent chemotactic and chemokinetic agent for leukocytes. Leukotriene B 4 causes in vitro leukocyte accumulation, modulates pain responses and causes changes in vascular permeability. The peptido-lipid conjugates leukotriene C 4 , D 4 and E 4 play a lesser role as mediators of inflammation and collectively account for the biological activity known as "slow reacting substance of anaphylaxis". Leukotrienes C 4 , D 4 and E 4 are potent smooth muscle contractile agents and are, therefore, believed to be important mediators of asthma and other hypersensitivity reactions. Prostaglandins on the other hand are not causative agents of inflammation, but rather synergise with other inflammatory mediators such as histamine and bradykinin in the production of oedema and pain.
The causes of all inflammatory diseases are unknown and there are no known cures. The aetiology of each condition is often genetically-related, and is usually precipitated by environmental factors. In all inflammatory diseases there is an infiltration of inflammatory cells into the affected areas which leads to a release of mediators of the inflammatory process and concomitant damage to surrounding tissue.
Treatment of inflammatory diseases is normally based on the use of steroidal and non-steroidal anti-inflammatory drugs (NSAIDs). Steroidal drugs include the corticosteroids, for example, cortisol, prednisone, prednisolone, etc. The NSAIDs include the salicylates (e.g. aspirin), pyrazolon derivatives (e.g. phenylbutazone), para-aminophenol derivatives (e.g. phenacetin and acetaminophen), fenamates (e.g. mefenamic acid and flufenamic acid), propionic acid derivatives (e.g. ibuprofen, naproxen, fenoprofen, flurbiprofen and ketoprofen), indomethacin and tolmetin. Both classes of drugs act on arachidonic acid metabolism by inhibiting reactions in the pathways leading to the formation of prostaglandins and leukotrienes. All of the aforementioned drugs have attendant undesirable side-effects with prolonged use and in recent times some NSAIDs have been contra-indicated in certain inflammatory diseases (Rampton, D. S. and Hawkey, C. J. Gut (1984) 25, 1399).
NSAIDs have been reported to inhibit both the cyclooxygenase pathway and the lipoxygenase pathway. In particular, they appear to inhibit formation of 11- and 15-hydroxyeicosatetraenoic acid (HETE). Many cyclooxygenase and lipoxygenase pathway inhibitors are currently being investigated with a view to their being used in therapy.
Benoxaprofen, an NSAID which specifically inhibits 5-lipoxygenase, in addition to cyclooxygenase, was found to markedly improve the inflammatory skin disease psoriasis. However, benoxaprofen was found to produce adverse side effects and its use in such treatment was discontinued. The search is on-going for effective and potent anti-leukotriene agents for use against inflammatory disease by inhibition of the production of the highly potent products of the 5-, 11- and 15-lipoxygenase systems.
Taurine (2-aminoethanesulphonic acid) is found in blood plasma, urine, breast milk, saliva, cerebrospinal fluid, sweat, platelets, leukocytes, muscle, brain, skin and liver. Free taurine is found in millimolar concentrations, especially in tissues that are excitable, rich in membranes and generate reactive oxidants. The function of taurine is not known but because it is abundant where reduced oxygen molecules are generated, and where other toxic substances such as bile salts, retinoids and xenobiotics are found, it is believed that its function is related to attenuation of toxic compounds. Three metabolites of taurine have now been identified viz isethionic acid (2-hydroxyethanesulphonic acid, taurocyamine (guanidotaurine) and taurocholic acid.
Taurine has been tested as an adjunct treatment of hypercholesterolemia and in cardiovascular disorders. Taurine at 1 g per day for seven days reduced or prevented alcohol-withdrawal symptoms (Ikeda, H. Lancet (1977), 2, 509).
French Patent Publication FR-A-7241 describes pharmaceutical compositions for the treatment of arterial disease, comprising taurine and derivatives thereof.
Pharmaceutical compositions for the treatment of psoriasis and comprising at least one zwitterionic aminosulphonic acid (ZASA) compound having a pKa value at 20° C. in the range 6.0-8.3 are the subject of U.S. Pat. No. 4,544,656, hereby incorporated by reference. The zwitterionic compounds include inter alia N-2-hydroxyethylpiperazine-N'-ethanesulphonic acid (HEPES). In U.S. Pat. No. 4,544,656 the anti-psoriatic effect of the ZASAs is attributed to the suppression of neutrophils. This has now been shown to be incorrect as hereinafter described. A variety of drug types are conventionally employed in the treatment of psoriasis due to the different aspects of the disease. Such drugs include anti-inflammatory drugs, anti-proliferative or cytostatic drugs and in severe cases cytotoxic drugs such as methotrexate.
U.S. Pat. No. 4,753,942, hereby incorporated by reference describes the use of the ZASAs specified in U.S. Pat. No. 4,544,656, for the topical treatment of arthritis and/or rheumatism in human patients. As demonstrated hereinafter in Example 7 skin penetration due to percutaneous absorption was not observed following topical administration of HEPES. To alleviate the symptoms of arthritis and rheumatism it would be necessary for the ZASAs to be absorbed percutaneously.
SUMMARY OF THE INVENTION
The present invention provides a method of stimulating myeloperoxidase activity in a patient in need of such stimulation, which comprises administering to said patient as active agent an effective amount of a zwitterionic compound selected from:
taurine (2-aminoethanesulphonic acid),
2(N-morpholino)ethanesulphonic acid (MES),
N-(2-acetamido)iminodiacetic acid (ADA),
piperazine-N,N'bis(2-ethanesulphonic acid (PIPES),
N-(2-acetamido)-2-aminoethanesulphonic acid (ACES),
N,N-bis(2-hydroxyethyl)-2-aminoethanesulphonic acid (BES),
3-(N-morpholino)propanesulphonic (MOPS),
N-N[tris(hydroxymethyl)-methyl]-2-aminoethanesulphonic acid (TES),
N-2-hydroxyethylpiperazine-N'-2-ethanesulphonic acid (HEPES),
N-2-hydroxyethylpiperazine-N'3-propanesulphonic acid ((H)EPPS),
2-(cyclohexylamino)ethanesulphonic acid (CHES) or 3-(cyclohexylamino)propanesulphonic acid (CAPS),
and/or an N-halo derivative thereof.
BRIEF DESCRIPTION OF THE FIGURE
The accompanying Figure is a schematic representation of the sequence of events in a neutrophil following an inflammatory stimulus.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
It has now been found that the aforementioned zwitterionic compounds and the N-halo derivatives thereof act as stimulators of the enzyme myeloperoxidase and as leukotriene inactivators as hereinafter described.
By virtue of their ability to inactivate leukotrienes, said zwitterionic compounds and N-halo derivitives thereof can be used in the treatment of inflammatory conditions or diseases, more especially inflammatory conditions or diseases that are progressive and result from autoimmunity.
In one aspect, the invention provides use of said zwitterionic compounds and/or the N-halo derivatives thereof for the treatment of chronic inflammatory conditions or diseases and the active agent is caused to enter the systemic circulation.
In another aspect, the invention provides use of taurine and/or an N-halo derivative of any zwitterionic compound as hereinbefore specified for the treatment of chronic inflammatory conditions or diseases. Thus in this aspect of the invention there is embraced topical administration of such compounds.
Chronic inflammatory diseases include rheumatoid arthritis and other inflammatory joint diseases such as ankylosing spondylitis and psoriatic arthritis, inflammatory skin diseases (psoriasis, eczema and dermatitis herpetiformis), chronic inflammatory bowel disease (Crohn's disease and ulcerative colitis), inflammatory liver disease (chronic active hepatitis and alcoholic hepatitis) and sarcoidosis of the lung.
The zwitterionic compounds and the N-halo derivatives thereof hereinbefore specified hereinafter referred to collectively as zwitterionic compounds except where the context requires otherwise also have other activities in vivo and further uses in therapy as hereinafter specified by virtue of their ability to stimulate the activity of myeloperoxidase. These further activities will be illustrated by reference to the accompanying Figure.
At the cellular level the sequence of events involved in an inflammatory reaction are as follows:- Particulate stimuli (e.g. bacteria) first become coated with complement or antibodies, whereas soluble stimuli (e.g. chemotactic peptides or calcium ionophores) act directly on leukocytes, for example, the neutrophils (1) and monocytes. The coated particles or soluble stimuli engage surface receptors on the cell which cause conformational changes leading to stimulation of the "respiratory burst" and activation of phospholipase. These will be dealt with separately, although both happen simultaneously.
In inflammatory diseases, the inflammatory process is activated in the absence of an apparent pathogenic insult. It is postulated that in many chronic inflammatory conditions that complement binds to the neutrophil surface receptors resulting in a perpetuation of the inflammatory reaction through the cyclical sequence of events depicted in the accompanying Figure, since no known pathogen is involved in such inflammatory conditions.
1. Respiratory Burst
As depicted in the Figure, molecular oxygen is converted to superoxide by NAD(P)H oxidase and is then dismutated to hydrogen peroxide by superoxide dismutase (SOD). This is toxic to the cell and is converted to water and oxygen in the cytosol by catalase. The myeloperoxidase (MPO) system can also convert hydrogen peroxide to hypochlorous acid (in the presence of chloride). Hypochlorous acid thus produced can convert leukotrienes C 4 , D 4 and E 4 to inactive metabolites.
Hypochlorous acid inactivates leukotriene B 4 by oxidative cleavage and/or halogenation. The stimulated cell releases calcium into the cytoplasm (2) which by a series of events leads to release of other inflammatory mediators from the cell (e.g. neutral proteinases). These cause tissue damage and activate the complement system, (factors which can stimulate more cells). Leukotriene B 4 and complement can cause more cells to enter the area of inflammation. Neutral proteinases can also activate the kinin system, which causes vasodilation and hence mobilisation of more cells. Superoxide can cause tissue damage directly, and can activate leukotriene production.
2. Production of Leukotrienes and Prostaglandins
The activation of phospholipase by calcium leads to release of arachidonic acid (which is stored in the membranes of all cells). The free arachidonic acid can then proceed via the lipoxygenase pathway to produce leukotrienes or by the cyclooxygenase pathway to produce prostaglandins. Prostaglandin E 2 is a major cyclooxygenase metabolite and this has the capacity to stimulate cyclic AMP formation leading to depression of the process which leads to release of inflammatory enzymes. Prostaglandin E 2 also depresses the action of leukotriene B 4 and thus limits the inflammatory process. Leukotriene B 4 can also stimulate release of inflammatory enzymes from the cell at the site of inflammation. Since leukotrienes are inactivated by hypochlorous acid, the inflammatory process is self-limiting i.e. by its own products.
The zwitterionic compounds hereinbefore specified stimulate MPO by reacting with hypochlorous acid. It is proposed that formation of the corresponding N-halo derivatives prevents feedback inhibition of hypochlorous acid on MPO leading to enhanced enzyme activity and increased metabolism of reactive oxidants as hereinafter demonstrated.
As used herein the term reactive oxidant embraces hydrogen peroxide and even hypochlorous acid.
The zwitterionic compounds can be used in the treatment of patients with hereditary MPO deficiency, a genetic disorder in which MPO is deficient in neutrophils and monocytes leading to susceptibility to infection.
By virtue of their action on MPO, the zwitterionic compounds cause removal of reactive oxidants by enhancing the metabolism thereof.
Thus the invention provides a method of using such zwitterionic compounds in the removal of reactive oxidants by enhancing the metabolism thereof. Accordingly it is proposed that such zwitterionic compounds can be used in cancer therapy and as general anti-neoplastic agents.
As indicated above, the zwitterionic compounds also indirectly stimulate production of hypochlorous acid.
It is well known that hypochlorous acid has strong anti-bacterial properties, and its production during the respiratory burst hereinabove described plays an important role in killing bacteria which are ingested by inflammatory cells in the event of infection. Thus the enhancement of MPO in vivo by the compounds hereinbefore specified in accordance with the invention has a bactericidal effect due to the promotion of hypochlorous acid production.
Accordingly, in a further aspect of the invention there is provided use of a zwitterionic compound as hereinbefore specified as an antibacterial agent.
The zwitterionic compounds hereinabove specified were first described by Good, N. E., et al. Biochemistry (1966) 5, 467, hereby incorporated by reference.
Preferred zwitterionic compounds for use in accordance with the invention are HEPES and taurine, subject to the above limitation.
Preferred N-halo derivatives of zwitterionic compounds for use in accordance with the invention are HEPES halamine and taurine halamine. Preferred N-halo derivatives are the N-chloro and N-iodo derivatives.
The invention also provides a method wherein a zwitterionic compound as hereinbefore defined is administered simultaneously, separately or sequentially with an N-halo derivative of a zwitterionic compound as hereinbefore defined.
The invention further provides a pharmaceutical composition comprising a combination of a zwitterionic compound as hereinbefore specified and an N-halo derivative of such a zwitterionic compound.
It will be appreciated that a combination of a zwitterionic compound and an N-halo derivative of such a zwitterionic compound will potentiate the effect of either compound used alone. Indeed, such combinations have been found to produce a synergistic effect in in vitro studies as hereinafter demonstrated.
The N-halo derivatives of the zwitterionic compounds as hereinbefore defined can be prepared by reacting the corresponding zwitterionic compounds with a hypohalous acid or a salt thereof.
When a salt of a hypohalous acid is used, the salt is preferably an alkali metal salt, more especially sodium.
Medicaments for use in accordance with the invention preferably contain the active ingredient in an amount of 0.05-5% by weight.
Medicaments for use in accordance with the invention may be administered locally or systemically depending on the proposed use of the active ingredient in accordance with the invention. By systemic administration is meant any mode or route of administration which results in effective levels of active ingredient appearing in the blood or at a site remote from the site of administration of said active ingredient.
The medicaments for systemic administration according to the invention may be formulated for enteral, parenteral or topical administration. Indeed, all three types of medicaments can be used simultaneously to achieve systemic administration of the active ingredient.
Suitable formulations for oral administration include capsules (hard or soft gelatine capsules) dragees, pills, tablets, including coated tablets, elixirs, suspensions and syrups, including controlled release forms thereof.
Suitable preparations for parenteral administration include injectable solutions and perfusion solutions. The injectable solutions may include intramuscular, intravenous and subcutaneous injectable solutions.
Medicaments for use according to the invention also include rectal suppositories and vaginal pessaries. A particularly suitable formulation for the treatment of inflammatory bowel disease is an enema.
Suitable formulations for topical administration include creams, gels, jellies, mucilages, pastes and ointments. The active ingredient may also be formulated for transdermal administration.
The invention will be further illustrated by the following Examples. It will be understood that the specification and examples are illustrative but not limitative of the present invention and that other embodiments within the spirit and scope of the invention will suggest themselves to those skilled in the art.
EXAMPLE 1
Taurine chloramine is prepared as follows: Taurine (500 mg) is dissolved in water (50 ml). Sodium hypochlorite (approx. 1N in 0.1N) is diluted in 1 in 100 with water. 50 ml of the taurine solution is reacted with 50 ml of the diluted sodium hypochlorite. The taurine chloramine thereby obtained is freeze dried to remove residual hypochlorite.
EXAMPLE 2
Tablets having the following composition are prepared:
______________________________________HEPES 4 mgHEPES Chloramine 4 mgLactose 50 mgAvicel 40 mgMagnesium stearate 6 mg______________________________________
by mixing the active ingredients with the other constituents and compressing the product to form the tablets.
EXAMPLE 3
Capsules are prepared having the following composition:
______________________________________HEPES 3 mgHEPES Chloramine 3 mgLactose 90 mgMagnesium stearate 7 mg______________________________________
by intimately mixing the above ingredients and pouring the mixture into hard gelatine capsules.
EXAMPLE 4
A sterile aqueous solution appropriate for parenteral use, having the following composition, is prepared:
______________________________________HEPES 4 mgHEPES Chloramine 4 mgWater for injectables 2 ml______________________________________
the solution is filled into sterile ampoules.
EXAMPLE 5
Suppositories are prepared, having the following composition:
______________________________________HEPES 5 mgHEPES Chloramine 5 mgLactose 300 mgWitespol W (Witespol ® 1.5 gis a Trade Mark) 45 g.s.p.______________________________________
The active ingredient is mixed with the lactose and then uniformly suspended in the Witespol® W 45 and heated to a molten mass in conventional manner. The suspension is poured into cooled moulds to form suppositories weighing 1.5 g.
EXAMPLE 6
A vanishing cream is made up of the following:
______________________________________ % w/w______________________________________Oil PhaseLiquid paraffin 30Span ® 65 (Span is a 1Trade Mark)Cetosteryl alcohol 5Propyl parabens 0.1Aqueous PhaseCarbopol ® 934 gel 36.5(1.0%) (Carbopol isa Trade Mark)Tween ® 85 (Tween is a 2Trade MarkGlycerol 20Taurine 5Methyl parabens 0.4______________________________________
A 1% Carbopol® 934 gel is prepared by dispersing 2 g of Carbopol® in 150 g water. The pH is adjusted to 7 with 1N NaOH. The gel is then brought to 200 g with water. The oil phase is heated to 70° C. and added to the water phase in a mortar and sheared for 30 min. with gradual reduction of temperature.
EXAMPLE 7
Investigation of skin penetration and percutaneous absorption of HEPES
The skin penetration and percutaneous absorption of radioactivity following topical administration of a single does of 14 C-HEPES (approximately 100 mg 5% cream containing 70 uCi 14 C) was investigated in two groups of six healthy male volunteers. The dose was applied to intact skin in one group and to skin stripped 10 times with scotch tape in the second group. The unabsorbed material was removed after 12 hours and the area of application was stripped 10 times in order to determine skin penetration. Blood, urine and faeces samples were collected up to 120 hours after dose application for assessment of total radioactivity.
No radioactivity was detected in any of the plasma or faecal samples, with the exception of one subject in the "stripped skin" groups for whom 0.11% of the applied dose was detected in the 48-72 hour faecal sample. Mean urinary excretion of radioactivity in the "intact" and "stripped" groups respectively was 0.07+0.08 (S.D.) and 0.20±0.22 (S.D.) percent of the applied dose.
Isolated abnormalities in biochemistry, haematology and urinalysis screens were not considered to be related to 14 C-HEPES administration.
In summary, a single topical dose of 14 C-HEPES was well tolerated in this study in both "intact" and "stripped" skin groups and there was negligible absorption of radioactivity.
IN VITRO STUDIES
Mechanism of Action
The mechanism of action of the aforementioned compounds acting as NSAIDs has been elucidated using taurine and HEPES as the ingredient except where otherwise stated, and psoriasis and other inflammatory skin diseases as a model for inflammatory disease due to the necessity to obtain permission from the regulatory authority before undertaking trials involving internal administration.
Patients were selected with mild to moderate plaque-type psoriasis on the basis of clinical and histological evidence of disease. Normal volunteers were selected from laboratory personnel without personal or family history of inflammatory disease. Disease control groups included: a) patients with eczema, acne and dermatitis herpetiformis; and b) patients with Crohn's disease and ulcerative colitis.
Blood samples from each subject were drawn into sodium heparin Vacutainers® (Vacutainer is a Trade Mark). The inflammatory cells (neutrophils) were isolated by dextran sedimentation and FICOLL-PAQUE® (FICOLL-PLAQUE is a Trade Mark) gradient centrifugation. Viability and purity were assessed by fluorescence microscopy, using ethidium bromide and acridine orange staining.
In all studies, the parameters of interest were measured after preincubation in the absence or presence of 40 mM taurine, pH 8.0 or 10 mM HEPES or other zwitterions, pH 6.0, for 1 min. at 37° C. It was demonstrated that the preincubation step was necessary for stimulation of MPO activity. Preliminary studies demonstrated that taurine or HEPES did not bind to the enzyme to produce a stimulatory effect. As indicated above the stimulation of MPO was found to be due to reaction of hypochlorous acid with taurine or HEPES, which prevents feedback inhibition of hypochlorous acid on MPO and, therefore, allows more of the enzyme to remain in its active state.
Determination of Chemiluminescence
Chemiluminescence activity of the peripheral blood neutrophils was tested using the method of Bloomfield, F. J. and Young, M. M. (Inflammation, (1982) 6, 257, hereby incorporated by reference), using calcium ionophore (2μ Molar) as stimulant instead of opsonized zymosan. Chemiluminescence is a measure of the production of reactive oxidants by neutrophils in response to an inflammatory stimulus. It was observed that there was significant reduction in chemiluminescence activity by neutrophils in the taurine-treated and HEPES-treated cells compared to control cells in all groups. The results are given in Table 1.
TABLE 1______________________________________Chemiluminesence production by neutrophils preincubated in10 mM HEPES or 40 mM taurine expressed as percentage activityof control (without zwitterion). HEPES Taurine n Mean S.E.M. n Mean S.E.M.______________________________________Psoriasis (31) 26.9 ± 3.25 (10) 15.5 ± 2.10Normal (29) 28.8 ± 4.24 (8) 12.7 ± 1.77D.C.*(a) (22) 28.8 ± 3.84 (20) 20.3 ± 1.85D.C.*(b) (37) 25.4 ± 6.4 (17) 30.5 ± 8.6______________________________________ D.C.* = Disease Controls as hereinbefore specified
In the experiments carried out, it was observed that HEPES and taurine had significantly reduced the observed response, either by inhibition of the inflammatory response (the respiratory burst) or by removal of reactive oxidants by a process hitherto unknown.
To test these hypotheses, a number of experiments were carried out.
Investigation of degranulation
Stimulation of the inflammatory process in neutrophils, not only activates the respiratory burst, but as a consequence, is also associated with release of lysosomal enzymes from the cells in a process called degranulation. Degranulation of lysosomal enzymes was stimulated in neutrophils from each group of subjects, using calcium ionophore as inflammatory stimulant. The results are given in Table 2.
TABLE 2______________________________________Degranulation by neutrophils preincubated in 10 mM HEPESexpressed as percentage activity of control (without HEPES). n Mean S.E.M.______________________________________Psoriasis (10) 104 ± 15.7Normal (28) 104 ± 15.6D.C.*(a) (6) 87.2 ± 12.1______________________________________ D.C.* = Disease Controls as hereinbefore specified
It was observed that there was no difference in degranulation by neutrophils preincubated with HEPES compared to control cells preincubated without HEPES. It was also observed that there was no significant difference in degranulation by neutrophils preincubated with taurine compared to control cells (data not shown). This suggests that HEPES or taurine does not cause suppression of neutrophils. It appeared, therefore, that the reduced chemiluminescence observed in the presence of HEPES or taurine (see Table 1) could have been due to removal of reactive oxidants produced during the respiratory burst.
Determination of Catalase and Myeloperoxidase
To test the hypothesis of increased removal of reactive oxidants by the action of HEPES or taurine, two enzymes involved in their removal were measured in the neutrophils after preincubation with HEPES or taurine. It was observed that, whereas HEPES or taurine had no effect on catalase activity (data not shown), MPO activity was significantly enhanced in all subjects in the presence of 10 mM HEPES or 40 mM taurine. The results are given in Table 3.
TABLE 3______________________________________Myeloperoxidase activity of neutrophils preincubated in10 mM HEPES or 40 mM taurine expressed as percentage activityof control (without zwitterion). HEPES Taurine n Mean S.E.M. n Mean S.E.M.______________________________________Psoriasis (44) 247 ± 30.1 (20) 591 ± 61.8Normal (24) 228 ± 25.4 (19) 564 ± 38.3D.C.*(a) (14) 198 ± 17.1 (9) 473 ± 33.7D.C.*(b) (20) 211 ± 56.4 (12) 485 ± 49.2______________________________________ D.C.* = Disease Controls as hereinbefore specified
These results suggested that as a consequence of enhanced myeloperoxidase activity the reactive oxidant, hydrogen peroxide, was being removed more rapidly and converted to hypochlorous acid (see Figure). These observations accounted for the reduced chemiluminescence activity observed in the presence of HEPES (see Table 1). It will be observed that myeloperoxidase is significantly more active in the presence of taurine than in the presence of HEPES.
Production of hypochlorous acid
The data obtained suggested that there was increased metabolism of hydrogen peroxide through the myeloperoxidase-halide system in the presence of HEPES. Increased production of hypochlorous acid by chlorination of hydrogen peroxide was also demonstrated in the presence of HEPES or taurine. The results are given in Table 4.
TABLE 4______________________________________Hypochlorous acid production by neutrophils preincubated in10 mM HEPES or 40 mM taurine expressed as percentage activityof control (without zwitterion). HEPES Taurine n Mean S.E.M. n Mean S.E.M.______________________________________Psoriasis (25) 193 ± 10.7 (18) 167 ± 34.7Normal (15) 211 ± 12.5 (15) 152 ± 14.1D.C.*(a) (20) 152 ± 8.3 (20) 142 ± 32.1______________________________________ D.C.* = Disease Controls as hereinbefore specified
It is known that hypochlorous acid plays a central role in the modulation of the inflammatory process. Taurine can form a chloramine in the presence of hypochlorous acid. Reaction of hypochlorous acid with HEPES or taurine would prevent feedback inhibition of hypochlorous acid on MPO and this would account for the enhanced enzyme activity demonstrated in the presence of HEPES or taurine (See Table 3).
Therefore, stimulation of MPO by HEPES and other zwitterions not only leads to a reduction of toxic oxygen radicals (as shown by chemiluminescence) but also leads to increased production of hypochlorous acid and chloramines which causes breakdown of leukotriene B 4 .
Production of N-halo derivatives of zwitterionic compounds (halamines).
In the presence of hypochlorous the aforementioned zwitterionic compounds form stable halamines as shown in the scheme hereunder.
HOCl+H.sub.2 N--R→ClNH--RH+H.sub.2 O
where R is the remainder of the zwitterionic compound.
In a further experiment such halamine formation was demonstrated by the method of Weiss et al (J. Clin. Invest. (1982) 70, 598, hereby incorporated by reference).
Using spectrophotometric procedures the zwitterionic compounds show no absorption between 210 and 280 nm in the ultraviolet range.
Hypochlorous acid absorbs maximally at 290 nm. The halamines formed by the zwitterionic compounds absorb maximally at 250 nm and this was demonstrated by incubating the zwitterionic compounds with hypochlorous acid.
It is proposed that formation of chloramines prevents feedback inhibition of hypochlorous acid on MPO leading to enhanced enzyme activity (See Table 3) and increased metabolism of reactive oxidants resulting in reduced chemiluminscence (See Table 1) as indicated above.
Inactivation of Leukotrienes
It is known that the MPO-halide system plays an important role in the breakdown of active leukotrienes (C 4 , D 4 and E 4 ) to inactive chiral sulphoxides and diastereoisomers of 6-trans-leukotriene B 4 (Lee, V. Y., et al. Clin. Sci. (1982) 63, 219, hereby incorporated by reference). This effect is due to the action of hypochlorous acid produced from hydrogen peroxide in the cells, by the MPO-halide system, on the active leukotrienes.
Leukotriene B 4 has also been demonstrated to be inactivated by the MPO-halide system, possibly by oxidative cleavage or halogenation (Henderson W. R., Toig, A. and Klebanoff, S. J. Immunol. (1982) 128, 2609, hereby incorporated by reference) and such inactivation of leukotriene B 4 would have potent anti-inflammatory action. It was therefore proposed to test the hypothesis that HEPES could inactivate leukotriene B 4 by indirect stimulation of MPO leading to increased production of hypochlorous acid from cellular hydrogen peroxide. It was initially demonstrated that hypochlorous acid, taurine chloramine or HEPES-chloramine cause degradation of standard leukotriene B 4 , as measured by radioimmunoassay (data not shown). Table 5 demonstrates that preincubation of cells with 10 mM HEPES or 40 mM taurine significantly reduced leukotriene B 4 in the supernatants of stimulated neutrophils of all groups. This effect was also demonstrated in monocytes, which also have the capacity to produce large amounts of leukotriene B 4 (data not shown). These results show that HEPES and taurine can indirectly cause inactivation of leukotrienes, particularly leukotriene B 4 and can be used therefore in all conditions characterised by raised leukotriene levels, including chronic inflammatory conditions.
In further studies, we observed that normal cells preincubated with HEPES in the presence of 1 mM potassium iodide showed no measurable leukotriene B 4 in the supernatants demonstrating an increased breakdown of active leukotriene B 4 by hypoiodous acid (Table 5). These data support the concept that other halide cofactors may be more effective than chloride in this system.
For the methodology used in the in vitro studies hereinafter described reference should be made to McLoughlin, D. M. et al. Biochem. Soc. Trans. (1991) 19:73-78 hereby incorporated by reference, except where otherwise stated.
The chemicals for the invention are readily available from chemical laboratory suppliers e.g. Sigma Chemical Company, St. Louis, Mo.
TABLE 5______________________________________Leukotriene B.sub.4 production by neutrophils preincubated in10 mM HEPES or 40 mM taurine expressed as percentage activityof control (without zwitterion). HEPES Taurine n Mean S.E.M. n Mean S.E.M.______________________________________Psoriasis (24) 22.4 ± 6.62 (16) 66.5 ± 10.94Normal (13) 55.8 ± 8.90 (16) 64.8 ± 8.30D.C.*(a) (13) 24.9 ± 8.99 (6) 73.3 ± 9.95D.C.*(b) (28) 16.7 ± 6.42 (9) 78.0 ± 8.60Normal + (4) 0 ± 0 -- --iodide______________________________________ D.C.* = Disease Controls as hereinbefore specified
Since inflammatory diseases are increasingly being associated with enhanced production of leukotrienes (Ford-Hutchinson, A. W., J. Allergy Clin. Immunol. (1984) 74, 437, hereby incorporated by reference), the results indicated in Table 5 demonstrate that HEPES or taurine can be used to inactivate inflammatory leukotrienes and lead to an improvement of inflammatory diseases.
The other zwitterionic compounds have been investigated and show similar effects on chemiluminescence and MPO activity. Table 6 is a summary of the effects of zwitterions on MPO and chemiluminescence activity. The same procedures were used as in the case of the MPO and chemiluminescence estimations for HEPES or taurine.
TABLE 6______________________________________Myeloperoxidase and chemiluminescence activity of normalneutrophils preincubated in 10 mM zwitterionic compound ex-pressed as percentage activity of control (without zwitterion). Myeloperoxidase ChemiluminescenceZwitterion n Mean S.E.M. n Mean S.E.M.______________________________________MES (6) 264 ± 15.9 (6) 3.15 ± 0.67ADA (4) 214 ± 32.3 (6) 1.45 ± 0.27PIPES (6) 199 ± 23.1 (6) 4.08 ± 0.97ACE (4) 166 ± 18.2 (6) 12.90 ± 2.75BES (6) 138 ± 14.1 (6) 4.95 ± 0.93MOPS (6) 134 ± 13.4 (6) 7.27 ± 1.53TES (6) 129 ± 20.1 (6) 15.60 ± 2.41(H)EPPS (4) 348 ± 15.1 (6) 50.90 ± 7.38CHES (4) 120 ± 4.8 (6) 68.40 ± 6.36CAPS (4) 115 ± 3.6 (6) 87.90 ± 8.87______________________________________
No overall correlation was observed between myeloperoxidase enhancement and chemiluminescence activity. However, it was demonstrated that (H)EPPS, MES, PIPES and ACES had a marked effect on MPO activity with BES, MOPS and TES having a lesser effect on MPO stimulation. CHES and CAPS had little effect. Chemiluminesence activity was markedly reduced in the presence of all zwitterions except (H)EPPS, CHES, and CAPS.
IN VIVO STUDIES
The effect of taurine injected intracerebroventricularly (i.c.v.) or subcutaneously (s.c.) and HEPES infected intraperitoneally (i.p.) on the modulation of carrageenan-induced paw inflammation in rats was investigated. In addition, the effect of taurine on reactive oxidant (RO) production by isolated rat peripheral blood mononuclear cells (PBMC) was also studied using chemiluminescence.
Intracerebroventricular injection of taurine
The studies were conducted on inbred Wistar strain albino rats (120-180 g) of either sex. The rats were housed in colony cages at an ambient temperature of 25°±2° C. and fed on standard pellet chow. The rats were anaesthetized using pentobarbitone sodium, their hind paws were marked and the volume measured. Stock taurine solutions were prepared in 0.9% NaCl and 10 μl was injected into the right lateral ventricle. The control animals were injected with 10 μl of 0.9% saline solution. 30 min. after the taurine injection, paw oedema was induced by carrageenan (100 μl of 1% suspension in 0.9% saline), injected below the plantar aponeurosis of the hind paws. One hour following the carrageenan injection the hind paw volume was measured again. A 5 ml blood sample was taken from each animal into sodium heparin Vacutainers. Chemiluminescence activity was assayed in the PBMC isolated from each animal.
Subcutaneous injection of taurine and intraperitoneal injection of HEPES
These studies were also conducted on inbred Wistar strain albino rats (120-180 g) of either sex. The rats were anaesthetized using pentobarbitone sodium prior to marking each hind paw and measuring paw volume. 10 μl of stock taurine or HEPES solution was made up to 0.5 ml using 0.9% NaCl and injected subcutaneously (taurine) or intraperitoneally (HEPES) into the experimental animals. The control animals received 0.5 ml of 0.9% NaCl subcutaneously. 30 min after the injections were administered, paw oedema was induced using carrageenan. One hour following carrageenan administration the hind paw volume was measured. A 5 ml blood sample was taken from each animal into sodium heparin Vacutainers and used for chemiluminescence measurement.
Isolation of PBMC
Whole rat blood (5 ml) was collected into sodium heparin Vacutainers, added 5 ml dextran, mixed thoroughly by inverting several times and allowed to sediment at room temperature for approximately 30 min. The plasma layer was removed and added to an equal volume of 0.9% saline, and centrifuged at 800 g for 5 min. at 20° C. The supernatant was disposed and the pellet retained. Residual erythrocytes were lysed by sequential addition of 3 ml of filtered deionised H 2 O and 1 ml 3.6% NaCl. The cells were centrifuged at 800 g for 5 min. and the supernatant discarded. The pellet was resuspended in 5 ml of 0.9% NaCl. This pellet contained the PBMC. The percentage of monocytes in rat PBMC is estimated at 10% of total cells and this was used for further calculations.
The results of i.c.v. injection of taurine (500 μg), on carrageenan-induced paw oedema are summarised in Table 7. Taurine administered centrally produced a dose-related attenuation of paw oedema. The 500 μg dose of taurine produced a 54% reduction in paw oedema, whereas the 50 μg dose of taurine produced a 21% reduction in paw oedema. However, the anti-inflammatory effect was only statistically significant with the 500 μg dose of taurine (P<0.05). Table 7 also outlines the results of s.c. administration of taurine (500 μg). There was an 18% reduction in paw oedema but this was not statistically significant. Intraperitoneal injection of HEPES (500 μg) produced a 50% reduction in paw oedema which was statistically significant.
TABLE 7______________________________________Effect of i.c.v. and s.c. administered taurine and i.p. administeredHEPES on carrageenan induced paw oedema in rats expressed aspercentage increase in paw volume. Control Experimental n Mean S.E.M. n Mean S.E.M.______________________________________I.C.V. (500 μg taurine) (4) 46 ± 8 (4) 21 ± 8*I.C.V. (50 μg taurine) (5) 38 ± 10 (5) 30 ± 4S.C. (500 μg taurine) (6) 33 ± 4 (6) 27 ± 2I.P. (500 μg HEPES) (4) 46 ± 5 (4) 23 ± 4*______________________________________ Significant difference from controls is indicated by *P < 0.05.
Table 8 shows the effect of i.c.v. injection of taurine (500 or 50 μg), and s.c. injection of taurine (500 μg) on the chemiluminescence response of isolated PBMC. For both concentrations of i.c.v. injection of taurine there was a statistically significant reduction in chemiluminescence (P<0.05). S.c. administration of taurine (500 μg), did not produce a significant reduction in chemiluminescence.
TABLE 8______________________________________Effect of i.c.v. and s.c. administered taurine on chemiluminescenceactivity of isolated PBMC from rats expressed as percentageactivity of control (without taurine). n Mean S.E.M.______________________________________I.C.V. (500 μg) (3) 47.3 ± 16.9*I.C.V. (50 μg) (4) 42.4 ± 2.3*S.C. (500 μg) (6) 101.1 ± 22.1______________________________________ Significant difference from controls is indicated by *P < 0.05.
It was found that taurine administered centrally produced a dose-related attenuation of carrageenan-induced paw inflammation. 500 μg of taurine injected i.c.v. produced a 54% reduction in paw oedema, whereas 50 μg of taurine produced a 21% reduction. However, the anti-inflammatory effect was only statistically significant with the 500 μg dose taurine (P<0.05). S.c. administration of taurine (500 μg) produced an 18% reduction in paw oedema but it was not statistically significant. For both concentrations of i.c.v. injected taurine there was a statistically significant decrease in chemiluminescence (P<0.05). However, administration of taurine subcutaneously (500 μg) did not produce a significant reduction in chemiluminescence.
As stated above the anti-psoriatic effect of the ZASA's is not attributable to the suppression of neutrophils as alleged in U.S. Pat. No. 4,544,656. Rather as demonstrated herein the mechanism of action of HEPES and other zwitterions is related to activation of myeloperoxidase which causes catabolism of leukotriene B 4 and as a consequence reduces the inflammatory response. | 1a
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CROSS-REFERENCE TO RELATED APPLICATIONS
This application is the U.S. National Stage under 35 U.S.C. §371 of International Application No. PCT/EP2012/066086, entitled “PHARMACY PICKING DEVICE COMPRISING A UNIVERSAL SUPPLY-AND-CONTROL MODULE,” filed on Aug. 17, 2012, which claims the benefit of European Application No. 11183529.4, filed on Sep. 30, 2011, each of which is hereby incorporated by reference in its entirety for all purposes.
FIELD OF THE INVENTION
The present invention relates to a pharmacy order picking apparatus, and, in particular, to a pharmacy order picking apparatus having a universal supply and control module.
BACKGROUND
The installation or setup of modern pharmacy order picking apparatuses generally requires three working days. As soon as the order picking apparatus has been completely set up, startup takes place, followed by calibration of the storage locations and filling. Two further days are required for this purpose, and a time span for equipping the apparatus can be extended if a large order picking apparatus is being installed in a pharmacy. The usual operation of the pharmacy is therefore disrupted for at least five days.
SUMMARY
It is the task of the present invention to make available a pharmacy order picking apparatus that can be set up and equipped in a pharmacy within a shorter time span and thereby in clearly most cost-advantageous manner than order picking apparatuses that are usual today.
This task is accomplished, according to the invention, by a pharmacy order picking apparatus comprising a housing with a plurality of shelf boards disposed one on top of the other, at least one operating device that can be moved horizontally and vertically in front of the shelf boards on a guide, having a gripping apparatus for storing and/or retrieving medication packages on or from the shelf boards, wherein the operating device can access medication packages situated in a working region, a conveying apparatus for transporting medication packages to be stored, wherein the conveying apparatus extends, at least in part, into the working region of the operating device, and a housing coupling interface that is disposed on an outer wall or within a recess of the housing, and on which the conveying apparatus borders in a predetermined position, and a universal supply and control module having the following assemblies: a feed apparatus for medication packages to be put in storage, an identification and measurement apparatus for identifying and measuring medication packages to be put in storage, operator input/output devices for input and reproduction of data and instructions by or to an operator, control electronics that control the assemblies disposed in the supply and control module, a voltage supply assembly for all the electrical assemblies of the supply and control module, a mechanical module coupling interface complementary to the housing coupling interface, and at least one electrical interface for coupling all the electrical assemblies disposed within the housing, in such a manner that their voltage supply is made available by the voltage supply assembly of the supply and control module, wherein the at least one electrical interface comprises an interface for the operating device, with which the control electronics are coupled in such a manner that the control electronics can transmit control signals to the operating device, and wherein the supply and control module is disposed adjacent to the housing, in such a manner that mechanical coupling between the housing and the supply and control module is produced by way of the housing coupling interface and the module coupling interface, so that medication packages to be put in storage are transferred to the conveying apparatus in or on the supply and control module, in a position known to the control electronics.
The pharmacy order picking apparatus according to the invention comprises two essential components, namely a housing and a universal supply and control module, where the supply and control module according to the present invention can be used with numerous housing variants. The housing itself comprises a plurality of shelf boards disposed one on top of the other, and at least one operating device that can be moved horizontally and vertically in front of the shelf boards, on a guide, having a gripping apparatus for storing and/or removing medication packages on or from the shelf boards, where the operating device can access medication packages situated in a working region. The housing furthermore comprises conveying apparatus for transporting medication packages to be stored, where this conveying apparatus extends at least in part into the working region of the operating device, so that the latter can pick no medication packages from the conveying apparatus and convey them onto a predetermined shelf board. The conveying apparatus borders on a housing coupling interface at a predetermined position, which interface is disposed on an outer wall or within a recess of the housing, where of course even those conveying apparatuses that extend outward through the housing coupling interface border on the housing coupling interface.
The pharmacy order picking apparatus according to the invention furthermore comprises a universal supply and control module having a number of assemblies, namely a feed apparatus for medication packages to be put in storage, an identification and measurement apparatus for identifying and measuring medication packages to be put in storage, operator input/output devices for input and reproduction of data and instructions by and to an operator, control electronics that control the assemblies disposed in the supply and control module, a voltage supply assembly for all the electrical assemblies of the supply and control module, a mechanical module coupling interface complementary to the housing coupling interface, and at least one electrical interface for coupling all the electrical assemblies disposed within the housing, where this coupling is carried out in such a manner that the voltage supply of the electrical assemblies disposed in the housing is made available by the voltage supply assembly of the supply and control module.
The aforementioned assemblies can be installed separately in the supply and control module, but it is also possible that multiple assemblies or apparatuses are combined with one another, where it is ensured, however, that the respective functions of the individual assemblies/apparatuses can be implemented. Thus, it is possible, for example, that the identification and measurement apparatus is combined in a collective assembly with the feed apparatus, where this assembly then makes the functions of the individual assemblies available.
Furthermore, it is also possible that parts of assemblies of the housing are integrated into assemblies of the supply and control module (an example of this follows below). Therefore, if assemblies or apparatuses are mentioned within the scope of this application, this is not meant to imply that these are all structured separately.
The at least one electrical interface comprises an interface for the operating device, with which the control electronics are coupled in such a manner that the control electronics can transmit control signals to the operating device.
The supply and control module is disposed adjacent to the housing, in such a manner that mechanical coupling between the housing and the supply and control module is produced by way of the housing coupling interface and the module coupling interface, so that medication packages to be put in storage are transferred to the conveying apparatus in or on the supply and control module, at a position known to the control electronics.
In the pharmacy order picking apparatus according to the invention, a major portion of the electrical assemblies is disposed in the supply and control module, and these assemblies, which are essential for proper operation of the order picking apparatus, can already be connected in the factory and synchronized with one another and calibrated. It is no longer necessary to connect the different electrical assemblies with one another and calibrate the on site, during installation of the order picking apparatus.
During the setup or installation of an order picking apparatus according to the invention, first the housing, which makes the actual storage location for the medication packages available, by way of the multiple shelf boards, is set up. The housing and the related shelf boards themselves can be set up very rapidly, because this is a rather simple design. Only the operating device that can be moved on a guide requires a connection with the central control electronics of the order picking apparatus.
As soon as the housing has been set up, the supply and control module is disposed at the housing coupling interface, and mechanical coupling between the housing and the supply and control module is produced by way of the module coupling interface. Furthermore, an electrical break-through between the operating device and the control electronics is produced by way of the at least one electrical interface (in other words also between the housing and the supply and control module), so that the control electronics can transmit control signals to the operating device. In the order picking apparatus according to the invention, only one mechanical and one electrical connection therefore have to be produced; all the other error-prone electrical connections were already produced before the start of setup of the order picking apparatus, namely during production of the supply and control module. The setup time is significantly reduced by this because the work for electrical connection and coupling of different assemblies no longer needs to be performed on site, but rather is already performed at the manufacturer's location, during production of the supply and control module.
The universal supply and control module should be disposed at the housing coupling interface with its module coupling interface. The coupling interface of the housing can be disposed on any desired outside wall; the precise placement, of the coupling interface in the housing itself is primarily determined by the spatial conditions in a pharmacy. If the aforementioned spatial conditions permit, it is preferred that the housing has a recess (for example at a corner, if the housing itself is structured to be rectangular), in which the universal supply and control module is disposed. In this method of placement of the supply and control module in a recess of the housing, it is furthermore preferred that the front of the universal supply and control module ends with the front of the housing.
Storage the medication packages takes place on a plurality of shelf boards, disposed one on top of the other, in front of which an operating device having a gripping apparatus can be moved horizontally and vertically. To increase the accommodation capacity of the order picking apparatus, it is preferred that the plurality of shelf boards disposed one on to of the other form two shelf rows, between which an alleyway is defined, in which the guide of the operating device is disposed in such a manner that the operating device having the gripping apparatus can access the shelf boards of both shelf rows. In such a case, the gripping apparatus, as such, can be rotated about the vertical axis, for example, or can have movable gripping laws that can be moved into the shelf boards on both sides of the alleyway.
Because of the great storage capacity, it can be practical, particularly in the case of such a configuration of the order picking, apparatus, to use a plurality of operating devices. The use of the term “shelf rows” is not supposed to imply that these must run parallel to one another. If the spatial conditions require, the “rows” can also be curved; in such a case, the guide of the operating device(s) must be adapted accordingly.
The operating device is displaceable along the guide (x direction), for one thing. Furthermore, at least the gripping apparatus of the operating device is displaceable in terms of height (y direction). The drive for the movement of the gripping apparatus in the y direction is disposed on the operating device itself. The drive unit for the movement of the operating device along the guide can be disposed on the operating device itself, for one thing. In this case, the operating device to displaced together with the drive unit, on a fixed guide. To reduce the cables required between the operating device and the control electronics of the order picking apparatus, however, it is preferred that the drive unit for the movement of the operating device is disposed in the universal supply and control module. This drive unit is then coupled with the operating device, for example by way of a belt drive, and moves the operating device in the x direction, along the guide. Such an arrangement furthermore has the advantage that in the event or a malfunction of the drive unit for the movement in the x direction, the drive unit itself is easier to reach and to replace, if necessary. Furthermore, it is advantageous that the heat produced by the drive unit is not dissipated directly into the storage space of the medication packages. To avoid complicated coupling between drive unit and operating device, it is preferred that at least a part of the drive unit is introduced into the housing, by way of an opening in the latter, after installation of the supply and control module, so that a drive belt, for example, can be easily coupled.
The feed apparatus of the supply and control module serves for placement of the medication packages in storage, where the feed apparatus is the location of the order picking apparatus at which the operator supplies the medication packages to the apparatus himself.
A single package or a plurality of medication packages is placed into or onto the feed apparatus by an operator.
It is particularly preferred that a section of the conveying apparatus of the housing is passed out of the housing at the housing coupling interface, and projects into the universal supply and control module by way of the module coupling interface, and, in this connection, mechanical coupling between the housing and the supply and control module is produced. In such a case, the medication packages in the supply and control module are transferred to the conveying apparatus at a position known to the control electronics. This has the advantage that only one conveying apparatus is provided in the order picking apparatus, and thereby the additional construction effort for a second conveying device in the supply and control module is eliminated. In this case, a section of the conveying apparatus makes a part of the feed apparatus available (see above).
However, it can become necessary, for structural reasons, for example, that a conveying apparatus is also provided in the supply and control module, which then is part of the feed apparatus. The packages are then placed by the operator onto the conveying apparatus of the supply and control module, and are transferred from the conveying apparatus in the module be the conveying apparatus of the housing, in the region of the transition between housing coupling interface/module coupling interface.
The feed apparatus can also comprise a drawer system into which medication packages are placed by a user. This drawer system can be structured in such a manner that it is passed into the housing at the transition between housing coupling interface/module coupling interface, and, in the housing, is passed into the working region of the operating device. Although this her disadvantages with regard to the operability of the order picking apparatus, the costs are correspondingly lower, because the medication packages are essentially introduced into the housing by hand (where they are then taken up by the operating device). In this case, the conveying apparatus is made available by a component of the feed apparatus.
In on preferred exemplary embodiment, the conveying apparatus comprises an endless conveyor belt onto which the medication packages are transferred. Such an endless conveyor belt is cost-advantageous and can be quickly replaced in the event of damage. This endless belt can extend all the way into the supply and control module (see above).
Because of the concentration of the electrical assemblies in the supply and control module, the heat development is restricted to a small space. To avoid an overly high temperature in the supply and control module, the universal supply and control module preferably comprises a ventilation apparatus having an air intake device, air guides, and air exits. The air guides are preferably configured in such a manner than no air enters into the housing, in order to thereby prevent the storage region for the medication packages from heating up. It is practical if the air intake device is disposed in the bottom region, and the air exits are disposed in the upper region of the supply and control module.
BRIEF DESCRIPTION OF THE DRAWINGS
In the following, the present invention Will be described with reference to the drawing, in which
FIGS. 1A and 1B show schematic top views of a first and a second exemplary embodiment of the order picking apparatus according to the invention,
FIG. 2 shows a schematic side view of a further exemplary embodiment of the order picking apparatus according to the invention, and
FIG. 3 shows a detailed, slanted view of a supply end control module of a further exemplary embodiment of the order picking apparatus according to the invention.
DETAILED DESCRIPTION
FIG. 1A shows a schematic top view of a first exemplary embodiment of the order picking apparatus 1 according to the invention, having a housing 10 and a supply and control module 20 . On an outer wall, the housing 10 comprises a housing coupling interface 15 , and the supply and control module 20 also comprises a coupling interface 26 on an outer side. The supply and control module 20 is disposed at the housing coupling interface 15 of the housing 10 , on the outer wall of the housing 10 , specifically in such a manner that the module coupling interface 26 lies opposite the housing coupling interface 15 , and thereby mechanical coupling between the housing 10 and the supply and control module 20 is made available.
The housing 10 comprises a conveying apparatus 14 , which is introduced into the supply and control module 20 at the housing coupling interface 15 , from the latter through the module coupling interface 26 , and the section of the conveying apparatus 14 passed through the supply and control module 20 is part of the feed apparatus 21 , not shown in any detail in this view. A plurality of shelf boards 11 is disposed in the housing 10 , which boards form two parallel shelf rows. An alleyway is defined between the shelf rows, and a guide 15 for the operating device 12 and its gripping apparatus 13 is disposed in this alleyway. Furthermore, an electrical connection is made available between the housing 10 and the supply and control module 20 , by way of the interface 27 .
FIG. 1B shows a schematic top view of a second exemplary embodiment of the order picking apparatus 1 according to the invention. In this exemplary embodiment, as well, the order picking apparatus 1 comprises a housing 10 . In contrast to the first exemplary embodiment shown in FIG. 1A , the housing 10 comprises a recess in which the supply and control module 20 is disposed. In this second exemplary embodiment, as well, the housing 10 comprises a conveying device 14 , where a section of this conveying device 14 is passed into and through the supply and control module 20 by way of the housing coupling interface 15 and the module coupling interface 26 . Furthermore, an electrical interface 27 is disposed adjacent to the coupling interfaces 15 , 26 . The housing 10 comprises a number of shelf boards 11 in this exemplary embodiment, as well, which form two shelf rows in the exemplary embodiment shown, which define an alleyway between them, in which a guide 16 for an operating device 12 having a gripping apparatus 13 is disposed. In the exemplary embodiment shown in FIG. 1B , the drive unit for the movement of the operating device along the guide 16 (x direction) is disposed within the supply and control module 20 and coupled with the operating device 12 in such a manner that the latter can be moved along the x direction. Corresponding coupling can take place using a belt drive, for example, where in such a case, corresponding deflection rolls must be provided in the housing or at the guide 16 .
FIG. 2 shows a schematic side view of a further exemplary embodiment of the order picking apparatus 1 . This comprises a housing 10 and a supply and control module 20 . A plurality of shelf boards 11 , disposed one on top of the other, are disposed in the housing 10 , on which boards a plurality of medication packages 40 are or can be disposed. An operating device 12 can be moved in the x direction, on a guide 16 . This operating device 12 comprises a gripping apparatus 13 , which can be moved in the y direction. The drive unit for the movement of the operating device 12 in the x direction can be disposed at the foot of the operating device 12 , for example, but also in the supply and control module 20 ; the precise placement of the drive unit depends on the spatial configuration of the order picking apparatus (see description of FIGS. 1A and 1B ). Furthermore, a conveying apparatus 14 having an endless conveyor belt 14 a is disposed in the housing 10 , where in the exemplary embodiment shown, a section of the conveying apparatus 14 extends through the housing coupling interface 15 and the module coupling interface 26 into and through the feed apparatus 21 of the control and supply module 20 . In the exemplary embodiment shown, the part of the conveying apparatus 14 that exits out of the housing 10 is part of the feed apparatus 21 , so that transfer of the medication packages from a separate conveying apparatus in the supply and control module 20 onto a conveying apparatus of the housing is not required.
The module coupling interface 26 of the supply and control module 20 is disposed on an outer side or outer wall of the supply and control module, facing the housing, where the module itself is disposed in such manner, with regard to the housing 10 , that mechanical coupling between the housing 10 and the supply and control module 20 is made available by we of the housing coupling interface 15 and the module coupling interface 26 . Mechanical coupling is furthermore achieved by way of introducing the section of the conveying apparatus 14 into the feed apparatus 21 and passing it through.
Furthermore, an electrical connection exists between the housing 10 and the supply and control module 20 , at the electrical interface 27 . For one thing, the voltage supply of all the electrical assemblies within the housing takes place by way of this interface, and for another, control signals from the control electronics are transmitted to the operating device 12 , by way of a special interface or an interface section. As can be seen in FIG. 2 , there are only two interfaces between the housing 10 and the supply and control module 20 , namely a mechanical one and an electrical one; the work during installation or setup of the order picking apparatus is therefore restricted to one interface, with regard to coupling of electrical components, so that the setup time is clearly reduced.
In the exemplary embodiment shown, an identification and measurement apparatus 22 is disposed in the supply and control module 20 , within the feed apparatus 21 . In other exemplary embodiments, the identification and measurement apparatus can also be disposed outside of the feed apparatus 21 . The universal supply and control module 20 furthermore comprises operator input/output devices 23 (a monitor having a touch screen) for input and reproduction of data and instructions by or to the operator. The control electronics 24 , and, adjacent to them, the voltage supply assembly 25 are disposed in the lower section of the supply and control module 20 . These two assemblies generate a major portion of the heat that occurs in the supply and control module 20 , so that in the exemplary embodiment shown, an air intake device 30 is disposed under these assemblies, by way of which cool outside air is passed to the supply and control module 20 . The air drawn in is passed through the module by way of air guides, not shown, and exits out of the supply and control module 20 in the upper region, at air exits 31 this connection, the air guides are preferably configured in such a manner that no air enters into the housing 10 , in order to minimize introduction of heat and dirt into the housing in this manner.
FIG. 3 shows a detailed slanted view of a supply and control module 20 of a further exemplary embodiment of the order picking apparatus according to the invention. The supply and control module 20 comprises an air intake 30 of a ventilation apparatus in the lower region. Furthermore, the voltage supply assembly 25 and the control electronics 24 are disposed in the lower region. The feed apparatus 21 is disposed above the control electronics 24 . In the exemplary embodiment shown, this apparatus comprises a vertically movable barrier 21 a that serves, among other things, to lay medication packages onto to conveying means not shown in a defined orientation. In the exemplary embodiment shown, the feed apparatus 21 does not comprise a conveying apparatus for the medication packages. This apparatus is made available, as is particularly described in FIG. 2 , by the housing of the order picking apparatus, at the housing coupling interface of which a section of the conveying apparatus projects out of the housing, and during assembly of the order picking apparatus, is introduced into the feed apparatus, thereby causing the section of the conveying apparatus that projects out of the housing to become part of the feed apparatus 21 . A region for operator input/output devices 23 is provided above the feed apparatus 21 , where in the exemplary embodiment shown, these devices are not shown, for the sake of clarity. In this exemplary embodiment, a redundant uninterruptible power supply 28 is furthermore disposed in the upper region of the supply and control module 20 . Finally, air exits 31 are disposed in the ceiling section the supply and control module 20 . | 1a
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BACKGROUND OF THE INVENTION
This invention involves a device and method of using the device to facilitate essentially all exercise of a person's hand and wrist. More specifically, the device definitely aids in wrist flexion and extension as well as ulnar and radial deviation, and is even effective for supination and pronation of the hand and wrist.
The incidence of carpal tunnel syndrome is a relatively common malady among persons using the wrist and hands, including typists, dental hygienists, piece workers, chiropractors, meat cutters and the like. Carpal tunnel syndrome involves breakdown of the tunnel such that the median nerve is aggravated or possibly injured in contact with the bones of the wrist. Surgery has certainly not always been successful and entails risk. Immobilization cocks the wrist to take pressure off the median nerve. While a variety of treatments have been suggested, including surgery, none of the treatments provide an absolute answer to the problem. Further, racket sports such as tennis and racquetball sometimes cause the player to strain a tendon, pull a muscle and generally suffer from various ailments grouped under the title "Tennis Elbow". Manipulation can in many cases improve the positioning of the bones and ligaments to reduce pressure on the median nerve. Physical therapy including ultrasound is sometimes effective in combination with other techniques. Absolute abstinence from using the hand and arm is sometimes prescribed. Stretching and strengthening exercises have been recommended and are effective in treating the syndrome. However, the techniques are difficult to master to achieve the best results.
Various devices such as the hand and wrist exercising device of U.S. Pat. No. 4,836,531 to Mikhail Niks describes a device which is used to exercise the wrist through a pronation and supination movement. The exerciser device described in U.S. Pat. No. 2,819,081 to John Touraine describes a device also to exercise the wrist and arm in a rotating movement. None of the above devices or any of the various treatments have provided a satisfactory solution alone or in combination to treat tennis elbow and/or carpal tunnel syndrome.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a device and method that will aid a person in the exercise of the hands, wrist and lower arm in essentially all movements to the fullest degree of movement possible.
It is an additional object to provide a device and method to achieve full movement in the three couplets of flexural and extension, ulnar and radial deviation, and even pronation and supination.
It is a further object of the present invention to provide a device that will allow support for the hand and wrist and aid in hand and wrist exercises with the movement of the device maintaining a proper rocking action to aid in the exercise.
A particular object of the present invention is to provide a full flexural movement of the small bones in the wrist to aid in manipulation and improve the condition of the carpal tunnel syndrome sensory involvement sufferer.
It a particular object of the present invention to provide a device that may be kept at the person's work station to be used at regular intervals to stretch the fatigued members and aid in the prevention of carpal tunnel syndrome.
It is a specific object of the present invention to provide a device on which the person rests the ends of the fingers on one horizontal member and supports the wrist at the break on a rear horizontal member and that the distance between those horizontal members is adjustable and fixed for various hand sizes.
An aspect of the invention is a device on which a person can place a wrist and ends of digits two through four, all of one hand, to rock the device on a surface to aid in exercising. The device includes two upper horizontal members each including two ends and a length with a horizontal top surface. The device further includes two body members each including two upper ends and a curved bottom surface that includes a center section that can rest on the surface and in combination support the device, and two rounded sections extending from the center section in opposite directions. The device also includes connection means to connect the two body members to fix the bottom surfaces in a parallel relationship to each other, wherein the bottom surfaces are in a curved plane which abuts the surface as the device is rocked back and forth. The device further includes attachment means to attach the ends of the two upper horizontal members to the upper ends of the two body members and to fix the horizontal top surfaces of the two upper horizontal members in parallel relationship to each other at a distance from each other that when the wrist of the one hand is rested flat on one horizontal top surface the tips of digits two through four of the hand span the distance and can rest on the opposite horizontal top surface, and above the curved plane a sufficient distance that when the wrist of the one hand is rested flat on one horizontal top surface and the tips of digits two through four of the hand are rested on the opposite horizontal top surface and the device is rocked back and forth on the curved plane, the maximum range of motion of the wrist is reached.
It is preferred that the attachment means be adjustable to adjust the distance between the horizontal top surfaces of the two upper horizontal members without changing length or shape of the curved plane. It is also preferred that the attachment means include extension members extending from each upper end of the body members, wherein the ends of the two upper horizontal members are rigidly connected to the extension members, and that the attachment means further include pivot connection means pivotally connecting lower ends of the extension members to the upper ends of the body members allowing the distance between the two upper horizontal members to be adjusted and fixed in a chosen position. It is further preferred that the center sections of the curved bottom surfaces be about one inch long and be curved end to end on a line with a radius of at least about four inches and the rounded sections of the bottom surfaces have a radius of about one to about three inches. It is more preferred that the center sections of the curved bottom surfaces be about one inch long and are curved end to end on a line with a radius of about three inches to about ten inches. It is most preferred that the center sections of the curved bottom surfaces be about one inch long and be curved end to end on a line with a radius of about five inches and the rounded sections of the bottom surfaces have a radius of about two inches. It is also preferred that a distance of upper horizontal surfaces above the center sections of the curved bottom surfaces be about three to five inches, and more preferred be about four inches. It is further preferred that the length of the upper horizontal surfaces and a distance between the curved bottom surfaces both be about four inches. It is preferred that at least one and more preferably only one of the upper horizontal members include a plurality of rings positioned horizontally and sized to receive ends of the digits of the hand. It is further preferred that the attachment means rotatably attaches the upper horizontal member comprising a plurality of rings to allow it to turn around a lengthwise axis.
Another aspect of the invention is a method of a person exercising a wrist that includes providing a device as described above. The method further includes placing the device on a flat surface resting on the curved bottom surfaces and placing a wrist on the horizontal top surface of one of the upper horizontal members and at least one end of digits two through four of the same hand on the horizontal top surface of the remaining upper horizontal member spanning the distance between the horizontal top surfaces, and rocking the device back and forth repetitively on the curved plane of the curved bottom surfaces. It is preferred that the method further include providing the device wherein at least one of the upper horizontal members comprises a plurality of rings positioned horizontally and sized to receive ends of the digits of the hand, and then inserting ends of the digits of the hand into the rings and resting an inside surface the wrist on the remaining upper horizontal member prior to rocking the device.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of a device of the present invention.
FIG. 2 is a cross-sectional view taken along 2--2 of FIG. 1.
FIG. 3 starting position shows use of the device illustrated in FIGS. 1 and 2 in a flexural extension exercise.
FIG. 3a shows use of the device thereof in flexure.
FIG. 3b shows use of the device thereof in extension.
FIG. 4 show the use of the device illustrated in FIGS. 1 and 2 with a pronation exercise.
FIG. 4a shows use of the device thereof in ulnar deviation.
FIG. 4b shows use of the device thereof in radial deviation.
FIG. 5 is a partial perspective view a second embodiment of the invention.
FIG. 5a is a cross-sectional view taken along lines 5a--5a of FIG. 5.
FIG. 6 is a partial front elevational view of a third embodiment of the invention.
FIG. 6a is a cross-sectional view taken along lines 6a--6a of FIG. 6
FIG. 6b is a cross-sectional view similar to FIG. 6a with the attachment disengaged.
FIG. 6c is a cut-away front elevational view similar to FIG. 6 with the extensions rotated.
FIG. 7 is a perspective view of a fourth embodiment of the invention.
FIG. 7a is a partial cross-sectional view taken along lines 7a--7a of FIG. 7.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Exercise device 10 is illustrated in FIG. 1 constructed of left body member 12 and right body member 14 connected through horizontal rod connection member 16, rear upper horizontal member 18 and front upper horizontal member 20. All of these members may be constructed of a variety of materials including thermoplastic polymers, wood, aluminum and any of the various materials of that class. It is preferably light in weight and may be connected in to a integral unit permanently or may be able to be broken down by providing that each member force fit into the other. Device 10 may be used in any horizontal position and the sides are identified for clarity purposes only. Rear upper horizontal member 18 is connected at end 24 to upper end section 38 of right body member 14 and at end 26 to upper end section 34 of the left body member 14. Likewise, front upper horizontal member 20 is connected at end 30 to upper end section 40 of right body member 14 and at end 32 to upper end section 36 of left body member 12. Horizontal member 18 provides horizontal top surface 22 while front horizontal member 20 provides horizontal top surface 28. With body members 12 and 14 connected together, a curved rocking plane is formed by curved bottom surface 42 of member 12 and curved bottom surface 44 of member 14 on which device 10 rocks forwardly and backwardly to aid in the exercise of the hand and wrist. Curved bottom surface 42 includes center section 46 as well as rear curved end section 48 and front curved end section 50. The sections of curved bottom surface 44 are shown in FIG. 2 consisting of center section 58, front curved section 60 and rear curved section 62. In this embodiment, the center sections of bottom curved surfaces 42 and 44 are each about one inch long with a curvature of a radius of about five inches with the front and rear curved sections having a radius of about two inches. The vertical distance between a line drawn between upper horizontal surfaces 22 and 28 and a line drawn between center sections 46 and 58 is about four inches. The length of the upper horizontal surfaces are both about four inches.
In FIGS. 3 through 4b, use of device 10 is illustrated. FIGS. 3 through 3b illustrate flexion and extension movements while FIGS. 4 through 4b illustrate ulnar and radial deviation movements. In FIG. 3, hand 52 is placed on device 10 resting digits 54 two through four (digits three and four are hidden) on front horizontal top surface 28 and the inside of wrist 55 on rear horizontal top surface 22 spanning the distance of about six inches between these upper horizontal surfaces. Device 10 rests with center sections 46 and 48 resting on table surface 56. In FIG. 3a, pressure is applied by the digits to rock the device 10 forwardly on front curved sections 50 and 60 bending wrist 55 in a flexion movement up to a maximum range of movement of about eighty degrees. While continuing to maintain the digits 54 and wrist on the upper horizontal surfaces, device 10 is rocked rearwardly as illustrated in FIG. 3b rocking the device onto rear curved end sections 48 and 62 conducting an extension exercise up to a maximum range of motion of about seventy degrees. This exercise is repeated a multiplicity of repetitions for best benefit. To conduct the ulnar and radial deviation exercise hand 52 is placed on device 10 as illustrated in FIG. 4 with the end of digit four 64 resting on front upper surface 28 and side of wrist 55 resting on rear upper horizontal surface 22 with the hand 52 in a generally vertical position. Again at the start of this exercise, and when at rest, device 10 rests on center sections 46 and 58. In conducting ulnar deviation movement, as illustrated in FIG. 4a, device 10 is rocked forwardly so that it rests on front curved sections 50 and 60 to attain a maximum range of motion of about thirty degrees. Continuing exercise as illustrated in FIG. 4c, device 10 is rocked rearwardly so that it rests on rear curved end sections 48 and 62 on table surface 56 to achieve radial deviation up to a maximum range of motion of about twenty degrees. Although not illustrated, the device can also provide a pronation and supination exercise. The thumb and little finger (first and fifth digits) are stretched across the device, one resting on the front horizontal surface 22 and the other resting on the rear horizontal top surface 28. Again, the device is rocked forwardly and rearwardly on the curved plane of the bottom surfaces 42 and 44 to achieve a range of motion close to the maximum.
The balance of the embodiments illustrated in the later figures all include mechanisms to adjust the distances between the upper horizontal surfaces. It also should be understood that the invention includes a continuous horizontal surface stretching between the front and rear upper horizontal surfaces. To conserve material and to limit the weight of the device it is preferred to provide an adjustment that allows the distance between the upper horizontal surfaces to be reduced to about five inches and increased to about seven inches to compensate for different hand sizes. In FIG. 5, and all subsequent figures all similar elements to that of device 10 are designated with a "prime" or multiple "primes" after any number designation identifying an element of device 10. In device 68, as shown in FIG. 5, all the upper end sections of the body members are separate part extensions although only upper end section 34' is illustrated. Upper end 70 of left body member 12' interfits between depending sections 72 and 74 of upper end section 34'. Bolt 76 extends through aligned holes through sections 72 and 74 and end 70 sandwiched between the two depending members. Wing nut 78 pressures the three parts together to hold upper end extension 34 in any chosen position. The balance of device 68 is similar to device 10 and similar attachments are provided for the balance of the three upper end sections/extensions 36', 38', 40', not illustrated herein. A portion of device 80, again like device 10 where not shown, is illustrated in FIG. 6, showing connection between the body members and the separate but connected upper end extensions 34", 36", 38", and 40". Spaced teeth 82 are positioned on a convex arc on the ends of base body member 12". As shown in FIG. 6 teeth 82 engage complimentary teeth 84 opposed and extending from a concave surface of upper end extension 34". As further illustrated in FIG. 6a, the two parts are held together in pivotal connection by bolt 86 with spring 88 positioned in recess 90 allowing body member 12" to be biased away from engagement of extension 34", to disengage teeth 82 and 84 from each other. As shown in FIG. 6b, this mechanism allows the radial alignment of member 34" from body member 12" to change the length between the upper horizontal surfaces as illustrated in FIG. 6c. Once aligned to the right distance, engagement is released to allow the teeth to reengage under spring pressure to hold the device as illustrated in FIG. 6a. Device 92 as shown in FIGS. 7 and 7a incorporates an alternative embodiment for adjustment of distance between the upper horizontal surfaces as well as a modified front upper horizontal member 102. Adjustment of the length between the upper horizontal surfaces is attained by providing upper end 94 of base member 12'" with serrated hole 96 and providing a complimentary overlapping extension 98 with ridged pin 100 force interfitting into hole 96 in various radial positions to adjust the angle between extension member 36'" and base member 12'". Front horizontal member 102 includes round rod ends which interfit into horizontal holes 104 on the inside surfaces of extension members 36'" and 40'" with a force fit, but allowing the member to be rotated in position for other exercises. Rings 106 are sized to receive the fingers of the hand for improved stability of the device during exercise of flexion and extension. Rear upper horizontal member 18'" is identical to that of member 18 in device 10.
While this invention has been described with reference to the specific embodiments disclosed herein, it is not confined to the details set forth and the patent is intended to include modifications and changes which may come within and extend from the following claims. | 1a
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CROSS REFERENCE TO RELATED APPLICATIONS
U.S. patent application Ser. No. 11/927,866 filed Oct. 30, 2007 (Our Ref. 2-5169-110), is hereby incorporated by reference herein in its entirety.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not applicable.
REFERENCE TO MICROFICHE APPENDIX
Not applicable.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates generally to an agricultural implement, including a floating header. More particularly, the present invention relates to an improved suspension system for agricultural implements having one or more floating headers wherein the suspension hydraulic cylinders are also used to lift the header for transport.
2. Background Art
A three-point mounted mower with a suspension system is disclosed in U.S. patent application Ser. No. 5,417,042. Disclosed in this application is an example of a mower suspension system with separate elements having a first and a second chamber and separate fluid inlets. These pairs are intended for different functions. One pair is used to lift to a transport position while the other pair is used to transfer oil during operation to suspend the header.
Another example of a three-point mounted mower is disclosed in U.S. Pat. No. 6,085,501. This patent describes a machine where the frame is not lifted to raise the header to a transport position, but where there are effectively two separate cylinders, one to lift into transport, another to suspend the header. The patent describes separate hydraulic rams.
An example of a typical suspension for a trailed mower or mower conditioner is disclosed in U.S. patent application Ser. No. 6,055,800, wherein a cylinder lifts the frame and header to a transport position, while a spring provides a lift force to suspend the header in working position.
The multiplicity of components for lifting and suspending a floating header on a fixed-frame agricultural implement increases complexity, cost, while decreasing reliability.
There is, therefore, a need for a method and apparatus for both lifting and providing suspension for a floating header on a fixed-frame agricultural implement such as a mower.
BRIEF SUMMARY OF THE INVENTION
An object of the present invention is to provide a suspension system for implements having a floating header. The suspension system shall permit the floating header to contact the ground with an appropriate pressure. Another object of this invention is to provide the suspension using the same hydraulic cylinders used to lift the floating header.
In a first embodiment of the present invention, rams in the lift/flotation cylinders of the suspension system are in compression as they raise the header. In a second embodiment of this invention, the ram of the lift/flotation cylinder is in tension as it lifts the floating header.
In both embodiments, a hydraulic accumulator is used to allow for changes in a hydraulic cylinders' extension during operation without the usual valve manipulation to achieve those position changes.
A take-up cylinder is incorporated with lift/flotation cylinders and the hydraulic accumulator to raise and lower the header. When the take-up cylinder is fully retracted, the hydraulic accumulator and the lift/flotation cylinders have reached their greatest pressures, and the lift/flotation cylinders their full extension so the header is fully raised.
A valve is then opened slightly to allow the hydraulic accumulator to depressurize and the take-up cylinder to extend somewhat with the header under the force of gravity. When a predetermined pressure is achieved in the hydraulic accumulator, the valve is again closed. At this predetermined pressure, the header bears on the ground surface with the required force.
In the second embodiment, a lift/flotation cylinder is connected to the hydraulic accumulator by its retract port, thereby raising a sub-frame by retraction. The process is the same as that given for the first embodiment.
Other objects, advantages and novel features of the present invention will become apparent from the following detailed description of the invention when considered in conjunction with the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of a towed agricultural mower having two hydraulic suspension cylinders mounted on the outer edges wherein the header is in a raised position;
FIG. 2 a is a first side elevation view of the agricultural mower with an accumulator also visible;
FIG. 2 b is a second side elevation view of the agricultural mower with the header in a lowered position;
FIG. 3 is a schematic representation of the mower hydraulic system;
FIG. 4 is an exploded view of the hydraulic circuit in the embodiment of FIG. 1 ;
FIG. 5 a is an isometric view of a mower in a transport configuration in an alternative embodiment as used on a multi-frame mower having the main frame and sub-frame connected by a single, one-way suspension cylinder;
FIG. 5 b is a side elevation view of the rear of the mower in the alternative embodiment shown in FIG. 5 a;
FIG. 5 c provides a visual layout of the hydraulic circuit in the alternative embodiment as in FIG. 5 a ; and
FIG. 5 d is a schematic representation of the alternative embodiment of the mower hydraulic system.
DETAILED DESCRIPTION OF THE INVENTION
The agricultural mower to which the present invention is applied is a towed, trailed, or drawn mower. This is in contrast to a tractor-mounted mower. Towed mowers have different suspension needs than do mounted mowers, as towed mowers are supported by the ground, independent of the tractor.
Referring now to the drawings wherein like reference numerals correspond to the same or similar parts throughout the drawings, the present invention includes a system for suspending a header 6 from a fixed-frame agricultural mower using hydraulic cylinders 14 and an accumulator 40 . (A fixed-frame, for the purposes of this document, including the claims, is herein defined as a frame that does not articulate linearly relative to a ground-engaging wheel axle.) The header 6 , in turn, supports a cutter bar 9 . In a first embodiment, shown in FIGS. 1-4 , a fixed-frame, towed mower 1 is equipped with two one-way hydraulic suspension cylinders 14 located at the outer edges of the frame 15 and supporting the header 6 via pivoting links 42 . The pitch control hydraulic cylinder 13 controls the orientation of the cutter bar 9 in relation to the ground, known as pitch, while the tongue swing cylinder 17 is used to control the orientation of the tongue 2 in relation to the frame 15 .
FIG. 3 illustrates the hydraulic circuits, including the tongue circuit for controlling tongue swing cylinder 17 , with a first tractor remote valve, and the header circuit for controlling the pitch control cylinder 13 and hydraulic suspension cylinders 14 with a second tractor remote valve. The header circuit provides three functions including control of header tilt, flotation, and lift. The flotation is provided by a hydro-pneumatic accumulator 40 used to exchange volumes of hydraulic fluid with the lift/flotation cylinders. This function is necessary when the header 6 is lowered, to allow the header 6 to follow the terrain, which occurs in the first embodiment when the lift/flotation cylinders 14 are retracted, wherein they cooperate with the accumulator 40 . An upper pressurized gas chamber of the hydro-pneumatic accumulator 40 is under pressure. The pressure is shared with a lower chamber of the hydro-pneumatic accumulator 40 , open to the hydraulic system.
The header circuit also includes a take-up cylinder 41 and a valve 39 . The take-up cylinder 41 controls the oil volume displaced for lifting and lowering the header. The valve 39 may be a manually operated ball valve that can be opened to allow flow, or closed to block flow. The valve 39 may alternatively be a solenoid operated valve capable of allowing flow when a solenoid is energized, and blocking flow then a solenoid is de-energized. The present invention is not limited to these types of valves. The functions of the valve 39 are described below.
In operation the towed mower 1 is hydraulically connected to a tractor (not shown) which provides a source of oil and is used to pump oil into the mower hydraulic systems to perform a variety of functions including:
1) to control the position of the mower 1 relative to the tractor, the cylinder 17 , as controlled by the first tractor remote valve 85 is extended or retracted, thereby changing the orientation of the tongue 2 relative to the frame 15 ; 2) to control the position of the header 6 relative to the ground, the second tractor remote valve 87 is moved to one extreme position which will cause the header 6 to lift, and when moved to the other extreme position will cause the header 6 to lower, and when left in the middle position will hold the header 6 in a set position; 3) charging the lift/flotation circuit.
Charging of the lift/flotation circuit is necessary in order to insure that the take-up cylinder 41 , a component of the mower hydraulic system, yet not strictly speaking a part of the suspension system, is properly filled with oil. The lift/flotation cylinders 14 and the tractor remote valve 87 can be directly connected or isolated by means of the valve 39 . In the first embodiment, as illustrated in FIG. 4 , the valve 39 is set in a manifold at the base of the take-up cylinder 41 . Charging is completed by allowing oil to flow through the valve 39 , when opened, through the lines to the take-up cylinder 41 , while first allowing air to escape at the take-up cylinder, and then to fully extend that cylinder, while also purging air out of the lines between the valve 39 and the lift/flotation cylinders 14 and the pressure gage 60 . The tractor remote valve 87 is held in the position to force oil to the circuit until the lift/flotation cylinders 14 are in the extended position, and the header 6 is lifted to the transport position shown in FIG. 2 a.
After this first step of the charging procedure, the valve 39 is locked, isolating the lift/flotation cylinders 14 from direct connection to the tractor hydraulics. In the present embodiment for a fixed-frame mower 1 as in FIGS. 1 , 2 a and 2 b , the accumulator 40 is biased so as to act like a compressive spring by plumbing it to the extend port of the lift/flotation cylinders 14 , most clearly shown in FIGS. 3 and 4 . Thus, during this first step of the charging procedure, the tractor lifts the cutter bar 9 and pressurizes the accumulator 40 . To complete the charging procedure the tractor remote valve 87 is opened to the tractor hydraulic fluid reservoir so that it does not force oil through the remote valve 87 . This allows the oil to flow from the take-up cylinder 41 to the tractor hydraulic reservoir. Then the valve 39 is opened, either manually or electronically by the operator, to allow gravity to work against the accumulator 40 to lower the cutter bar 9 to the ground. The hydraulic system pressure can be viewed on a pressure gauge 60 so that the operator can bleed the valve 39 to allow the cutter bar 9 to press against the ground with appropriate pressure. This is done by pre-determining mower model-specific values for hydraulic system pressure at which the operator can close the valve 39 to maintain. The bias of the accumulator 40 to lift the cutter bar 9 keeps the cutter bar 9 from digging into the ground surface, yet is sufficiently small to allow gravity to press the cutter bar 9 against the surface and maintain continuous contact. This property of the cutter bar 9 is herein defined for the purposes of this document, including the claims, as “float.”
Oil in the mower hydraulic system will constantly be seeking to occupy volume so as to obtain equilibrium pressures throughout the system. If the take-up cylinder valve 39 is locked, oil flow is restricted to flowing between the suspension cylinders 14 and the accumulator 40 . Thus, with the valve 39 locked, the cutter bar 9 cannot be lifted or lowered via the tractor hydraulic system but only by the exchange of oil between the cylinders 14 and accumulator 40 as would be caused by variations in the force the ground exerts on the cutter bar 9 due to ground surface irregularity while mowing.
As the mower passes over uneven ground, the ground exerts changing forces on the cutter bar(s) 9 . The oil can flow between the cylinders 14 and the accumulator 40 to constantly maintain system pressure so that good contact between the cutter bar 9 and the ground is maintained.
In the first embodiment for a fixed-frame mower, the suspension cylinders 14 are attached to a pivoting link 42 such that extending the cylinders 14 causes the header 6 to lift, while retracting the cylinder 14 lowers the header 6 to the ground. In an alternative embodiment, valuable to mowers which may have separate configurations for transport and mowing, a single one-way suspension cylinder 14 may be used as shown in FIGS. 5 a - 5 d . This cylinder 14 could pivotally connect, for instance, to a main frame 15 and a rear sub-frame 62 where the main frame 15 is fixed and the rear sub-frame 62 is allowed to lift, lower, or roll about an axis parallel to a direction of travel. In FIG. 5 a , the rear sub-frame 62 maintains its orientation to the ground by a four-bar linkage comprising an upper link set 12 and a lower link set 11 . The four-bar linkage is described more fully in U.S. patent application Ser. No. 11/927,866, filed Oct. 30, 2007, and is hereby incorporated by reference herein in its entirety.
The rear sub-frame 62 is pivotally attached to a front sub-frame 10 , to which the header 6 is ultimately attached. The rear sub-frame 62 is a link within the four-bar linkage, and the orientation of the sub-frame 62 is dictated thereby. The front sub-frame 10 may be permitted to pivot relative to the rear sub-frame 62 in order to orient the header 6 in an appropriate position for operation or transport.
Swing arm cylinders 65 are provided on both sides of the agricultural mower 1 to pivot the tool bars 9 relative to the front sub-frame 10 .
In this second embodiment, the hydraulic system works by the same principles as in the first embodiment. However, the single cylinder 14 attached to the mower 1 as stated is configured to lift the sub-frame 10 , 62 by retracting and to lower the sub-frame 10 , 62 by extending. In this embodiment the accumulator 40 is plumbed to the retract port of the cylinder 14 , as clearly illustrated in FIGS. 5 c and 5 d.
Operational Process (Either Embodiment)
1) Open the take-up valve 39 .
2) Using the tractor as the power source, pressurize the mower hydraulic system. The sub-frame/header 6 will rise to a maximum height due to full retraction of the take-up cylinder 41 and to fully stroking the cylinders 14 .
3) Close the take-up valve 39 .
4) Put the tractor in float.
5) Crack the valve 39 slowly to bleed excess pressure until the appropriate pressure is read from the gauge. The appropriate pressure will be established for each individual towed mower 1 model on which the present invention is incorporated.
6) Lock the valve 39 at an appropriate pressure. The cutter bars 9 will contact the ground with the hydraulic suspension of the present invention giving it the appropriate amount of contact pressure. The mower 1 is operational.
As an alternative to step 2, using the tractor as the power source . . . , the pressure to the mower hydraulic system may be provided from the gas side of the accumulator 40 . Pressurized air, nitrogen, carbon dioxide, argon, helium, or any other appropriate gas may be used to effect this pressurization.
The embodiments of the novel suspension system herein described may be utilized for any implement making use of a floating header. The invention is not intended to be limited to agricultural mowers.
The above embodiments are the preferred embodiments, but this invention is not limited thereto. It is, therefore, apparent that many modifications and variations of the present invention are possible in light of the above teachings. It is, therefore, to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described. | 1a
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BACKGROUND AND SUMMARY OF THE INVENTION
This invention relates to a package that can be used to display articles to prospective purchasers. More particularly, the package has applicability for the alternative display and enclosure of articles having a closed loop configuration such as a bracelet, wristwatch, and the like.
Although packages constructed for the alternate enclosure and display of articles such as wristwatches and the like are known, a recurrent problem with such devices is that they generally do not offer any effective barrier for the prevention of the removal of the articles displayed therein by prospective purchasers. Also, when such safety means are provided, they are either cumbersomely constructed, or, if not, their operation becomes too obvious when the salesperson removes the wristwatch or similar article to demonstrate same for the purchaser.
A further desirable feature of a package of this type would be that it could be held by the prospective purchaser so that he or she could get the "feel" of the merchandise and still not be able to easily remove the article from the package so as to accordingly reduce incidental thefts of merchandise short of the person taking the entire package and the contents thereof. Another common drawback of known package constructions is that although many provide cover and base portions, no interrelationship exists between such cover and base portions so as to enhance the function of the package as a whole.
It is accordingly an object of the present invention to provide a package of the aforementioned general type in which the cover and base portions interrelate in such a manner so that the package may be utilized in an attractive display mode and yet alternatively function as a shipping container or mailing package for the articles displayed and contained therein.
A further object of the present invention is the provision of a package having base and cover portions which interrelate in such a manner that the cover portion functions as a stop means in the package display mode such that an article holder slidably disposed within the base portion may not be removed and thus provide a safety or anti-theft feature to the package.
A still further object of the present invention is the provision of a package having a base with which a slidable article holder is associated such that articles having a closed loop configuration, such as wristwatches and the like, may be easily displayed in an attractive upright setting, yet the article holder and the article supported thereby may be easily removed as a unit for closer examination of the article by the customer.
These and other objects of the invention are accomplished by the provision of a package including base and cover portions adapted to essentially nest with each other in an open display mode and co-act in the enclosure mode so as to form a closed package suitable for shipment and storage. An article holder is associated with the base and is adapted to pivotably slidably move into and out of an access opening provided in the front face thereof. The overall configuration of both the base and cover portions is box-like and both the cover and base are of a similar shape, such that the cover may be superimposed over the base in such a manner that the two components appear as a single unit. In this regard both the base and cover components are provided with a front wall of minor vertical extent and rear wall of major vertical extent such that the cover front wall is disposed in face-to-face position with the base rear wall and the cover rear wall in part serving to enclose the front access opening provided in the base when the package is in its enclosure mode. In the display mode, the cover essentially is superimposed upon the base with the front wall thereof serving to prevent the outward movement of the article holder from the front access opening of the base.
Other objects, features, and advantages of the invention shall become apparent as the description thereof proceeds when considered in connection with the accompanying illustrative drawings.
DESCRIPTION OF THE DRAWINGS
In the drawings which illustrate the best mode presently contemplated for carrying out the present invention:
FIG. 1 is a perspective view showing the package construction of the present invention disposed in its generally open display mode such that an article such as the wristwatch shown may be displayed to prospective customers in an apparent open manner yet providing some measure of anti-theft protection;
FIG. 2 is a perspective view similar to FIG. 1 but showing the cover portion thereof upwardly removed, rotated 180°, and thereafter disposed in its alternate position with respect to the base so as to form the enclosure mode of the package;
FIG. 3 is a side elevational view taken along the line 3--3 of FIG. 2;
FIG. 4 is a side elevational view similar to FIG. 3 but showing the cover portion disposed in its open display mode;
FIG. 5 is a side elevational view similar to FIG. 4 but showing the manner in which the article holder is removably slidably positioned with respect to the base, the cover having been removed for such purpose;
FIG. 6 is a sectional bottom view taken along the line 6--6 of FIG. 3;
FIG. 7 is a partial sectional view taken along the line 7--7 of FIG. 3;
FIG. 8 is a partial sectional view taken along the line 8--8 of FIG. 7; and
FIG. 9 is an exploded prespective view showing the particular manner in which the package of the present invention functions in its display mode.
DESCRIPTION OF THE INVENTION
Turning now to the drawings and particularly FIG. 1 thereof, the package 10 of the present invention is shown in its open display mode wherein the cover 12 is disposed in superimposed position over the base 14. From such view it may be apparent that the cover and base are both of essentially the same or similar configuration, but that the cover is of slightly larger dimensions such that it may be disposed over the base in the manner depicted. Alternatively, the cover and base may be disposed with respect to each other to form an essentially fully enclosed package such as shown in FIG. 2 of the drawings.
The base and cover components are generally of hollow box-like configuration. The base includes a peripheral platform or supporting pad 16 terminating in a peripheral flange or ledge 18 from which the base proper upwardly extends. Such base includes opposed sidewalls 20, a top wall 22, a rear wall 24 serving to interconnect said sidewalls and said top wall together, and front wall 26 of minor vertical extent and formed by laterally spaced front wall portions 28. Each of sidewalls 20 is roughly of a L-shaped configuration wherein the rear wall 24 is the stem, the top wall the top, and the front wall the front of said L-configuration. The sidewalls terminate at the forward extent thereof in a front edge 30 having a downwardly forwardly curve and terminating at the front wall portions 28. A pair of face walls 32 inwardly extend towards each other from the side edges 30 and terminate in spaced relationship to each other so as to define a front access opening 34. Such face walls 32 thus form extensions of said sidewalls and accordingly may be considered portions thereof.
The lower end of such access opening 34 is provided with secondary sidewalls 36 downwardly extending from the inner terminal edge of the front faces 32 and at the upper end thereof with an upper secondary sidewall portion 38. Each of the lower secondary sidewalls 36 is provided with an inwardly extending ledge 40 of generally L-shaped configuration. Each of the upper secondary sidewalls 38 is provided with a pair of inwardly extending ledges 42 to form an undercut slot 44 having an open bottom both for a purpose which will hereinafter be more evident. The base 14 is usually formed without a bottom wall for ease in molding, however, that area at the bottom of the access opening 34 generally corresponding with or forming a continuation of the ledge 18 is provided with a rearwardly extending tongue 46 connected at the front thereof to such ledge and inwardly terminating in a lateral edge 48.
The base 14 is adapted to receive an article holder 50 having a generally planar foot 52 to which a generally C-shaped upwardly extending loop 54 is connected by means of a connecting wall 56 at one side thereof. The other side of the foot is purposefully left open so as to form an open slot 58 between the upper surface of the foot 52 and the lowermost segment of the loop 54. The article support foot 52 is also provided with an upstanding forwardly disposed face plate 60. In addition, pivot means are included in the loop segment 54 in the form of a pair of laterally spaced upstanding ears 62 at the upper extent thereof, that is, the cooperation of the ears 62 and the slots 44 form such pivot means. It may thus be apparent that an article having a closed loop portion such as the supporting wristband of a wristwatch may be disposed over the loop segment 54 and supported thereby as in the fashion illustrated in FIG. 1. The open slot 58 serves to facilitate laterally sliding such wristwatch band or other closed loop article onto and around the supporting surface of the segment 54, said loop normally being expandable so as to clear ear 62. The foot 52 also includes a rearwardly disposed downwardly extending heel portion 64 forming a ledge 66 at the forward portion thereof.
In operation, the article holder 50 is adapted to be slidably positioned into and out of the base 14 through the front access opening 34 thereof. Initially, the holder 50 is manipulated to a position as shown in FIG. 5 wherein the ears 62 thereof are positioned in the open-bottomed slots 44 so as to fixedly position the upper portion of the holder 50 with respect to the base and thereafter the remaining lower portions of the holder may be pivotably swung about such pivot means by forcing such lower portions rearwardly into the access opening 34. In such reagrd, the heel portions 64 of the foot 52 are adapted to engage the tongue 46 so as to downwardly flex the same as the holder moves into the access opening 34. At the same time, lateral edge portions of the foot 52 are adapted to engage beneath the inwardly extending ledges 40 so as to further guide the pivotal movement of the holder and to ensure against the removal of the holder through the access opening except by the reverse of the above described pivotal movement. When the article holder has been fully disposed within the accesss opening 34 as by the alignment of the from plate 60 with the front wall portions 28, the heel 64 rides over the terminal edge 48 of the tongue such that the ledge 66 coacts therewith so as to provide a positive stop. It should be borne in mind, however, that when it is desired to fully or more closely examine the watch disposed on the article holder 50, the article holder and the watch supported thereon can be simply removed from the base by the aforementioned reverse pivotal movement, a downward movement of the rear end of the tongue facilitating such movement. In such display position as illustrated in FIG. 4, it should also be clear that the watch cannot be removed from its position within the base except by removing the article holder on which it is supported since there is not room enough between the edges of the loop segment 54 and the terminal edges of the front faces 32 of the secondary walls 36. In addition, the positioning of the ears 62 within the undercut slots 44 prevents such removal.
Turning now to the construction of the cover 12, such is also of hollow box-like configuration and of a shape similar to the outside dimensions of the base 14, but slightly larger in size such that the cover 12 may be disposed thereover. The cover includes opposed sidewalls 63, a top wall 65, a rear wall 67, and a front wall 68. The extent of the rear wall 67 is such that it connects both the sidewalls 63 and the top wall 65 together while the vertical extent of the front wall 68 is drastically foreshortened and generally conforms in height to the front wall portions 28 of the base 14. It may thus be apparent that the cover 12 may be superimposed upon the base 14 in the display mode as shown in FIGS. 1, 4, and 9 such that the top, rear, front, and sidewalls of the cover are disposed face-to-face with the equivalent walls of the base, that is, the cover sidewalls 63 are disposed face-to-face with the base sidewalls 20, the cover rear wall 67 is disposed face-to-face with the base rear wall 24, and the cover top wall 65 is disposed face-to-face with the base top wall 22. In addition, the cover front wall 68 is disposed adjacent to and in face-to-face disposition with the front wall portions 28 but further extends entirely across the lower front of the access opening 34. In this manner then, the central or intermediate portions of the cover front wall 68 are disposed face-to-face or in contact with the front face plate 60 of the article holder 50 so as to prevent its forward movement in the display mode of the package 10 and accordingly forms an effective barrier or stop means whereby the article holder cannot be readily removed from the base in such mode. Such stop means is not immediately noticable to those unfamiliar with the construction of the package such that it forms an effective anti-pilferage feature. Accordingly, unauthorized removal of the article holder and the wristwatch supported thereon is prevented. Thus when a customer desires to more closely examine the watch, the salesperson may swiftly remove the cover and in an unobvious manner withdraw the watch and its article support and permit the prospective customer to examine such under his or her observation, but without the customer noticing what, if any, barrier normally exists to the removal of the article from the base in such display mode.
In may instances it is also desirable to utilize the package as a shipping or storage sontainer and such enclosure mode is depicted in FIGS. 2 and 3 of the drawings. When it is desired to change from the display mode to the enclosure mode, the cover 12 is upwardly withdrawn from the base, rotated 180°, and thereafter is disposed over the base such that the sidewalls, the top wall, and the rear wall (63, 65, and 67, respectively) of the cover 12 serve to fully enclose the cut-away display face of the base 14. In this regard it should be pointed out that the cover front wall 68 is adapted to contact the lower portions of the base rear wall 24 so as to insure correct positioning of the cover with respect to the base. Also, in this regard to top wall 22 of the base is provided with a laterally extending detent 69 which is adapted to mate with a similarly shaped groove 70 provided in the undersurface of the cover top wall 65. This interaction between detent 69 and groove 70 is present in both the display and the enclosure modes of the package as shown most clearly in FIGS. 3 and 4. To accomplish this purpose and so as to further provide a cover which may be superimposed upon the base, the depth of both the cover top wall 65 and the base top wall 22 are approximately equal and each approximately one-half the depth of their respective side walls.
As it may be desirable upon occasion to incorporate instructional or warranty pamphlets with the wristwatch package 10 of the present invention, the rear wall 24 of the base is provided with a forwardly directed step 72 such that the upper portions 74 of the rear wall are spaced from the inner surface of the cover rear wall 67. The cover sidewalls are additionally provided with a pair of vertically extending inwardly directed ears 76 so as to in effect define a vertical slot 78 between such ears and the rear wall 67. A pamphlet or other article 80 of generally flat, thin overall planar construction may be slipped behind such ears 76 and maintained within the slot 78 by frictional engagement. The forwardly directed step 72 provided in the rear wall 24 of the base 14 serves to provide the necessary space to accomodate the added thickness of such article 80.
While there is shown and described herein certain specific structure embodying the invention, it will be manifest to those skilled in the art that various modifications and rearrangements of the parts may be made without departing from the spirit and scope of the underlying inventive concept and that the same is not limited to the particular forms herein shown and described except insofar as indicated by the scope of the appended claims. | 1a
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CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application is related to U.S. patent application Ser. No. ______, filed simultaneously herewith and entitled “Soil Conditioning Rotary Reel for Secondary Tillage Operations”.
BACKGROUND OF THE INVENTION
[0002] The present invention relates generally to primary tillage implements used in agriculture and, more specifically to a soil conditioning rotary reel for use in conjunction with primary tillage tools. Another design is disclosed for use in secondary tillage operations, i.e., such as behind secondary tillage tools like harrow.
[0003] As used herein, “primary tillage” refers to tillage where the ground working is deeper and the soil is turned, as for example, with moldboard and chisel plows, at depths greater than four inches. “Primary tillage” is distinguished, for example, from secondary tillage and various cultivation techniques such as disks, “spider” wheels and sweeps, as well as combinations of devices that normally cultivate the surface to nominal depths of two inches, but as deep as three to four inches. In general, primary tillage operations are performed on compacted soil after crop harvest, so such operations may advantageously create clods of larger size and less firming to maintain moisture content. On the other hand, secondary operations are directed toward the creation of an idealized seedbed, i.e., smaller clods, with more soil firming.
[0004] For many years, harrows with either spikes or coil tines have been mounted to the rear of seedbed preparation tools to level and firm the soil and to promote moisture conservation. Similarly, in the past, for clod crushing and further firming, rollers with cast iron wheels have been pulled across the partially prepared seedbed. However, for medium and small clods, such equipment does not exhibit much soil-pulverizing action and additionally tends to push such clod(s) into the soil.
[0005] More recently, rotary pulverizing reels have been used that are from 10 to 14 inches in diameter. A series of bars are welded on a spiral lengthwise across the reel. These bars can be either rounds of approximately ¾ to 1 inch in diameter, or flat bars that are, for example, ¼×1½ inches. These units can be either pull-type, as an additional unit behind the secondary tillage machine, or mounted by arms to the rear of the secondary tillage machine. The bars are welded on in a slight spiral to avoid bumping and “chunking” through the field as it is pulled. As the bars come down to the soil there is a beating action caused by the edge of the bar striking the clod(s). As the reel bottoms out it also creates a firming action to the soil.
[0006] The flat bars are generally configured so there is an approximate 3-4 inch space between successive bars. The bars are also positioned on the reel so that if a straight edge is laid against the flat part of the bar the line of the straight edge will not go through the centerline of the reel. They are positioned in this way so that as they come down they provide more of a firming action on the soil and do not scoop the soil as they leave the rear side of the reel.
[0007] Furthermore, many types of drag harrows have been used behind primary tillage tools, such as moldboard and chisel plows, to break large clods and smooth out the soil surface. Chisel plows leave a large amount of residue near the surface. Harrows pull some of the partially buried residue out. They also bunch residue. Reels do not drag residue.
[0008] It would be a distinct advantage to have available a tool that breaks down clods and firms the soil, while avoiding the aforementioned problems and difficulties.
SUMMARY OF THE INVENTION
[0009] It is an object of the instant invention to provide a soil conditioning rotary reel for primary tillage that will provide improved soil firming and more clod breaking capability.
[0010] It is another object of the instant invention to provide a soil conditioning rotary reel for primary tillage wherein the bars are formed in such a way that, for example, in an eight-bar reel, both the inner and outer surfaces of the bars strike clods in the soil—providing and eight-bar reel with 16 clod crushing surfaces.
[0011] It is a further object of the instant invention to obtain the maximum amount of soil pulverizing and soil firming with a minimum amount of weight (since weight added to the back of secondary tillage tool is detrimental in that if too much is added the unit becomes hitch light.)
[0012] It is a further object of the instant invention to provide a soil conditioning rotary reel for primary tillage that provides improved soil firming characteristics, as desired under the operating conditions, with less down-pressure required from the mounting mechanism.
[0013] It is an even further object of the instant invention to provide a soil conditioning rotary reel with formed bars that require few support plates and are much stronger and resistant to bending when the reel strikes rocks or other field hazards/obstructions.
[0014] These and other objects features and advantages are obtained by providing a soil conditioning rotary reel for primary tillage implements, the reel incorporating formed bars slightly spiraled along the length thereof that increase the overall strength of the reel and, because of the shape of the formed bars, support plates and end plates, efficiently break up clods while avoiding plugging of the reel, even in moist conditions.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] FIG. 1 is an elevated perspective view of a reel made in accordance with the principles of the instant invention;
[0016] FIG. 2 is a left end view of the reel of FIG. 1 , showing the bar orientation and bearing mounting plate;
[0017] FIG. 3 is similar to FIG. 2 except it depicts a bar striking a clod;
[0018] FIG. 4 is an end view of a larger, heavier primary tillage reel; and
[0019] FIG. 5 is similar to FIG. 4 ; however, the reel is rotated to allow depiction of the bars as they rotate through the soil.
DETAILED DESCRIPTION OF THE INVENTION
[0020] Referring to FIG. 1 , a perspective view of a reel 1 , for use with secondary tillage implements, in accordance with the present invention can be seen. Arrow, 2 depicts the direction of rotation for maximum soil firming. The end plates, 3 , provide a mount for the bearings, each with a center hole 4 , providing placement for the bearings. Mounting holes, 5 , are located generally around the center hole 4 in each end plate to allow for attachment of the bearings, by bolts, for instance. Intermediate support plates, 6 , are generally evenly spaced along the longitudinal axis of reel 1 and supply support for the bars. Reel 1 is shown with five intermediate support plates; however, the actual number may vary, depending primarily on the length of the reel. Reel 1 is further shown with eight formed bars, 7 ; but, the reel can be made with more or less depending on the desired overall diameter and desired spacing between the bars.
[0021] Referring now to FIG. 2 , the cross-sectional shape and the positioning of the formed bars 7 relative to the longitudinal axis of the reel 1 are more easily discemable. Dotted line 10 is a parallel line with the outer portion of the formed pulverizing bar 12 . This position is similar to prior art reels with flat bars. The curved angular shape 14 provides firming to the soil. With the formed area 14 additional clod pulverizing is accomplished. Also, there is more soil firming for better seed/soil contact.
[0022] Referring now to FIG. 3 , one of the bars 7 is shown to have an inner portion 16 and an outer portion 18 . A clod, 20 , is shown being struck by portion 16 . A dotted line clod, 22 , is shown in a location that will cause it to be struck by portion 18 as the reel rotates forward (direction of arrow 2 ). Reel bar 24 is in a position so that the soil firming occurs as it rotates forward. This provides a broader firming action than a round bar or a flat bar.
[0023] If too much down pressure needs to be applied to the reel it can result in floating the secondary tillage machine out of the ground, especially the outer portion of the wings where the machine is lighter.
[0024] Looking at FIG. 4 , an alternative embodiment for use behind a primary tillage tool, such as a chisel plow or heavy offset tandem disc can be viewed. The primary tillage tool reel support plates, 3 , are attached to a shaft, 30 . The area designated 32 , is a protruding portion to which the bars, 7 , are attached. The dashed line 36 , to the right of the shaft 30 , depicts the angle relative to the center shaft of the outer portion of the formed bars. This orientation of the formed bars results in a more aggressive chopping action into large chunks of soil and root crowns. Arrow 2 again depicts the direction of rotation.
[0025] Ground line G in FIG. 5 is an idealized soil profile. The bars, 7 , have an area designated 40 . As the reel rotates in the direction of arrow 2 , 40 will move down toward the idealized soil profile line, G. As it moves downwardly in the direction of rotation, area 40 will strike large clods and root crowns. As the reel continues to rotate, area 42 strikes the idealized soil line and reaches a point where it is lower than the area marked 44 .
[0026] Area 44 is shown in a position where it is approximately horizontal, but it will rotate higher to a larger angle as it moves past shaft 30 , while 42 rotates lower. It is important to note that moist soil that is being knifed into by 42 now cannot flow freely up into the center of the reel, causing plugging. The area designated 44 will resist soil movement along the inside surface of 42 . Also, a notch, 48 , is cut in the support plate so that there is minimal area for soil “stickage” as it flows off of 44 . As the reel rotates forward and begins leaving the soil line G, the area designated 52 begins somewhat of a kicking motion and loosens soil that was firmed earlier by 44 when it was in the more horizontal position as 42 entered the soil. While 44 is in the near horizontal position and as it bottoms out, soil is restricted from entering the center of the reel, preventing plugging.
[0027] Again referring to 52 , as the outer portion of the bar is now beginning to leave the soil profile, and while a slight kicking action results as it leaves the soil profile, area 54 is now in a near vertical position that is not firming soil. Area 56 does not have substantial contact with the soil even when some loose soil is above the idealized soil line G. The result is that as the reel rotates and each bar leaves the soil profile, firming action is minimized.
[0028] The result is that the large formed bars provide more soil movement and less firming than round or flat bars. With the outer bar orientation of line 36 on the right side (or forward travel side) rather than the left side (rearward of direction of travel) as shown on the secondary reel ( FIGS. 2 and 3 ) less firming occurs on the primary reels.
[0029] The formed bar reel for use with primary tillage tools is a much heavier unit. For example, a reel may be constructed that is approximately 16 or 18 inches in diameter and may have five or six heavy, wide formed bars. These bars may be 5/16 or ⅜ inches thick and 3½ or 4 inches wide. Forming the wide, heavy bars results in two to three times more strength than a similar flat bar.
[0030] On primary tillage rotary reels the formed bars are oriented to provide more soil movement for soil leveling and less firming than the secondary reels or round or flat bars. Primary tillage tools are generally operated in the fall and soil firming in the fall is undesirable. Looser soil soaks up rainfall more quickly, reducing runoff. In the fall it is desirable for the bars to cut into large clods that are often the result of harvest compaction, and also root crowns to help smooth out high spots and knock soil out of root crowns so that it is easier to prepare the seed bed the following spring.
[0031] On primary tillage tools, many times the soil is very moist and operators must run in adverse conditions. For example, in using a bar 4 inches wide, the area 44 , is slightly more than 2 inches if you include the bend radius, providing a substantial area to prevent soil flow to the center of the reel thereby preventing reel plugging.
[0032] The primary tillage reel is designed with larger bars with more space between the bars. The bars are positioned to avoid soil firming and avoid plugging with moist soil. Chisel plows often operate in wet fall conditions and also soil that may be frozen 1 to 3 inches. The primary rotary reel helps break compacted or frozen chunks of soil and smooth the surface. | 1a
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Field of the invention: Botanical classification/cultivar designation: Doritaenopsis Orchid cultivar SOGO F2451.
BACKGROUND OF THE INVENTION
The present invention comprises a new and distinct cultivar of Doritaenopsis Orchid, a hybrid of Doritis×Doritis of the family Orchidaceae, and hereinafter referred to by the cultivar name, SOGO F2451. The genus Doritaenopsis is a member of the family Orchidaceae.
Doritaenopsis comprise a group of bigeneric hybrids generally intermediate in character between the parent genera, which are suitable for cultivation in the home or greenhouse. The parent genera of Doritaenopsis are predominantly epiphytic or rock dwelling, and are native to tropical Asia, Malay Archipelago, and Oceania. The species typically have 2-ranked fleshy oblong or elliptic leaves affixed to a short central stem (monopodial growth), which vary in size from 5 to 8 inches to over 2 feet. The leaves may be entirely green or mottled with silver grey.
Doritaenopsis orchid, often referred to ‘Moth Orchids’ in the horticultural trade, are frequently used to furnish cut flowers for the florist trade, or sold as flowering potted plants for home or interiorscape.
Doritaenopsis produce upright racemes, often with many showy flowers, which open in succession beginning with the lowermost. The flowers possess three sepals, and three petals, the lateral ones being alike. The lowermost petal, called the labellum, is three lobed and is often more brightly colored than other flower segments. Flower colors are frequently various shades of pink, white and yellow.
Doritaenopsis orchids are typically propagated from seeds. However, Doritaenopsis is capable of being asexually reproduced from offshoots, which frequently arise from the lower bracts of the inflorescence. The resulting plants are detached from the mother plant and may be planted in a suitable substrate.
‘SOGO F2451’ is a product of a planned breeding program conducted by the inventor in Kaohsiung County, Taiwan, R.O.C. The objective of the breeding program is to create new uniform pot-type Doritaenopsis Orchid cultivars having attractive flower coloration. The inventor has been addressed himself to the Orchids breeding since 1985.
‘SOGO F2451’ was discovered by the inventor from within the progeny of a cross-pollination of one Doritaenopsis orchid, Dtps. ‘SOGO Gotris’ and one Doritaenopsis orchid, Dtps. ‘SOGO Golden’ on February 1999, in a controlled environment in Kaohsiung County, Taiwan, R.O.C.
Asexual propagation by tissue culture in a laboratory in Pingdong County, Taiwan, R.O.C. has been used to increase the number of plants for evaluation and has demonstrated in a controlled environment in Kaohsiung County, Taiwan, R.O.C. that the unique combination of characteristics as herein disclosed for the new Doritaenopsis Orchid are firmly fixed and are retained through successive generations of asexual reproduction.
SUMMARY OF THE INVENTION
The following traits have been repeatedly observed and are determined to be basic characteristics of ‘SOGO F2451’ which in combination distinguish this Doritaenopsis Orchid as a new and distinct cultivar:
1. Yellow overlaid with purple toward pink base and the red purple with white border colored labellum. 2. Freely flowering habit. 3. Upright, freely branching and sturdy flowering stems. 4. Excellent postproduction longevity.
Plants of ‘SOGO F2451’ differ primarily from plants of the parent cultivars in flower color. The main color of petals of Dtps. ‘SOGO Gotris’ is RHS 5A, and the pattern color thereof is RHS 46A. The main color of the petals of Dtps. ‘SOGO Golden’ is RHS 13A. Since this latter parent has a monochromatic flower, there is no pattern color.
Currently, there is no commercial cultivar to which ‘SOGO F2451’ can be meaningfully compared.
BRIEF DESCRIPTION OF THE DRAWINGS
The accompanied photographic illustrations show typical plant and flower characteristics of ‘SOGO F2451’ with colors being as true as possible with illustrations of this type.
FIG. 1 is a side view of a plant of ‘SOGO F2451’ flowering in the pot of 13 cm.
FIG. 2 is a close-up view showing the characteristics of the flower.
FIG. 3 is a close-up view showing the characteristics of the leaf.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
‘SOGO F2451’ has not been observed under all possible environmental conditions. The phenotype may vary significantly with variations in environment such as temperature, light intensity, fertilization and day length without any change in the genotype.
The observations and measurements describe plants grown in Kaohsiung County, Taiwan, R.O.C. under the conditions, which approximate those generally used in commercial practice.
In the following description, color references are made to The Royal Horticultural Society (R.H.S.) Colour Chart.
Plants used for the aforementioned photographs and the following detailed botanical description were 18 months in maturity and grown in the pots of 13 cm, in a controlled greenhouse with day-night temperature around 25-18 degree Celsius, and light intensity between 15,000-20,000 lux natural light, in Kaohsiung County, Taiwan, R.O.C.
Origin: Seedling from a cross of selected Doritaenopsis and Phalaenopsis but unnamed parentage. Classification: Doritaenopsis hybrid cv. ‘SOGO F2451’. Propagation: Asexual propagation by tissue culture. Plant description:
Plant height.— Soil level to top of foliar plane is about 10 to 15 cm. Plant height.— Soil level to top of inflorescences is about 40 to 50 cm. Plant diameter.— Is about 30 to 35 cm. Growth habit.— Compact, small, dark-green leaves and a relatively short raceme. Flowers per stem.— Approximately 35 to 45.
Foliage description:
Quantity.— Approximately 6 to 8 leaves are produced before flowering. Size of leaf.— 15 to 20 cm long and 5 to 7 cm wide. Shape.— The leaf blade is short and elliptic with a cuneate base and an obtuse tip. The leaf blade is leathery and thick. The middle vein protrudes, while the other veins are not visible in the thick leaf blade. Attitude.— Horizontal and on two sides parallel. Color.— Upper surface: Dark-green, RHS 139A. Lower surface: Light-green, RHS 146A.
Inflorescence description:
Flower type and habit.— Single zygomorphic flowers arranged in racemes. Flowers are roughly pentagonal in shape. Flowering stems upright, freely branching and sturdy. Plants freely flowering; plants typically produce one to three branched flowering stems with at least 28 to 35 flowers each. Fragrance.— No fragrance. Natural flowering season.— From February to April in the southern part of Taiwan. The flower spikes can be induced under the controlled environment, of which day-night temperature at 25-18 degree C. for 2 weeks. Post - production longevity.— Plants of ‘SOGO F2451’ maintain good leaf and flower substance for about three to four months on the plant under interior environmental conditions. Lastingness of cut flowers has not been observed. Inflorescence length.— About 20 to 25 cm. Inflorescence diameter.— About 32 to 37 cm. General impressions of petals and sepals.— Horizontal elliptical in shape, about 5 cm of flower width in front view. Sepals.— There are 3 sepals which are fleshy and glabrous in texture, with straight margins and in elliptical shape, about 2.7 cm in length and 2 cm in diameter. The main color of dorsal sepal is RHS 8A, the pattern color of dorsal sepal is 58A. The main color of lateral sepals is RHS 8B, the pattern color of lateral sepal is 58A. Petals.— There are 2 open petals which are fleshy and glabrous in texture, with margins weakly undulate and in elliptical shape, about 3.7 cm in length and 2.4 cm in diameter. The main color of petals is RHS 4B, the pattern color of petals is 58A. Labellum ( lip ).—The lip whiskers are absent, shape of apical lobe is ovate, approximately 1.8 cm long and 1.4 cm wide. The base color of apical lobe is RHS 71A, the tip color of apical lobe is RHS 71A. Peduncles.— Length about 45 cm, diameter about 5 mm, upright, strong and sturdy, with smooth and glabrous texture. Color is RHS N200A. Pedicels.— Length about 3.4 cm, diameter about 2 mm. Aspect about 80.degree from vertical. Strong, with a texture of smooth and glabrous. Color RHS 145D, towards the base, overlaid with RHS 150B.
Reproductive organs: The stamens, style and stigmas are fused into a single, short structure called the column, possessing one terminal anther with pollen grains united into a pollinia, which are covered by an anther cap. The stigma is located under the column behind the pollinia. The ovary is inferior with three carpels present. The plant has not produced seed.
Column.— Approximately 11 mm long and 5 mm wide, RHS 72B. Pollinia.— Two, about 1 mm oval masses of pollen present, RHS 21A. Ovary.— 6 to 8 mm long and 2.6 mm in diameter, RHS 75B.
Roots: Fleshy, approximately 6 mm wide and green, RHS 188B. Plant disease resistance/susceptibility: No specific resistance or susceptibility observed. General observations: Doritaenopsis ‘SOGO F2451’ produces two or more inflorescence with flowers having sepals and petals in the color of yellow overlaid with purple toward pink base. A red purple with white border labellum. The inflorescence is strong, erect and sturdy, relatively short, and easily packaged for shipping. The plant grows very quickly to marketable size. ‘SOGO F2451’ can be economically propagated via tissue culture. | 1a
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BACKGROUND OF THE INVENTION
[0001] The present invention relates to golf clubs and in particular to a golf club with a near vertical shaft allowing a more natural and accurate swing.
[0002] Known golf clubs include an often large angular offset between the golf club shaft and head position, pushing the golf club head away from a golfer during a swing. As a result, in order to align the club head with the ground horizontally, the golfer must hold the club with the golf club shaft at a slant relative to the vertical, angling down and away from the golfer. The golfer grasps the top grip portion of the shaft and assumes a stance with the shaft and grip slanted toward the waist, stomach, or chest area and spaced away from the golfer's body between approximately two and twelve inches.
[0003] Using known golfing methods, the head of the club is placed forward of the golfer's body and behind the ball position, either on the grass of a putting green or on the grass of a fairway. The golfer stands back from the ball position so that the head of the club is generally placed several inches from the toe of the golfer's shoes, (for example, when using a putter) or up to fifty inches away, (for example, when using a driver). The degree of the shaft's slant depends on the golfer's physical height, on the club the golfer is using, and on how much the golfer extends the arms away from the body. Nevertheless, in most cases and situations, the golf club shaft is slanted considerably down and away from the golfer, whether the golfer leans forward to “face” the ball directly or whether the golfer turns their feet or hips a little to the right or to the left. This preparation and positioning, and procedure to make the back swing and the return swing to hit the ball, is commonly referred to as “addressing the ball.”
[0004] Further, because the golfer holds the club head away from the body, a small lateral torque perpendicular to the swing is present during the swing. While this torque is small, it nevertheless may interfere with the natural “pendulum” motion of the swing and cause a small angular deflection of the club face which the golfer must compensate for. The small angular error in the club face may result in a large position error in the balls final position.
[0005] Therefore, the known methods for addressing the ball do not provide a natural swing for some golfers and a new golf club allowing a different method for addressing the ball and the swing is needed.
BRIEF SUMMARY OF THE INVENTION
[0006] The present invention addresses the above and other needs by providing a golf club having a bent hosel. The hosel is approximately five inches long and the bend is approximately centered on the hosel. The hosel is connected to the golf club base to angle toward the golfer. At its middle, or approximately two and one half inches above the golf club base, the hosel is bent away from the golfer to a nearly vertical angle. The shaft of the golf club is connected to the upper portion of the bent hosel causing the shaft continue at the nearly vertical angle. The novel angling of the hosel and shaft allow an average golfer to consistently hit straighter shots beginning with a putter, but including golf irons and golf woods.
[0007] In accordance with one aspect of the invention, there is provided a golf club providing a more natural swing. The golf club including a head, a hosel, a shaft, and a grip. The head includes a substantially vertical face for hitting a golf ball and a base configured to reside approximately horizontally when the face hits the ball. The hosel is attached to the head at a point on the left side of the head, when viewed facing the face. The hosel includes a lower portion at a first angle between vertical and sloping upward to the left and an upper portion at a second angle between vertical and sloping upward to the right. The shaft extends up from the upper portion of the hosel at a third angle between vertical and sloping upward to the right. The grip is attached at the top of the shaft. The lower portion of the hosel preferably slopes to the left and the upper portion of the hosel preferably slopes to the right, and the shaft is preferably aligned with the upper portion of the hosel.
[0008] In accordance with another aspect of the invention, there is provided a method for a golfer to apply a more natural golf club swing. The method includes: grasping the grip of a golf club, the golf club having a shaft aligned with the grip and attached to a hosel which is attached to a head of the golf club, and swinging the golf club with the head of the golf club passing approximately under the golfer's grasp. The hosel includes an upper portion aligned with and attached to the shaft and sloping upward and towards the golfer, or vertical, and a lower portion attached to a head of the golf club at a point on the head away from the golfer.
[0009] In accordance with yet another aspect of the invention, there is provided a more accurate golf club using a short back-swing, such as a quarter-back-swing or a half-back-swing. The present invention applies to putters in particular because putting benefits from greater accuracy more than other phases of golf. However, the present invention may be adapted for a “chipper” and several “short irons,” clubs which may be used around the putting green and where accuracy is more important than distance. Further, the present invention may be adapted for any fairway iron where the club is not used to make shots at long distances.
[0010] In accordance with still another aspect of the invention, there is provided a golf club not requiring a “great arc” type swing. Although prior-art clubs may make accurate shots, they are compromised to also provide leverage and swing speed. One of several ways to achieve swing speed is by swinging with a great arc. In order to make the great arc feasible, club shafts are constructed to slant away from the golfer. In this way, the club head could be a foot to more than a yard away from the golfer's feet. Having this space from where the golfer stands to where he places the club face behind the ball provides the golfer with the room and freedom to swing his arms and hands in the great arc. This is done in conjunction with a powerful pivot at his hips (including shoulder and back turns), that direct the upper torso toward the intended direction of the ball. The great arc, however, is not necessary for putting or for hitting shots when the golfer is close to the putting green. It is the intention of this novel idea to construct a type of golf club that can be swung without the great arc in order to give the average golfer more consistency in making accurate shots both on the putting green and at the near approach area to a putting green.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWING
[0011] The above and other aspects, features and advantages of the present invention will be more apparent from the following more particular description thereof, presented in conjunction with the following drawings wherein:
[0012] FIG. 1 is a prior art golf club.
[0013] FIG. 2 shows a golfer holding the prior art golf club.
[0014] FIG. 3 shows forces present in a swing of the prior art golf club.
[0015] FIG. 4 is a portion of a golf club according to the present invention.
[0016] FIG. 5 shows the golfer holding the golf club according to the present invention.
[0017] FIG. 6 shows forces present in a swing of the golf club according to the present invention.
[0018] FIG. 7 shows the golfer holding a reverse golf club according to the present invention.
[0019] FIG. 8 shows forces present in a swing of the reverse golf club according to the present invention.
[0020] FIGS. 9A-9D show typical prior art golf clubs.
[0021] FIGS. 10A-10D show corresponding golf clubs according to the present invention.
[0022] Corresponding reference characters indicate corresponding components throughout the several views of the drawings.
DETAILED DESCRIPTION OF THE INVENTION
[0023] The following description is of the best mode presently contemplated for carrying out the invention. This description is not to be taken in a limiting sense, but is made merely for the purpose of describing one or more preferred embodiments of the invention. The scope of the invention should be determined with reference to the claims.
[0024] A rear view of a prior art golf club 10 is shown in FIG. 1 . The golf club 10 includes a head 18 having a face 18 a (see FIG. 3 ) for striking a golf ball, a grip 12 for grasping the club 30 , a short hosel 16 attached to the head 18 , and a shaft 14 connecting the grip 12 to the hosel 16 . At the point of the swing when the face 18 a of the head 18 strikes the golf ball, the face is substantially vertical but may slope back from the vertical on some clubs to provide some lift to the golf ball, and the base 18 b of the head is preferably approximately horizontal. The shaft 14 is generally required to be straight for competitive play, and the hosel 16 may be curved but is short and preferably not more than five inches long.
[0025] A golfer 20 is shown holding the prior art golf club 10 in FIG. 2 , and forces F 1 and F 2 present in a swing of the golf club 10 when the club 10 is at a point of making contact with the golf ball 24 are shown in FIG. 3 with the face 18 a facing up. The golfer 20 exerts a force F 2 required for the swing and impact of the face 18 a of the head 18 with the golf ball 24 , but an additional force F 1 is required to hold the head 18 of the club away from the golfer 20 . Although small, the required force F 1 may slightly bias the swing resulting in a slight angling of the face 18 a of the head 18 and a small variation in the intended trajectory of the golf ball 24 . Because the force F 1 is not a natural part of the swing, it is difficult for some golfers to learn to properly and consistently swing the prior art golf club 10 .
[0026] A rear view (i.e., the face of the head of the club into the paper) of the golf club 30 according to the present invention is shown in FIG. 4 . The head 18 of the golf club 30 includes a vertical centerline CL horizontally centered on the base 18 and a vertical line V parallel to the centerline CL. The golf club 30 preferably includes a bent (or curved) hosel 36 . The shaft 34 extends from the hosel 36 as with the golf club 10 , on the left side (or heel 17 ) of the head 18 when viewed from the rear of the head 18 . The hosel 36 includes a lower portion 36 a and upper portion 36 b . The lower portion 32 a is attached to the head 18 near the heel 17 , i.e., towards the golfer 20 . The lower portion 36 a preferably is vertical or slopes up and away from the vertical line V and towards the golfer 20 , and more preferably slopes away from the vertical line V at an angle A 2 from vertical, when the base 18 b of the head 18 is horizontal. The upper portion 36 b preferably is vertical or slopes slightly towards the vertical centerline CL, and more preferably slopes slightly towards the vertical centerline CL at a small angle A 1 from vertical, when the base 18 b of the head 18 is approximately horizontal. The angle A 1 is preferably approximately three degrees and the angle A 2 is preferably approximately 21 degrees. The head 18 further includes a toe 19 opposite the head 17 . In use, the heel 17 is the end of the head 18 closest to the golfer 20 and the toe 19 is the end of the head 18 farthest from the golfer 20 .
[0027] The hosel 36 is preferably connected to the heel 17 of the club head 18 and the lower portion 36 a points towards the golfer 20 as the golfer 20 normally stands as the golfer addresses the ball 24 . The lower portion 36 a had a length L 1 which is preferably between two to three inches and more preferably approximately 2.5 inches. The upper portion 36 b had a length L 2 which is preferably between two to three inches and more preferably approximately 2.5 inches. The overall length L 3 of the hosel 36 is preferably not more than five inches and is more preferably five inches. The shaft 34 is attached to the upper portion 36 b and is aligned with the upper portion 36 b and resides nearly vertically at the point of impact of the club head 18 with the golf ball 24 during a swing, at which point of impact the base 18 b of the head 18 is nearly horizontal.
[0028] The golfer 20 is shown holding the golf club 30 in FIG. 5 . The golfer 20 now holds the grip 12 with the grip 12 and shaft 30 nearly vertical when the base 18 b of the head 18 is horizontal and the grip 12 at the top of the shaft 12 nearly directly above (i.e., the head 18 of the club 30 is not displaced towards or away from the golfer 20 sufficiently to require any noticeable lateral force F 1 (see FIG. 3 ) to hold the club) on the head 18 at the point of impact and when the base 18 b of the head 18 of the golf club 30 is nearly horizontal. The grip 12 preferable is at least directly above some portion of the head 18 . The golf club 30 provides a vertical or upright shaft at the point of impact with the ball 24 allowing more accuracy than the golf club 10 having a shaft slanted away from the body as shown in FIG. 2 . Since leverage and the freedom to create a great arc swing are not essential when using the golf club 30 for making shots that are close to the putting green, the vertical or upright shaft allows the golfer 20 to utilize a more natural and thus more accurate swing.
[0029] The force F 2 present in a swing of the golf club 30 is shown in FIG. 6 . Because the shaft 30 is now nearly vertical at the point of impact with the ball 24 , the head 18 is nearly directly below the grip 12 , and the force F 1 of FIG. 3 is drastically reduced or eliminated. The golfer 20 is now free to swing the golf club 30 in a more natural manner with improved accuracy.
[0030] The golfer 20 holding a reverse golf club 30 ′ according to the present invention is shown in FIG. 7 and forces present in a swing of the reverse golf club 30 ′ are shown in FIG. 8 . The reverse golf club 30 ′ provides the same advantage as the golf club 30 because head of the club 30 ′ is nearly directly below the grip 12 of the club 30 ′ at the point of impact with the ball 24 , thus minimizing or eliminating the lateral force F 1 of FIG. 3 freeing the golfer 20 to swing the golf club 30 ′ in a more natural manner with improved accuracy.
[0031] Four typical prior art golf clubs 10 a - 10 d are shown in FIGS. 9A-9D . The golf clubs 10 a - 10 d all include shafts 14 angled away from vertical upwards and towards the golfer to allow room for a “great arc” type swing. As a result of the angle of the shafts 14 , the golfer must compensate for the resulting torque at the grip 12 , and errors may be introduced into the flight of the golf ball.
[0032] Four golf clubs 30 a - 30 d according to the present invention corresponding to the prior art golf clubs 10 a - 10 d are shown in FIGS. 10A-10D . The golf clubs 30 a - 30 d have nearly vertical shafts reducing or eliminating the torque around the grips 12 of the prior art golf clubs 10 a - 10 d thereby reducing or eliminating the errors introduced into the flight of the golf ball.
[0033] For the putting shot, a right-handed golfer would address the ball in the normal manner with perhaps a couple of exceptions. First, he would place his left leg so that the left shoe is as close to the ball as possible without it being in the way for a putter striking the ball during the performance of his shot. It is important that the golfer pushes the left hand back into his right hand without “breaking” (or bending) his wrists, and maintaining, without “breaking”, his wrists to make a solid contact during his return swing and follow through. The golfer should mentally “see” his vertical/upright shaft going directly to the target during its vertical/upright follow-through.
[0034] In regards to the “chipper” iron, and the other “irons,” it is suggested that until a golfer accustoms himself to this new system, that he should adjust his stance to an “open stance” as follows: assuming he is a right-handed golfer, the golfer puts his right foot toe at or near the place where the ball lies on the fairway grass and opens his stance by placing his left foot to partially spread away toward his left flank, thus creating the “open stance.” The open stance may help to prevent “shanking” the ball. The golfer preferably takes his club back with a good pivot and returns the club in his normal manner, but making certain that the vertical/upright shaft is pointing at the target as it is moving through the ball. At about the instant when the two hands are brought down into the ball in the usual manner, the golfer should have in his mind that approximately when the club head makes contact with the ball, that he turns his right hand slightly under his left hand in such a manner that the right forearm feels as if it is coming under the vertical/upright shaft during its movement toward the target. When the follow-through part of the swing is completed, that is to say when the golfer's hands have been extended to almost shoulder level elevation, the golfer might feel that his right forearm is underneath the shaft guiding it as it is finishes its movement aimed at the target. This final maneuver with this new type of hosel/shaft combination may help the golfer to achieve accuracy when the golfer makes his approach shots to the putting green.
[0035] While the invention herein disclosed has been described by means of specific embodiments and applications thereof, numerous modifications and variations could be made thereto by those skilled in the art without departing from the scope of the invention set forth in the claims. | 1a
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FIELD
[0001] This invention relates to the field of arthroplasty, and particularly to interpositional knee arthroplasty.
BACKGROUND
[0002] Arthroplasty involves the surgical reconstruction or replacement of a malformed or degenerated joint. With interpositional arthroplasty, a knee implant is placed between inflamed joint surfaces to keep them apart. Such knee implants are often referred to as knee spacers.
[0003] In one common interpositional arthroplasty procedure, a knee spacer is placed between the tibia and the femur. In particular, the knee spacer is implanted between either the medial or lateral condyle of the femur and the meniscus of the tibia. The knee spacer provides a surface for articulation of the femur relative to the tibia.
[0004] Knee spacers are generally designed to conform to either the femur or the tibia in an attempt to prevent dislocation of the knee spacer within the joint. Various methods have been proposed for conforming the knee spacer within the joint. For example, some knee spacers are formed with a posterior lip that extends distally over the tibia. Other knee spacers are designed to conform to the femur in an attempt to retain the spacer within the joint. However, it has been noted that many of these knee spacers do not prevent in vivo movement of the knee spacer. In vivo movement of the knee spacer is one factor that may significantly contribute to the pain a patient experiences following an interpositional arthroplasty procedure.
[0005] Accordingly, it would be advantageous to provide a knee spacer for an interpositional knee arthroplasty that may be secured in such a manner to prevent in vivo movement of the knee spacer relative to the femur or tibia. It would be of further advantage if such knee spacer could be secured to the tibia in a manner that does not violate the subcondylar plate. It would also be advantageous if the knee spacer could be easily fixed to the femur or the tibia.
SUMMARY
[0006] An interpositional knee arthroplasty is disclosed herein. The interpositional knee arthroplasty is configured for attachment to a lateral or medial condyle of a knee, each condyle including articular cartilage and subcondylar bone. The interpositional knee arthroplasty comprises a spacer and at least one fastener extending from the spacer. In one embodiment, the spacer comprises a kidney shaped plate. The fasteners are attached to one side of the spacer. Each fastener comprises a peg with at least one deformable fin attached to the peg. The deformable fins are cup shaped. In one embodiment, the spacer is also deformable such that a surface of the spacer may be contoured against the condyle.
[0007] In operation, a surgeon forms one or more holes in either the femoral or tibial condyle. In one embodiment, the holes do not perforate the subcondylar plate that forms the perimeter portion of the subcondylar bone. In this embodiment, the holes extend through the articular cartilage and into the subcondylar plate, but do not extend completely through the subcondylar plate. In an alternative embodiment, the holes formed by the surgeon extend completely through the subcondylar plate.
[0008] After the holes are formed in the condyle, the surgeon orients the spacer on the condyle with the fasteners directed toward the holes. The surgeon then presses against the spacer, forcing the fasteners into the holes. As the fasteners are forced into the holes, the deformable fins collapse. The collapsed fins act to wedge the pegs in the holes, thus securing the spacer to the condyle.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] FIG. 1 shows a top view of an interpositional knee arthroplasty;
[0010] FIG. 2 shows a fastener for the interpositional knee arthroplasty of FIG. 1 ;
[0011] FIG. 3 shows a bottom view of the interpositional knee arthroplasty of FIG. 1 ;
[0012] FIG. 4 shows a side view of the interpositional knee arthroplasty of FIG. 1 ;
[0013] FIG. 5 shows a cross-sectional view of the interpositional knee arthroplasty along line V-V of FIG. 4 ;
[0014] FIG. 6 shows a perspective view of a femur and tibia with a first interpositional knee arthroplasty of FIG. 1 attached to the lateral plateau of the tibia and a second interpositional knee arthroplasty attached to the medial plateau of the tibia;
[0015] FIG. 7 shows a proximal view of the tibia of FIG. 6 showing the first interpositional knee arthroplasty positioned in the lateral plateau and the second interpositional knee arthroplasty positioned in the medial plateau; and
[0016] FIG. 8 shows a cross-sectional view of the tibia of FIG. 6 showing holes formed in the tibial condyles and the peg members extending into the subcondylar plate of the tibia.
DESCRIPTION
[0017] With general reference to FIGS. 1-5 , an interpositional knee arthroplasty 10 comprises a spacer 12 and a plurality fasteners 14 extending from the spacer 12 . As explained herein, the arthroplasty 10 is configured for attachment to either the lateral or medial plateau of the tibia.
[0018] In the embodiment shown in FIGS. 1 and 3 , the spacer 12 comprises a plate that is generally kidney shaped when viewed from the top and bottom. The spacer 12 is greater in length measured from its anterior side 20 to its posterior side 22 than it is in width measured from its medial side 24 to its lateral side 26 . While the kidney shape of the spacer has advantages with respect to attachment of the spacer to the condyle, one of skill in the art will recognize that other shaped spacers may also be used.
[0019] The spacer 12 is comprised of a biocompatible material, either a polymer or metal such as ultra high molecular weight polyethylene (UHMWPE), polyurethane (PU), cobalt chrome (CoCr), or titanium (Ti). As shown in FIGS. 1 and 4 , the top surface 18 of the spacer 12 is generally smooth with rolling contours. These rolling contours are designed to mimic the surface of a condyle facing the meniscus of the tibia.
[0020] As shown in FIGS. 3 and 4 , the bottom surface 28 of the spacer 12 is generally flat with the fasteners 14 extending from the bottom surface 28 . In one embodiment, the spacer 12 is somewhat flexible, allowing the bottom surface 28 to be bent in order to match the curved surface of the condyle when the spacer 12 is attached to the condyle. This distortion of the spacer 12 to match the curved surface of the condyle is more easily achieved because of the kidney shape of the spacer. In particular, the kidney shape of the spacer facilitates spacer distortion such that the bottom surface 28 more closely conforms to the curved surface of the condyle. In an alternative embodiment, the spacer 12 is more rigid, but the bottom surface 28 of the spacer is curved, allowing the bottom surface 28 of the spacer to conform to the curved surface of the condyle.
[0021] With reference to FIG. 4 , the fasteners 14 may comprises peg members 15 that extend from the bottom surface 28 of the spacer 12 . The plurality of peg members 15 each include a rigid center peg 30 and a plurality of deformable fins 32 attached to the center peg. In the disclosed embodiment, the deformable fins 32 comprise cup structures 33 . Each cup structure 33 is secured at a central location to the center peg 30 and extends from such central location upward toward the bottom surface 28 of the spacer 12 . A first cup structure 33 is positioned at the end of the center peg 30 . A second cup structure is positioned at a midpoint of the center peg.
[0022] The cup structures 33 are secured to the center peg 30 by any of numerous methods. For example, the cup structures 33 may be secured to the center peg using adhesives or fasteners. In one embodiment, the center peg is comprised of a plurality of peg segments which are attached by one peg segment threadedly engaging an adjacent peg segment. In this arrangement, an extending screw portion of one peg segment is inserted through a center hole in a cup member and the adjacent peg sections are screwed together. This action clamps the center hole of the cup member between peg segments. Of course, numerous other methods may be used to secure the cup members 33 to the center peg, as will be recognized by those of skill in the art.
[0023] The center peg member is comprised of an appropriate rigid bio-compatible material, either a polymer or metal such as titanium or cobalt chromium. As shown in FIG. 5 , each center peg 30 extends into the spacer 12 through the bottom surface 28 , allowing the center peg to be fixed to the spacer. The center peg includes a threaded top portion 34 . The threads on the top portion 34 of the center peg 30 engage threaded holes 36 in the bottom of the spacer to secure the center peg to the spacer. Adhesives may be used in the holes 36 of the spacer 12 to further secure the peg members 14 to the spacer 12 . Of course, various other methods may be used to secure the center posts to the holes in the spacer, such as adhesives, friction fit, or snap fit arrangements, as well as other arrangements as will be recognized by those of skill in the art. Alternatively, the peg members may be integral with the spacer, such as an arrangement where the peg members are molded with the spacer as a one piece construction.
[0024] The deformable fins 32 or cup members 33 are designed in a manner and/or are comprised of an appropriate material that facilitates deformation of the fins. For example, the deformable fins 32 may be comprised of an appropriate deformable biocompatible material having relatively flexible characteristics, such as polyethylene or polyurethane. As explained in further detail below, the deformable cup members 33 are designed to collapse when forced into holes formed in the articular cartilage of the condyle. In alternative embodiments, the deformable fins 32 take different shapes other than that of cup members. For example, the deformable fins may comprise clover structures, spoked structures, circular structures that are not cupped, or numerous other designs. Furthermore, with certain designs, the deformable fins 32 may be comprised of a relatively rigid material instead of a flexible material. For example, in one embodiment, the deformable fins are comprised of a relatively rigid metal material arranged as a clover leaf cup structure. Such rigid metal fin structures will typically have a lesser thickness than fins comprised of more flexible material such as PE or PU.
[0025] With reference to FIG. 3 , the plurality of peg members 15 are placed on the bottom surface 28 of the spacer 12 in an arrangement that promotes a secure attachment of the spacer 12 to the condyle. In the arrangement of FIG. 3 , four peg members 15 are provided on the bottom surface 28 of the spacer 12 . However, depending on numerous factors such as the size of the patient and particular shape of the spacer, different numbers of peg members may be used in different configurations.
[0026] In order to secure the interpositional arthroplasty to either a femoral or tibial condyle, the surgeon first prepares the condyle by forming holes in the condyle. FIGS. 6-8 show an exemplary embodiment where an interpositional arthroplasty 10 is secured to each tibial condyle 43 and 44 . FIG. 8 particularly shows a cross-sectional view of the tibia 40 with holes 60 formed in the tibial condyles 43 and 44 .
[0027] Before the holes 60 are formed in the condyles 43 and 44 , the surgeon first clears the interior portion of the meniscus 46 . With the interior of the meniscus 46 cleared, the medial tibial condyle 43 and lateral tibial condyle 44 are open to receive an arthroplasty 10 . In one embodiment, the surgeon may also smooth the exterior articular cartilage 47 to prepare a surface for the spacer 12 .
[0028] Once the interior portion of the meniscus 46 is cleared, holes 60 are formed in the condyles 43 and 44 using a drill and guide arrangement. Such arrangements are common in prosthetic procedures. In this case, the drill and guide arrangement is configured to create a hole 60 in the condyle that extends to the subcondylar plate 48 . In one embodiment, the depth of the hole extends through the articular cartilage 47 , but does not extend completely through the subcondylar plate 48 . The actual depth of such a hole will depend upon the patient, but the typical depth of such a hole in the condyle that does not extend through the subcondylar plate 48 is less than eight mm. In an alternative embodiment, the hole created by the surgeon in the condyle extends completely through the subcondylar plate 48 , thus perforating the subcondylar plate. In any event, the diameter of the hole that is created in the condyle is slightly larger than the diameter of the center peg of a peg member, but smaller than the diameter of deformable a cup member 33 . This allows the peg member to be inserted into the hole while causing the cup members 33 to collapse.
[0029] After the holes are formed in the condyles, the surgeon aligns the peg members 15 with the holes in the condyle and manually presses against the spacer 12 to force the peg members 15 into the holes. FIG. 8 shows the peg members 15 inserted in the holes 60 . When the deformable cup members 33 are forced into the holes in the condyle along with a peg member 15 , the deformable cup members 33 collapse since the diameter of the hole 60 is less than the diameter of the cup members 33 . The deformed cup members 33 are collapsed into excessive space in the hole and wedge the center peg in the hole in a friction fit arrangement. The deformed cup members are represented in FIG. 8 by the rectangular portions positioned between the holes 60 and the peg members 15 . The wedging action of the deformed cup members effectively secures the arthroplasty to the associated condyle.
[0030] Following implantation, the spacer 12 of each arthroplasty 10 is secured to a condyle 43 or 44 and covers a substantial portion of the exterior surface of the condyle. In particular, each spacer 12 is configured to cover the articular cartilage 47 surface portion of the condyle that would normally contact the meniscus 46 of the tibia 44 . Thus, as shown in FIG. 6 , the top surface 18 of each spacer 12 is exposed to the femur 50 , with each top surface 18 directly opposed to a femoral condyle 51 , 52 . With the spacers 12 in place, inflamed joint surfaces on the femur and tibia are separated, thus relieving pain encountered by the patient. Furthermore, with the arthroplasty secured to the condyle, in-vivo movement of the arthroplasty is restricted, and less pain is encountered by the patient following the procedure. Also, because the arthroplasty may be secured without perforating the subcondylar plate, the patient may experience less pain following surgery along with a faster recovery time.
[0031] While FIGS. 6-8 shown an interpositional knee arthroplasty 10 attached to both the medial tibial condyle 43 and the lateral tibial condyle 44 , some surgeries may only call for the use of a single arthroplasty secured to a single condyle, depending on the needs of the patient. Furthermore, as mentioned above, the interpositional knee arthroplasty may be secured to either the tibial condyles or the femoral condyles.
[0032] Although the present invention has been described and shown with respect to certain preferred embodiments, it will be appreciated by those of skill in the art that other implementations and adaptations are possible. For example, although the pegs have been shown in the figures extending in a perpendicular fashion from the spacer, the pegs may also be positioned at an acute angle, such that the pegs enter the condyle at an associated angle. As another example, different shaped or different numbers of fins may be attached to each peg. Moreover, in addition to alternative embodiments, there are advantages to individual advancements described herein that may be obtained without incorporating other aspects described above. Therefore, the spirit and scope of the appended claims should not be limited to the description of the preferred embodiments contained herein. | 1a
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FIELD OF THE DISCLOSURE
The present invention relates to an applicator system, particularly an application assembly, configured for applying a coating or film to a substrate surface such as a floor.
BACKGROUND
Higher viscosity floor coatings (such as epoxies and polyurethanes) can be difficult to properly apply using known applicators. Typically, if the user applies too much force on the applicator, the coating becomes too thin and visible imperfections become evident. On the other hand, if the user applies too little force to the applicator, pools of the coating form and visible imperfections become evident. The present disclosure provides an applicator that addresses the above issues.
SUMMARY
The present disclosure, among other things, provides a device that can be used to spread a thin, even coating of liquid material on a surface. For example, the device can be used to apply floor shine on a floor surface. The device is configured such that the applicator portion of the device applies a generally constant contact force on the surface even when the force applied by the user on the tool varies.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 is a perspective view of a surface coating device according to an embodiment of the disclosure;
FIG. 2 is a side view of a lower portion of the device of FIG. 1 ;
FIG. 3 is a top view of the lower portion of the device of FIG. 1 ;
FIG. 4 is an assembly view of the lower portion of the device of FIG. 1 ;
FIGS. 5 a - c are schematic views showing the handle moving relative to the applicator;
FIG. 6 a is a perspective view of a connecting member that connects a handle and an applicator of FIG. 1 ;
FIG. 6 b is a top view of the connecting member of FIG. 6 a;
FIG. 7 a is a perspective view of a guide member that connects to the handle of FIG. 1 ; and
FIG. 7 b is a side view of the guide member of FIG. 7 a.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring to FIGS. 1-4 , a surface coating device according to one embodiment of the present disclosure is shown. The depicted coating device 10 includes a handle 12 , a connecting member 14 , and an accessory 16 . The handle 12 can be any structure that the operator can hold onto and use to control the accessory 16 .
In the depicted embodiment the handle 12 includes a first portion 18 that includes a distal end 20 of the handle 12 and a second end portion 22 that includes a proximal end 24 of the handle 12 . The distal end 20 is the end of the handle 12 that is closer to the accessory 16 , and the proximal end 24 is the end of the handle that is opposite the distal end 20 . In the depicted embodiment the handle 12 includes a shaft 26 and a guide member 28 attached to the shaft 26 at the first end portion 18 of the handle 12 . The shaft 26 in the depicted embodiment is sized such that the device 10 can be used while the operator is standing. It should be appreciated that the handle 12 can be of any suitable configuration. For example, the handle 12 can in an alternative embodiment be configured to be grasped by one hand rather than two. In the depicted embodiment the handle 12 also includes a hose 30 attached to thereto for dispensing fluid to the accessory 16 or to the surface to be coated.
In the depicted embodiment the accessory 16 includes a frame 32 that is configured to support an applicator 34 . In the depicted embodiment the applicator 34 is a pad. However, it should be appreciated that the applicator 34 in alternative embodiments need not be a pad. For example, the applicator could be a wiper blade, a cloth, a sponge, or a part of the frame itself. The frame 32 in the depicted embodiment has a length L 1 ( FIG. 3 ) that is between about 10-36 inches. However, it should be appreciated that the frame can be of many other sizes as well.
Referring to FIG. 2 , the end profile of the frame 32 in the depicted embodiment is generally convex relative to a surface to be coated. The convex profile of the frame 32 allows the applicator 16 to be in continuous contact with the surface (e.g., a floor surface) even if the applicator 16 rolls forward F or backward B ( FIG. 2 ) from its normal orientation. It should be appreciated that many other frame configurations are possible. For example, the end profile of alternative embodiments of the frame can be circular, elliptical, triangular, rectangular, or irregular.
Referring to generally to FIGS. 1-6 b and primarily to FIGS. 6 a and 6 b , the connecting member 14 is described herein in greater detail. The connecting member 14 includes a first end portion 35 attached to the accessory 16 and a second end portion 36 attached to the handle 12 . In the depicted embodiment the connecting member 14 has a generally triangular shaped with the first end portion 35 generally defining the base of the triangle and the second end portion 36 generally defining the apex of the triangle. The connecting member 14 includes an aperture 38 for receiving a portion of the handle 12 . The aperture 38 is located in the second end portion 36 of the connecting member 14 and is generally elliptical in shape.
In the depicted embodiment, the smaller diameter D 1 of the aperture 38 is about 1.2 inch and the larger diameter D 2 of the aperture is about 1.4 inch. In the depicted embodiment the smaller diameter D 1 is within about 5-15 percent the diameter D 2 of the guide member 28 . In the depicted embodiment the aperture 38 includes a pair of opposed notches in the D 1 direction which engage portions of the guide member 28 . In the depicted embodiment the width W 1 of the first end 35 is between 5 to 7 inches, the length L 2 from the first end to the second end is between 5 to 7 inches, and the thickness T 1 of the connecting member is between about ⅛-¼ inch. However, it should be appreciated that alternative embodiments of the connecting member 14 can be of many other geometric configuration and sizes.
In the depicted embodiment, the body of the connecting member comprises a flexible construction. More particularly, a portion of the connecting member 14 in the depicted embodiment comprises a rubber construction. It should be appreciated that the connecting member can have many other alternative geometries and can be made of many different types of materials. For example, the overall shape of alternative embodiments of the connecting member can be circular, elliptical, rectangular, cylindrical, or irregular, and portions of the connecting member can be constructed of a combination of polymeric material, wood material, and/or metal.
Referring to FIGS. 2 , 4 , 7 a , and 7 b , the guide member 28 is described herein in greater detail. In the depicted embodiment the guide member 28 includes a first end 40 which is domed shaped and a second end 42 that is hollow and configured to receive a portion of the shaft 26 . The guide member 28 of the depicted embodiment is detachable from the shaft 26 portion of the handle 12 via a fastener 44 ( FIG. 4 ) that traverses through the guide member 28 and a portion of the shaft 26 that is received within the guide member 28 . The guide member 28 includes a retaining arrangement 46 configured to engage the connecting member 14 . In the depicted embodiment the retaining arrangement 46 includes beads that hold the connecting member 14 at a location on the guide member 28 while allowing the guide member 28 and the connecting member 14 to move relative to each other. For example, in the depicted embodiment the guide member 28 can rotate about the axis of the handle 12 relative to the connecting member 14 .
In the depicted embodiment, the guide member 28 includes protrusions that are configured to be received in the notches of the aperture 38 of the connecting member 14 . The guide member 28 includes an overall length of L 5 , which is between about 3-5 inches. The guide member 28 includes protrusions on a first side of the guide member 28 at a distance L 3 , between about 3.5-4.0 inches, from the first end 40 of the guide member 28 for engaging the connecting member 14 . The guide member 28 includes protrusions on a second side of the guide member 28 at a distance L 4 , between about 3.0-3.5 inches, from the first end 40 of the guide member 28 for engaging the connecting member 14 . However, it should be appreciated that alternative embodiments of the guide member 28 can be of many other geometric configuration and sizes.
In the depicted embodiment, the protrusions on the guide member 28 cooperate to support the connecting member 14 . In the depicted embodiment the connecting member and the protrusion are connected without fasteners. It should be appreciated that the guide member 28 in alternative embodiments can be connected to the connecting member 14 in a different manner. For example, the guide member could be formed together with the connecting member as a single piece. In another alternative embodiment the guide member and the handle are formed of a single piece and the connecting member is fastened to the piece.
Referring to back to FIGS. 5 a - 5 c , schematic views of the device are shown. Generally, FIGS. 5 a - 5 c illustrate that the handle 12 can be moved in a number of ways without causing any portion of the applicator to lift off the surface. FIG. 5 a illustrates that the handle can be pivoted back and forth with the first end 40 of the guide member 28 on the surface while the applicator 34 maintains contact with the surface. In the depicted embodiment the applicator 34 can remain generally in the same position while the handle is pivoted back and forth. FIG. 5 b illustrates that the handle can be pivoted from side to side with the first end 40 of the guide member 28 on the surface while the applicator 34 maintains contact with the surface. In the depicted embodiment the applicator 34 can remain generally in the same position while the handle is pivoted from side to side. FIG. 5 c illustrates that the handle can be moved in any direction with the first end 40 of the guide member 28 on the surface, while the applicator 34 maintains contact with the surface, so long as the angle of the handle 12 to the surface is greater than α degrees. In the depicted embodiment the applicator 34 can remain generally in the same position while the handle is pivoted such that the angle α between the handle 12 and the floor remains greater than about 40 degrees. FIG. 5 c also illustrates that the handle 12 can be rotated about its axis while the applicator 34 maintains contact with the surface.
FIGS. 5 a - 5 c further illustrate that in the depicted embodiment the downward forced applied to the handle 12 is generally not transferred to the applicator 34 . The downward force applied by the operator onto the handle 12 is transferred to the surface via the first end 40 of the guide member 28 . Lateral forces (i.e., pulling and pushing forces) are generally transferred from the handle 12 to the applicator 34 . This functionality enables the operator to control the applicator 34 yet maintain a relatively constant contact force between the applicator 34 and the surface. It also prevents the applicator 34 from undesirably losing contact with the surface as a result of erratic movements of the handle 12 .
The above specification, examples and data provide a complete description of the manufacture and use of the composition of the invention. Since many embodiments of the invention can be made without departing from the spirit and scope of the invention, the invention resides in the claims hereinafter appended. | 1a
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RELATED APPLICATIONS
[0001] This application is related to and claims priority to U.S. Provisional Application No. 61/625,830, filed on Apr. 18, 2012, entitled “Application of RF Chip Implant in Treating Primary Focal Hyperhidrosis and Related Conditions and Device Thereof,” which is incorporated by reference herein in its entirety.
FIELD OF THE INVENTION
[0002] The invention relates to apparatuses for treatment of hyperhidrosis, Raynaud's phenomenon, cerebral ischemia, asthma and hypertension by pulsed radiofrequency nerve stimulation. In particular, the invention relates to the improvement of these conditions by stimulating at least one ganglion selected from the group consisting of T-1 through T-4 ganglia, cervical ganglia, renal ganglia or combinations thereof with a wireless, battery-less and lead-less stimulator.
BACKGROUND OF THE INVENTION
[0003] Hyperhidrosis:
[0004] Hyperhidrosis refers to profuse perspiration (excessive sweating) beyond the body's thermoregulatory needs. It is believed that an estimated 2-3% of Americans suffer from excessive sweating of the underarms (axillary hyperhidrosis) or the palms and soles of the feet (palmoplantar hyperhidrosis). For the purpose of discussion that follows, palmar hyperhidrosis (excessive sweating of the palms) will be stressed. Sweaty palms disorder is embarrassing, can hamper business interactions and cause social anxiety. Severe cases of palmar hyperhidrosis also have serious consequences, prohibiting people suffering from such a disorder to shake hands, lift any objects or work in professions that require contact with electricity.
[0005] Primary palmar hyperhidrosis is caused by overactivity of the sympathetic nervous systems, largely triggered by emotional stresses including anxiety, nervousness, anger and fear. Sympathetic nervous system is one of two major parts of the autonomic nervous system, the other being the parasympathetic system. In cases of palmar hyperhidrosis, the stellate ganglion and the first, second, third and forth thoracic ganglia of the sympathetic nerve chain are believed to play the major role in the abnormal signal generation to sweat glands of the palms.
[0006] There are various treatments available for palmar hyperhidrosis. Aluminum chloride is used in antiperspirants. However, patients suffered from hyperhidrosis require antiperspirants in high concentration to effectively treat the symptoms of the condition. Anticholinergic drugs have direct effect on sympathetic nervous systems although they have side effects. Botulinum injection on affected area may block neural control of sweat glands. However, such a treatment is expensive and short-term, with patients requiring to receive injection every 6 to 12 months.
[0007] Removal or destruction of sweat gland is one surgical option available for hyperhidrosis although such a treatment has many side effects. Endoscopic transthoracic sympathectomy (ETS), a minimally invasive surgical procedure, involves resection or clamping of the thoracic ganglion on the main sympathetic chain. Particularly, an en bloc ablation by laser vaporization of the T2 ganglion has proven to yield a permanent therapeutic effect for palmar hyperhidrosis. However, ablation of the targeted nerve cluster has a host of complications, including compensatory sweating, bradycardia, hypersensitive to light, lack of norepinephrine and acetylcholine, and possibly nerve regeneration. Clamping of the thoracic ganglion is intended to permit the reversal of the ablation procedure so as to minimize the aforementioned complications. However, it has shown that effective clamping also causes irreversible damages to the nerve, and patients continue to suffer similar side effects such as compensatory hyperhidrosis.
[0008] Electrical stimulation of the sympathetic nerve chain has been proposed to treat hyperhidrosis. The principle behind such approach involves disruption and modulation of hyperactive neuronal circuit transmission at specific sites in the sympathetic nerve chain. The procedure is also said to minimizes or possibly eliminate the complications from ETS. Currently, electrical stimulation of the nerve is usually carried out by surgically implanting a generator in the vicinity of the targeted nerve cluster, and then applying electrical modulation to the nerve through electrodes that are connected to the generator by lead. Conventional stimulation device, however, bears significant shortcomings. For example, the implantable generator requires a battery or power source, which means the size of the device cannot be too small. Also, an extension lead, containing electric wire, is attached to the generator and carries the electric pulses to the electrode that is attached to the nerves or tissues. This lead is undesirable as it may tangle with or disturb the nearby organs. If damaged, a leak and possibly more severe complications may occur as a result.
[0009] It is therefore the goal of the present invention to provide a miniature, battery-less stimulator that requires no extension lead.
[0010] Raynaud's phenomenon:
[0011] Raynaud's phenomenon is a disorder of the blood vessels, usually in the fingers and toes. It is a condition in which cold temperature or emotional stress causes blood vessel spasms that block blood circulation to the fingers and toes. Specifically, Raynaud's phenomenon is a hyperactivation of the sympathetic nervous system causing extreme vasoconstriction of the peripheral blood vessels, lead to tissue hypoxia. Typical symptoms are pain within the affected extremities, discoloration, and sensations of cold and/or numbness. The disorder can be distressing and in severe cases, dangerous when someone with Raynaud's is placed in cold climate.
[0012] Treatment for Raynaud's phenomenon may include prescription medicines such as nifedipine or diltiazem, though it has the usual side effects of headache, flushing, and ankle edema. An ETS can be performed by ablating the nerves that signal the blood vessels of the fingertips to constrict. But complications common to ETS would also occur.
[0013] Cerebral ischemia:
[0014] cerebral ischemia is a medical disorder where there is insufficient blood flow to the brain to meet metabolic demand. Typically ischemia occurs when one of the arteries that brings blood to a part of the brain is blocked by a blood clot or a cholesterol plague. The resulting lack of oxygen or cerebral hypoxia leads to death of brain cells or ischemic stroke. Cerebral ischemia is a leading cause of adult disability in the United States, killing nearly 150,000 people each year.
[0015] Tissue plasminogen activator (TPA) is an effective medication that lyses a clot and possibly restores blood circulation to the affected area of the brain. However, administering TPA has a very limited time window of only 3-4 hours. TPA also may not be suitable for patients with certain conditions, such as tendency to bleed, heart problems or diabetics, because there is the potential risk of serious brain bleed. Surgery, such as carotid endarterectomy, may also be performed on patients suffering from brain ischemia. The procedure aims to unlock carotid arteries, which supply blood to the brain, that have accumulated plaque or fat buildup in them. However, the inherent dangers of such surgical procedure prompt other safer and less invasive approach for the treatment of cerebral ischemia
[0016] Asthma:
[0017] Asthma is a chronic lung disorder that inflames and narrows the airways. The inner walls of an asthmatic's airways are swollen or inflamed. This swelling and inflammation makes the airways extremely sensitive to irritations and increases one's susceptibility to an allergic reaction.
[0018] Most asthma medications work by relaxing bronchospasm. Treatment is usually with an inhaled short-acting beta-2 agonist and oral corticosteroids. Side effects such as insomnia, anxiety, increased heart rate and tremor occur in some patients taking asthmatic medications.
[0019] Hypertension:
[0020] Hypertension is a medical condition in which the blood pressure in the arteries is elevated. An elevation of blood pressure increases the risk of developing cardiac disease, renal disease, atherosclerosis or arteriosclerosis, eye damage and stroke. It is estimated that hypertension affects approximately one in three adults in the U.S., —73 million people—clearly a serious public health problem.
[0021] Abnormally elevated sympathetic nerve activity is found to contribute to the progression of hypertension and renal disease. Therefore, hypertension, renal and heart failure can be treated by reducing the sympathetic efferent or afferent nerve activity of the kidneys. Medication such as rennin-angiotensin system inhibitors, calcium channel blockers or diuretics have been used to treat hypertension.
[0022] The causes of the prevalent diseases discussed herein can all be related to abnormal activities of the sympathetic nerve chain. Therefore, novel apparatuses of treating these diseases are presented to reduce the side-effects associated with the conventional approaches.
SUMMARY OF THE INVENTION
[0023] The present invention discloses apparatuses of treating physiological disorders caused by abnormality of sympathetic activities by implanting a pulsed radiofrequency stimulator at specific locations along the sympathetic chain of the patient.
[0024] In an embodiment, the present invention discloses a stimulator for treating a disease of a patient diagnosed with at least one of hyperhidrosis, Raynaud's phenomenon, cerebral ischemia, asthma or hypertension, comprising: a remote controller, a plurality of electrodes, a telemetry circuit configured for bilateral data transmission that provides pulsed radiofrequency via the electrodes to stimulate at least one ganglion along the sympathetic nerve chain, a coil that allows the telemetry circuit to be wirelessly controlled and charged by the remote controller, and an electrical sensor means that monitors the electrical states of the ganglion and the telemetry circuit wherein the stimulation parameters of the pulsed radiofrequency are adjusted based on the monitored electrical states. The at least one ganglion is selected from the group consisting of T-1 through T-4 ganglia, stellate ganglia, renal ganglia and combinations thereof.
[0025] According to the present invention, the stimulation parameters comprise pulse frequency, pulse width duration, current amplitude, voltage amplitude, duty cycle and waveform of the pulsed radio frequency. The electrical states of the ganglion comprise the bio-impedance of the ganglion being stimulated. The electrical states of the telemetry circuit comprise voltage level, current amplitude, impedance and temperature of the circuit.
[0026] In an embodiment, the invention provides a lead-less stimulator wherein the plurality of electrodes, the telemetry circuit, the coil and the electrical sensor means are configured in one stand-alone package. The plurality of electrodes is configured to spread around the stand-along package for optimal contact with the ganglion.
[0027] In an embodiment, the invention provides a stimulator comprises: a remote controller, a plurality of electrodes, a telemetry circuit configured for bilateral data transmission that provides pulsed radiofrequency via the electrodes to stimulate at least one ganglion along the sympathetic nerve chain, a coil that allows the telemetry circuit to be wirelessly controlled and charged by the remote controller, an electrical sensor means that monitors the electrical states of the ganglion and the telemetry circuit, and a physiological sensor means that monitors the physiological states of the patient wherein the stimulation parameters of the pulsed radiofrequency are adjusted based on the monitored electrical states and/or monitored physiological states. The physiological states comprise the heart rate, body and tissue temperatures, blood pressure and blood oxygen level of the patient.
[0028] In an embodiment, the invention provides a telemetry circuit configured to transmit the monitored electrical states and/or monitored physiological states to the remote controller wherein the remote controller may adjust the stimulation parameters based on the monitored electrical and/or physiological states. The remote controller may further be implemented in a preexisting mobile device.
[0029] In an embodiment, the invention provides a stimulator for treating a disease of a patient diagnosed with at least one of hyperhidrosis, Raynaud's phenomenon, cerebral ischemia, asthma or hypertension, comprising: a remote controller, a plurality of thermal conductors, a telemetry circuit configured for bilateral data transmission that provides thermal energy via the thermal conductors to stimulate at least one ganglion along the sympathetic nerve chain, a coil that allows the telemetry circuit to be wirelessly controlled and charged by the remote controller, and an electrical sensor means that monitors the electrical states of the ganglion and the telemetry circuit wherein the stimulation parameters of the thermal energy are adjusted based on the monitored electrical states.
[0030] In addition to the embodiments describe so far, the present invention further provides a stimulator for treating a disease of a patient diagnosed with at least one of hyperhidrosis, Raynaud's phenomenon, cerebral ischemia, asthma or hypertension, comprising: a remote controller, a plurality of diodes, a telemetry circuit configured for bilateral data transmission that provides optical irradiation via the diodes to stimulate at least one ganglion along the sympathetic nerve chain, a coil that allows the telemetry circuit to be wirelessly controlled and charged by the remote controller, and an electrical sensor means that monitors the electrical states of the ganglion and the telemetry circuit wherein the stimulation parameters of the optical irradiation are adjusted based on the monitored electrical states.
BRIEF DESCRIPTION OF THE DRAWINGS
[0031] FIG. 1 compares the pulsed radiofrequency waveform with the continuous radiofrequency waveform.
[0032] FIG. 2 is a schematic illustration of a patient having an endoscopic insertion site in the second or third intercostals space at the anterior axillary line.
[0033] FIG. 3 is a partial exposed view of the hemithorax displaying the endoscopic system incising the parietal pleura to expose the sympathetic nerve chain.
[0034] FIG. 4 is an expose view of the thoracic ganglia with the implantable stimulator positioned for pulse radiofrequency treatment.
[0035] FIG. 5 illustrates implantable stimulators sutured on targeted sympathetic ganglion.
[0036] FIG. 6 is a schematic diagram illustrating an implantable stimulator capable of providing pulsed radiofrequency according to an embodiment of the present invention.
[0037] FIG. 7 illustrates an embodiment of the wireless, battery-less and lead-less stimulator in one stand-alone package.
[0038] FIG. 8 is a schematic diagram illustrating an implantable stimulator capable of providing thermal energy according to an embodiment of the present invention.
[0039] FIG. 9 is a schematic diagram illustrating an implantable stimulator capable of providing thermal optical irradiation to an embodiment of the present invention.
DETAILED DESCRIPTION
[0040] In the following description, reference is made to the accompanying figures that form a part hereof, and in which are shown by way of illustration the several embodiments of the invention. It is to be understood that other embodiments are contemplated and may be made without departing from the scope or spirit of the present invention. The following disclosure is therefore not to be interpreted in a limiting sense. Rather, the scope of the invention is to be defined in accordance with the appended claims.
[0041] Novel method and apparatus have been developed to regulate sympathetic nerve activity to improve the conditions of a patient diagnosed with at least one of hyperhidrosis, Raynaud's phenomenon, cerebral ischemia, asthma or hypertension. Particularly, the method involves surgically implanting a wireless, battery-less and lead-less stimulator in the proximity of at least one ganglion along the sympathetic nerve chain, and applying pulsed radiofrequency (PRF) stimulations to the targeted ganglion until the symptoms are improved.
[0042] The efficacy of PRF treatment in nerve disorders has been well documented. In general, there are two types of PRF procedures. The first involves applying continuous radiofrequency (RF) to the targeted tissue, while the other involves using PRF. Biological changes in tissue during electrical stimulation can occur due to thermal effects, the high intensity electric fields, or as a result of both. PRF applies short pulses of RF signals from a pulse generator to the tissue. The heat produced during these pulses depends on the power deposition. In PRF, because the pulse duration is only a small percentage of the time between pulses, the average tissue temperature rise for the same RF voltage is much less for PRF than for continuous RF, as illustrated in FIG. 1 . Thus, higher voltages can be applied in a PRF procedure than are commonly used in RF without raising the tissue temperature into the denaturation range above 45° C. Recent studies also suggest that PRF operating at high frequency with sinusoidal waveform can better reduce thermal damage to the nerve, as compared to RF stimulation.
[0043] The sympathetic nervous system (SNS) is part of the autonomic nervous system, which also includes the parasympathetic system. The SNS activates the flight-or-fight response, and operates through a series of interconnected neurons.
[0044] There are two kinds of neurons involved in the transmission of any signal through the SNS: pre- and post-ganglionic. Sympathetic neurons of the spinal cord (or preganglionic neurons) communicate with peripheral sympathetic neurons (or postganglionic neurons) via a series of sympathetic ganglia. Within the ganglia, preganglionic neurons join postganglionic neurons through chemical synapses. At synapses within the sympathetic ganglia, preganglionic sympathetic neurons release acetylcholine, a chemical messenger (or neurotransmitter) that binds and activates nicotinic acetycholine receptors on postganglionic neurons. And in response, postganglionic neurons (with two notable exceptions) release noradreanline, which activates adrenergic receptors on the peripheral tissues.
[0045] The exceptions mentioned above are postganglionic neurons of sweat glands and chromaffin cells of the adrenal medulla. Postganglionic neurons of sweat glands release acetylcholine for the activation of muscarinic receptors. Chromaffin cells, act like postganglionic neurons, synapse with preganglionic neurons and stimulate the chromaffin to release norepinephrine and epinephrine directly into the blood.
[0046] Sympathetic nerves originate inside the vertebral column, toward the middle of the spinal cord in the intermediolateral cell column (or lateral horn), beginning at the first thoracic segment of the spinal cord and are thought to extend to the second or third lumbar segments. Because its cells begin in the thoracic and lumbar regions of the spinal cord, the SNS is said to have a thoracolumbar outflow. Axon (or nerve fiber), is a long, slender projection of a nerve cell, or neuron, that typically connects electrical impulses away from the neuron's cell body. Axon of the sympathetic nerves leave the spinal cord in ventral branches (rami) of the spinal nerves, and then separate out as “white rami” which connects to two ganglia extending alongside the vertebral column on the left and right.
[0047] The axons of the autonomic nerve cells in the nuclei of the cranial nerves, in the thoracolumbar lateral comual cells, and in the grey matter of the sacral spinal segments are called preganglionic sympathetic nerve fibers, while those in ganglion cells are termed postganglionic sympathetic nerve fibers. The postganglionic sympathetic nerve fibers converge in ganglia that are located alongside the vertebral bodies in the neck, chest, and abdomen. Specifically, the stellate ganglion is located laterally adjacent to the intervertebral space between the seventh cervical and first thoracic vertebrae. The first, second third and forth thoracic ganglia lie next to their respective vertebral bodies on either side of the thoracic cavity.
[0048] Physiological disorders associated with abnormal sympathetic nerve activity may be treated with electrical stimulation of the appropriate ganglia outside of the spinal column. In the present invention, the preferred effect is to use an implantable stimulator to modulate nerve activities with pulsed radiofrequency (PRF). Reference of the term “stimulate” or “stimulation” in this disclosure means application of PRF signal that may be either excitatory or inhibitory to a sympathetic ganglion affected by such signal. Proper PRF stimulation prevents the total destruction of the ganglion, thereby offers the advantage over the irreversible en bloc ablation procedure.
[0049] As used herein a stimulator is positioned “proximate to” or “in the proximity of” a sympathetic ganglion means a stimulator placed at a site capable of producing a direct PRF effect on tissue that if stimulated would result in the alleviation of the diseases' symptoms. By way of an example, a stimulator may be placed either directly on the tissue or about 10 mm or less from the tissue.
[0050] As use herein “adjusting stimulation parameters of pulsed radiofrequency” means adjusting pulse frequency, pulse width duration, current amplitude, voltage amplitude, repetition rate, duty cycle and/or pulse waveform of the pulsed radiofrequency.
[0051] A variety of approaches are available for upper thoracic implantation of stimulator. The common procedures are: posterior paravertebral thoracic sympathectomy, thoracoscopic sympathectomy and retroperitoneal lumbar sympathectomy. The preferred implantation method of the present invention is accomplished percutaneously using an endoscope system.
[0052] The implanting procedure starts with placing the patient under general anesthesia and intubated with a double lumen endotracheal tube. The double lumen endotracheal tube allows alternating one-lung ventilation. A single micro incision, preferably no longer than 5 mm, is made in the second or third intercostals space at the anterior axillary line that is identified as insertion site 101 , as shown in FIG. 2 . Now referring to FIG. 3 , a 5 mm-diameter endoscope 102 is inserted through the insertion site 101 into the thoracic cavity 103 . Identification of the first and second ribs, the targeted ganglia (T1-T4), the azygos vein, the brachiocephalic and subclavian arteries, and the parietal pleura is performed. The sympathetic nerve chain is visualized as the ganglionated, longitudinal cord structure located at the junction of the ribs and the vertebral bodies.
[0053] A wireless, battery-less and lead-less stimulator capable of generating PRF is then inserted via the insertion site 101 to a predetermined location along the sympathetic nerve chain that is associated with the physiological disorder being treated, as shown in FIG. 4 . For palmar hyperhidrosis, the stimulator is preferably placed in the proximity of the T2 and T3 ganglia. Palmar skin perfusion (PSP) and palmar skin temperature (PST) of the patient are monitored to verify that the correct ganglion is being stimulated. The stimulation parameters of the PRF may be further adjusted by the stimulator itself or wirelessly by a separate remote controller until proper PSP and PST responses are received. Once the symptom of the disorder is improved, the stimulator may be directly sutured or clamped to the nearby tissue or parietal pleura, as shown in FIG. 5 . Because the stimulator of the present invention is lead-less, the operating surgeons need not be concerned with lead migration or lead direction out of thoracic cavity as found in the prior art methods. Because the stimulator is further configured to be wirelessly powered, there is also no concern with power cable. Implanting an entirely stand-alone stimulator significantly simplifies and shortens the surgical procedure. A topical skin adhesive is used to close the tiny single incision after the stimulator is sutured or affixed. Upon completion of one side of the body, the other side is then done in similar fashion.
[0054] The stimulator employed in the present invention may also comprise an electrical sensor means that monitor electrical states of the ganglion and the stimulator. For example, impedance magnitude may be determined by the stimulator due to tissue regeneration of the stimulated ganglion or electrode encapsulation. Circuit parameters may be regulated internally by the stimulator's preprogrammed rules. The stimulator may also comprise a physiological sensor means that monitor the physiological states of the patient. Physiological factors such as body and tissue temperatures, heart rate, blood pressure or blood oxygen level of the patient may be determined. Accordingly, the treatment method of the present invention may further include a step of monitoring the electrical states of the ganglion and the stimulator. A further step of monitoring the physiological states of the patient may also be preformed. According to the monitored states, another step of adjusting the stimulation parameters of the PRF may be undertaken until the symptoms of the diseases are demonstrably relieved.
[0055] Electrical nerve stimulation involves applying an energy signal (pulse) at a certain frequency to the neurons of a nerve. The energy signal causes depolarization of neurons inside the nerve above the activation threshold, resulting in an action potential. The energy applied is a function of the current/voltage amplitude and pulse width duration. In the present invention, to effectively treat the aforementioned physiological disorders, the current/voltage amplitude of the PRF may be operated at a voltage between 1 volt and 60 volts. Preferably, PRF is applied at a low amplitude of 5 volts in sinusoidal waveform to stimulate the targeted ganglion without irreversibly damaging the nerve. The pulse frequency may be in the range of 10 KHz to 10 MHz, preferably set at 500 KHz. Repetition rate of the PRF may be operated at between 0.1 Hz and 10 Hz, preferably at 2 Hz. Pulse width duration is between about 0.1 ms and 500 ms, preferably set at 50 ms. These PRF parameters ranges are generally found to be effective in treating disorders such as hyperhidrosis, Raynaud's phenomenon, cerebral ischemia, asthma and hypertension.
[0056] An alternative embodiment of the present invention involves using thermal energy to stimulate at least one ganglion along the sympathetic nerve chain until the symptoms of the diseases are demonstratively alleviated. Particularly, a stimulator capable of applying thermal stimulation is percutaneously implanted in the proximity of the targeted ganglion. The stimulator may include thermal means that can produce a “cooling effect” on the sympathetic ganglion and its nearby tissue. Sympathetic outflow may be suppressed by directly cooling the ganglion with the stimulator of the present invention until its associated nerve sensitivity and metabolic activities are substantially diminished. In operation, nerve body may be cooled from normal body temperature, about 37° C., preferably down to 5° C., by the present stimulator without permanently damaging the ganglion. Conversely, the stimulator may include thermal means that can heat the sympathetic ganglion in order to excite its associated nerve and metabolic activities. Preferably, the heating may be carried out in the temperature range of 37° C., to 65° C. without permanently damaging the ganglion.
[0057] Another embodiment of the present invention involves applying optical irradiation to stimulate targeted sympathetic ganglion. Although electrical stimulation of nerves is quite effective, it comes with complications such as damage caused by the physical contact from the electrodes and the inability to stimulate with absolute precision, thereby causing undesired stimulation of the nearby tissues. Optical energy such as laser allows more controlled and selective spatial resolution of stimulation than electrical stimulation. Laser produces coherent light that has radiation waves that are in alignment with each other and are typically of a single wavelength. To achieve effective optical irradiation, the neurons must be driven at adequate rate to produce safe, reproducible action potentials.
[0058] In the present invention, a stimulator equipped with a light source driver and a plurality of diodes may be implanted near the sympathetic ganglion to evoke desired neural activity. Low-level laser diode or light-emitting diodes may be employed. Particularly, low-level, pulsed near infrared laser light may be used to elicit neural activation of the associated sympathetic ganglion. In one embodiment, a pulsed diode laser, with wavelength in the range of 1000 nm to 2000 nm, pulse duration in the range of about 1 ms to about 20 ms and repetition rate in the range of 1 Hz-10 Hz may be used to stimulate the ganglion until symptoms of the associated disorder are alleviated.
[0059] The following examples discuss each of the physiological disorders that may be treated by the stimulation method of the present invention by grouping the relevant ganglia associated with the disorder and the preferred parameters of the PRF used.
EXAMPLE 1
[0060] PRF stimulation may be applied to treat hyperhidrosis. Patients who are suffering from palmar hyperhidrosis or other forms of hyperhidrosis are found to have abnormal sympathetic activities with the T2 and T3 ganglia.
[0061] To treat palmar or axillary hyperhidrosis, the wireless, battery-less and lead-less stimulator is implanted over the inferior stellate ganglion and over upper thoracic ganglia. Preferably, the stimulator is positioned over the T2 and T3 ganglia. A rapid PRF that exceeds the natural cycling rate of the nerve polarization and depolarization (overpacing) is applied to the T2 and T3 ganglia until the nerve and its neurotransmitters are fatigued so that no signals can be further conducted. The PRF should be operated at a frequency of 500 KHz, current amplitude at 5 volts, repetition rate at 2 Hz, and pulse width duration at 50 ms. PSP and PST of the patient are monitored before, during and after PRF stimulation until the symptom of the palmar hyperhidrosis is alleviated.
EXAMPLE 2
[0062] Raynaud's phenomenon is a vasospastic disorder triggering discoloration of the fingers, toes and occasionally other areas. The disorder is caused by increased activation of sympathetic noradrenergic nerves controlling muscle tone of digit arteriolar walls.
[0063] Treatment of Raynaud's phenomenon is akin to the procedures conducted with patients suffering from palmar hyperhidrosis. PRF stimulation in the form of overpacing is applied to the T2 and T3 ganglia until symptom is improved. Preferably, the PRF should be operated at a frequency of 500 KHz, current amplitude at 5 volts, repetition rate at 2 Hz, and pulse width duration at 50 ms. Temperatures of the fingers are monitored before, during and after the PRF stimulation.
EXAMPLE 3
[0064] The cerebral blood vessels, particularly the pial vessels, have an abundance of non-adrenergic sympathetic nerve distribution that originates in the cervical ganglia and follows the carotid artery to project into the ipsilateral hemisphere. The intracerebral vessels constrict when sympathetic nerve is excited and dilated when these fibres are interrupted. Stellate ganglion block has shown to improve cerebral perfusion by reducing the cerebral vascular tone.
[0065] The first thoracic sympathetic ganglion fuses with the inferior cervical ganglion to make the stellate ganglion. Stellate ganglion sits at the top end of the sympathetic chain in front of the C7 vertebra of the neck. For the treatment of cerebral ischemia, a wireless, battery-less and lead-less stimulator is surgically implanted over the stellate ganglion. PRF in the form of overpacing is applied to inhibit sympathetic outflow. Preferably, the PRF should be operated at a frequency of 500 KHz, current amplitude at 5 volts, repetition rate at 2 Hz, and pulse width duration at 50 ms. Physiological conditions of the patient, such as heart rate and blood pressure, should be monitored before, during and after the procedure.
EXAMPLE 4
[0066] Sympathetic activities of the lower cervical and upper thoracic sympathetic ganglia may affect the tracheal, bronchial, and pulmonary systems. Therefore, proper PRF stimulation of the lower cervical and upper thoracic sympathetic ganglia may be conducted to treat asthma by alleviating the contraction of the smooth muscles of the airways.
[0067] Particularly, positioning a PRF stimulator in the proximity of T2 to T4 ganglia may help treating patients suffering from asthma. Adjusting the parameters of the stimulator to drive (increase) sympathetic output has proven to relax the airways. Preferably, the PRF should be operated at a frequency of 500 KHz, current amplitude at 5 volts, repetition rate at 2 Hz, and pulse width duration at 0.1 ms, until the symptom of the asthma has relieved. Physiological conditions of the patient, such as heart rate and blood pressure, should be monitored before, during and after the procedure.
EXAMPLE 5
[0068] Untreated hypertension can lead to central nervous complications such as stroke and vascular dementia. Patients suffering from hypertension may be found to have renal disease or abnormal renal function. An effective way to treat hypertension may involve controlling the afferent nerve signals from the kidney to the brain and blocking efferent nerve stimuli from entering the kidney.
[0069] A PRF stimulator of the present invention is used for renal denervation to reduce sympathetic nerve outflow. The stimulator is positioned in the proximity of renal artery, preferably in the region of T5 through T12 ganglion. PRF in the form of overpacing is applied to the targeted site until symptom of hypertension is demonstrably improved. Preferably, the PRF should be operated at a frequency of 500 KHz, current amplitude at 5 volts, repetition rate at 2 Hz, and pulse width duration at 50 ms. Systematic blood pressure and heart rate are monitored before, during and after the PRF stimulation.
[0070] Conventional electrical stimulator typically comprise a pulse generator capable of producing electric stimulation signals which are sent to targeted nerve by insulated leads coupled to the spinal cord by one or more electrodes. The pulse generator can either be implanted inside the patient or left outside the body. For temporary treatment where the pulse generator is left outside the patient body, an introducer equipped with electrode on the tip is surgically inserted and positioned in the vicinity of the targeted nerve. The proximal end of the introducer is left outside of the body and connected to a pulse generator. For the implanted application, an introducer is used to position the stimulation lead, which is affixed to the targeted tissue and left in place after the introducer is withdrawn. The lead is then connected to the pulse generator that is implanted somewhere in the body. A pulse generator used in the implanted application is usually equipped with a battery for power.
[0071] Lead is a device used to access the nerve targeted for stimulation. It is typically a bundle of electrically conducting wires insulated from the surrounding by a non-electrically conducting coating. The wires of the lead connect the pulse generator to the stimulation electrodes, which transfers the energy pulse to the nerve. Leads may be conventional percutaneous leads or paddle-type leads. Depending on the locations of the nerve and the pulse generator, the length of the lead usually ranges from 10 cm to 30 cm. Electrodes are conductive terminals, usually at the end of the lead, that may contact the nerve directly or contact tissues adjacent to the nerve. Electrodes can have different geometric configurations and can induce an electric field that affects the nerve activities. Electrodes are generally made with platinum (pt), gold (Au), titanium (Ti), stainless steel, or alloy.
[0072] The present invention discloses a novel implantable stimulator which is wireless, battery-less and lead-less. FIG. 6 is a schematic diagram illustrating one embodiment of the present invention. As shown in FIG. 6 , the stimulator includes a telemetric CMOS chip 100 , a coil 200 , and a plurality of stimulating electrodes 180 . The stimulator is percutaneously implanted in the proximity of the targeted ganglia 500 for PRF stimulation.
[0073] The plurality of electrodes 180 , the coil 200 , and the telemetric CMOS chip 100 are electrically interconnected and housed in one stimulator package. The size of the stimulator, which requires no battery and is implemented using CMOS technology, is no bigger than a microscopic chip. Preferably, the size of the stimulator shall not exceed 5 mm×15 mm. A power source 300 , configured within a remote controller 400 , wirelessly powers the CMOS chip 100 via the coil 200 . Power may be transmitted by inductive coupling or any other wireless charging mechanisms such as electromagnetic induction coupling, resonate inductive coupling, capacitive coupling, light (optical, laser), or radio frequency charging (e.g., 900 MHz band or radio or microwave). A preferred embodiment of the power source 300 may be a Class-E power amplifier, which provides higher power transmission efficiency than other conventional power amplifiers. Generally, high-frequency signals have shorter skin penetration than low-frequency signals. The preferred embodiment here is to use 1 MHz wireless signals to power the CMOS chip 100 of the stimulator.
[0074] A remote controller 400 , which houses the power source 300 , the receiver 301 and the feedback controller 302 , is configured to locate outside of patient body and away from the implanted stimulator. In addition to being a wireless power source for the implanted stimulator, the remote controller 400 may also receive signals transmitted from the CMOS chip 100 , and vice versa. The remote controller 400 may adjust the stimulation parameters of the PRF based on the received signals and transmit renewed parameter commands to the CMOS chip 100 until the symptoms of the diseases are improved. Note that in the present invention no wire is needed to connect the remote controller 400 with the CMOS chip 100 . In one embodiment, the remote controller 400 may locate up to 7 cm from the implanted stimulator. The remote controller 400 may also be implemented in preexisting device such as a mobile phone, a tablet, a laptop computer or any mobile equipment. By configuring the remote controller within a preexisting device, the patient may conveniently control and charge the implanted stimulator without further carrying an additional device
[0075] Referring to FIG. 6 , the CMOS chip 100 may comprise elements such as: rectifier 110 , voltage regulator 120 , PRF generator 130 , multiplexer 140 , RF signal receiver 150 , micro-controller 160 , transmitter 170 , analog digital converter 180 , physiological sensor 190 , and electrical sensor 191 .
[0076] In operation, wireless power provided by remote controller 400 may be rectified by rectifier 110 to convert the wireless power to direct current. Voltage regulator 120 may regulate the direct current to obtain steady voltage and remove signal noise. Rectifier 110 may also send current directly to the PRF generator to generate pulsed radiofrequency.
[0077] The stimulator of the present invention further comprises an electrical sensor means for monitoring the electrical states of the ganglion and the CMOS chip. The electrical sensor 191 may monitor the bio-impedance of the ganglion that is being stimulated. It may also measure the electrical and functional states of the CMOS chip 100 , for examples the voltage level, current amplitude, impedance, and chip temperature.
[0078] The stimulator of the present invention may further comprise a physiological sensor means for monitoring the physiological states of the patient being treated. The physiological sensor 190 may monitor the tissue and body temperatures, heart rate, blood pressure, blood oxygen level and/or other physiological states of the patient. In one embodiment of the present invention, the physiological sensor 190 may include a measuring means that can clamp or cuff to a blood vessel near the ganglion to allow measurement of the physiological states of the patient. The measuring means may be in any shape or size as long as it can clamp to a blood vessel.
[0079] The micro-controller 160 receives the monitored states from the sensors 190 and 191 , and may adjust the stimulation parameters of the PRF according to preprogrammed protocols. Stimulation parameters may include: pulse frequency, pulse width duration, current/voltage amplitude, repetition rate, duty cycle and/or waveform. In another embodiment, the monitored states received by the sensors 190 and 191 may be transmitted by transmitter 179 to the receiver 301 of the remote controller 400 . The remote controller 400 may adjust the stimulation parameters based on the monitored states and then transmit modulated parameter instructions to the RF signal receiver 150 of the CMOS chip 100 . In one embodiment, the remote controller 400 may be configured to display the electrical states of the CMOS chip 100 and the ganglion or the physiological states of the patient for ease of controlling the PRF stimulation parameters.
[0080] The present invention further teaches an implantable wireless and battery-less stimulator that requires no lead. FIG. 7 illustrates one embodiment of the present invention. This novel stimulator device combines a plurality of electrodes 13 , the CMOS chip 10 and the power receiver 11 in one stand-alone package which simplifies the implanting procedure as well as eliminates disturbance of tissues caused by lead. Under the stimulator package 14 , the CMOS chip 10 may be placed on a substrate layer 12 support by a component 15 . The component 15 may be a capacitor, a thermal source driver, an optical source driver and/or the sensor means. Power receiver 11 may be configured to couple the CMOS chip 10 inside the stimulator package 14 to minimize the stimulator size. The plurality of electrodes 13 may be configured to evenly spread around the stimulator package 14 or in any fashion that can provide optimal contact with the nerve tissue. On the circuit level, as shown in FIG. 6 , the PRF generator 130 of the CMOS chip 100 connects to the electrodes 180 via the multiplexer 140 . In structure, the electrodes 13 , surrounding the stimulator package 14 without leads, stimulate the targeted ganglion by applying appropriate PRF. The present invention removes the extension leads that connect electrodes with the stimulator in the prior art systems. A complete lead-less system may avoid problems such as lead fracture or lead leakage found in a lead-based system. It can also simplify implant procedure by allowing simple insertion of a single stand-alone stimulator in the proximity of the targeted ganglion without concerning lead anchoring, lead migration or lead disturbance. The stimulator embodiment illustrated in FIG. 7 also may be sutured directly to the nerve or nearby tissues such as pleura.
[0081] In another embodiment, the plurality of electrodes may be replaced with a plurality of thermal conductors or optical diodes, depending on the configurations of the CMOS chip inside the stimulator. Note that the shape of the stimulator package is not limited. Any package that can house the CMOS chip, power receiver and the plurality of electrodes/thermal conductors/light diodes in one stand-alone package falls under the scope of the present disclosure.
[0082] The stimulator of the present invention may further comprise a fastening means to help secure the stimulator to the nerve or nearby tissues. The fastening means may be in the form of a clamp, claw, cuff or any other configurations to facilitate securing of the stimulator. The fastening means may also be configured as the measuring means for the physiological sensor to help monitoring the physiological states of the patient.
[0083] To permit safe implantation, the stimulator may be encapsulated by biomaterials such as polydimethylsiloxane (PDMS) or epoxy-titanium. Coating the stimulator with PDMS or similar materials not only can protect the telemetric CMOS circuit, but also offer enhanced adhesion property to the nerve or nearby tissues.
[0084] FIG. 8 is another embodiment of the present invention that involves a wireless, battery-less and lead-less stimulator capable of applying thermal energy to stimulate targeted ganglion 500 . Such implantable stimulator comprises a CMOS chip 600 that includes: power rectifier 610 , voltage regulator 620 , thermal source driver 630 , thermal source/conductor 640 , RF signal receiver 650 , micro-controller 660 , transmitter 670 , analog digital converter 680 , physiological sensor 690 , and electrical sensor 691 . The stimulator is wirelessly powered by power source 300 of remote controller 400 via coil 200 . The CMOS chip 600 is configured for bilateral data transmission in which receiver 301 may also receive signals from transmitter 670 .
[0085] The thermal source driver 630 may convert electrical energy to temperature differentials. Specifically, the thermal source driver 630 may contain a Peltier cell or module that converts electrical voltage to thermal energy. Thermal energy may be in either cooling or heating form. The thermal source driver 630 applies thermal energy to the ganglion 500 via a plurality of thermal conductors 640 . Thermal energy is also precisely controlled by the micro-controller 660 to avoid permanently damaging the ganglion.
[0086] FIG. 9 is yet another embodiment of the present invention that discloses a wireless, battery-less and lead-less stimulator capable of applying optical irradiation to stimulate targeted ganglion 500 . The implantable stimulator comprises a CMOS chip 700 that includes: power rectifier 710 , voltage regulator 720 , light source driver 730 , a plurality of diodes 740 , RF signal receiver 750 , micro-controller 760 , transmitter 770 , analog digital converter 780 , physiological sensor 790 , and electrical sensor 791 . The stimulator is wirelessly powered by power source 300 of remote controller 400 via coil 200 . The CMOS chip 700 is configured for bilateral data transmission in which receiver 301 may also receive signals from transmitter 770 .
[0087] The light source driver 730 may be a laser diode diver that delivers precise current to the plurality of diodes 740 for optical stimulation of the ganglion. Diode laser is preferred in nerve stimulation because they are small, low-intensity and require relative little power. In one preferred embodiment, a low-power pulsed infrared laser driver may be used to drive the diodes. Other types of light source driver may also be employed in the stimulator of the present invention as long as safe and reproducible nerve action potential can be evoked.
[0088] While the invention has been described in connection with what is presently considered to be the most practical and preferred embodiment, it is to be understood that the invention is not to be limited to the disclosed embodiment, but on the contrary, is intended to cover various modifications and equivalents included within the spirit and scope of the appended claims. | 1a
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BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to an electronic animal containment or confinement system and, more specifically to a pet confinement system that contains a transmitter which generates a regulated signal through a boundary antenna made from a buried wire. The regulated signal creates a field signal of a predetermined width regardless of the length of the wire used to define the boundary antenna.
[0003] 2. Description of Prior Art
[0004] Over the years, electronic animal containment systems have become very popular because they use electronic signals traveling though a buried wire to create a boundary defining a predetermined area within a property. In this way, the property owner does not have to erect a fence in order to ensure that an animal is confined within a desired space.
[0005] In a typical electronic animal confinement system, a boundary signal emitter wire in the form of a boundary antenna is buried along the perimeter of a predetermined area of real property or ground in which a pet, such as a dog, is to be confined. A transmitter typically placed in a house or garage is electronically connected directly to the boundary antenna to energize the antenna with a magnetic field signal generated in the transmitter. The wire radiates the magnetic field signal to electronically define an imaginary “boundary” coincident with the wire. A receiver worn about the neck of the dog responds to the radiated signal as the dog approaches the perimeter boundary set up by the boundary antenna. The receiver includes circuitry designed to provide a shock to the dog to cause the dog to move away from the perimeter boundary. As a result, the dog may be kept in the yard without the need for a fence.
[0006] One well-known pet containment system is manufactured by Woodstream Corporation of Lititz, Pa. The pet containment system comes in two embodiments. The first is known as the 5140 Fence Free Pet Containment System and the second is known as the 5132 Fence Free Deluxe Pet Containment Systems. Both of these systems provide humane electrical stimulation in a safe and effective way to train a dog to stay within the boundaries of a yard.
[0007] While systems such as the ones mentioned above have met with great success, there is nevertheless room for improvement. One area where improvement is needed is in creating a magnetic force field of constant magnitude. In prior art systems, signal field width varies according to several factors, including the length and gauge of the wire defining the boundary antenna. In order to normalize the signal field width for installations of any size, a variable resistance must be added to the loop wire that defines the boundary antenna. This resistance must be added in series with the loop wire and the terminals of the transmitter. In prior art systems, the resistance may be added by use of discrete resistive elements or thorough incorporation or a potentiometer into the transmitter circuitry. No automatic adjustment system exists.
[0008] Also in stormy weather, the wire boundary antenna acts not only as a emitter of the magnetic field boundary signal but also as a vehicle for attracting lightening. Should lightening strike at or near the wire, the transmitter circuitry may be damaged or destroyed.
[0009] The present invention is directed toward solving these problems.
SUMMARY OF THE INVENTION
[0010] The basic elements of the inventive pet confinement system consist of a receiver that is secured to a collar that is worn by a dog around its neck. The receiver contains two probes that make contact with the skin of the dog so that when the dog gets too close to an electrified boundary, a shock is created within the receiver and passed through the probes into the dog as way to alert the dog that behavior such as approaching the fence should not be done. The receiver also contains a charger receptacle that mates with a complementary connection provided in a transmitter. It is the transmitter which is the subject of this invention.
[0011] The installation of a pet confinement system according to the subject invention begins by creating a boundary providing an area within which a dog is free to roam. In its simplest form, the pet confinement system comprises a wire that is buried in the ground in a loop with the ends of the wire being connected to the inventive transmitter. In this way, the boundary is defined about the entire property and the dog is free to roam anywhere within that boundary.
[0012] The inventive transmitter contains an input jack which accommodates a connection plug from a portable transformer in order to provide an input voltage for the system. Through the use of a full wave bridge rectifier, the input voltage can be AC or DC, but is preferably DC. The rectifier yields a DC voltage that passes through a voltage regulator which has an output port that provides operating voltage to circuit elements within the system.
[0013] The heart of the inventive transmitter is a microcontroller that provides various control signals to a voltage adjuster. An EEPROM is used to program a desired identification code (ID) which matches a comparable identification code set in the receiver that is worn by the dog. This identification code is constantly transmitted to a boundary antenna under the direction of the controller so that the receiver is able to detect and pick up the information that is also contained within the signal that carries the ID.
[0014] Also forming part of the invention is the boundary antenna which is made up of a wire that is buried in the ground. This boundary antenna transmits information from the microcontroller that includes the ID along with other information to cause the receiver to respond in different ways. One end of the boundary antenna is connected to a switch that passes through an arrangement of resistors to signal ground (a common electrical point on the Printed Circuit Board). The other end of the boundary antenna is connected to the output of an adjustable voltage regulator. This regulator has an input for receiving an input voltage Vcc from the full-wave bridge rectifier. The regulator also contains an adjustment port for receiving a signal from the voltage adjuster in order to change the magnitude of the output voltage appearing at the output of the regulator. The inventive circuit also includes an operational amplifier (OP AMP) that is used to amplify a voltage signal which represents the voltage passing through the resistor arrangement when the switch is on. The voltage signal is amplified by the OP AMP to a usable value and then placed into an A-to-D converter housed in the microcontroller. The transmitter also contains a switch array made up of a series of six push-button switches that are used to cause the microcontroller to ultimately adjust the current passing through the boundary antenna to yield a magnetic field of desired width appearing around and about the wire forming the boundary antenna.
[0015] In order to constructively measure the current flowing through the wire, set points are used. A set point is simply an A-to-D converter count which represents the desired loop current for a field width setting. Each of the five field width settings has its own set point. The set points were calculated using a spreadsheet and are based on an amplifier gain of 40. The set points are 54 for a field width of 1.5 ft. and an average loop current of 80 milliamps, 95 for a field width of 2.5 ft. and an average loop current of 140 milliamps, 124 for a field width of 3.25 ft. and an average loop current of 180 milliamps, 149 for a field width of 4.0 ft. and an average loop current of 220 milliamps, and 190 for a field width of 5.0 ft and an average loop current of 310 milliamps.
[0016] When a push-button switch is selected, evidencing a desired field width across the wire making up the boundary antenna, the microcontroller puts out a signal into the voltage adjuster which in turn causes the voltage regulator to put out an output current that passes through the boundary antenna. The desired set point count is monitored in the microcontroller and the microcontroller looks to see if the count represents a desired field width. If the count is too low, then the microcontroller causes the voltage adjuster to increase the output voltage from the voltage regulator. This interaction takes place until the microcontroller gets a set point reading from the data passing through the A-to-D converter that equals or exceeds the predetermined set point value for a desired field width. At that point, the microcontroller no longer yields signals for changing the voltage output of the voltage regulator and the field width passing through the wire of the boundary antenna remains at the desired value.
[0017] By virtue of the foregoing, there is thus provided an electronic animal confinement system with an improved transmitter that provides advantages in performance and utility over prior art systems.
[0018] Thus, it is an object of the present invention to provide an electronic animal confinement system that has an improved transmitter for providing a signal through a boundary antenna so that the field strength emanating from the boundary antenna is at a predetermined value regardless of the length of the antenna.
[0019] It is another object of the present invention to provide an improved system for protecting a transmitter in a pet confinement system against lightning strikes.
[0020] These and other objects and advantages of the present invention shall be made apparent from the accompanying drawings and the following detailed description.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] The accompanying drawings which are incorporated in and constitute a part of the specification illustrate embodiments of the invention and together with a general description of the invention given above and the detailed description given below serve to explain the principles of the invention.
[0022] FIG. 1 is a diagrammatic view of a property showing an installation of the subject invention.
[0023] FIG. 1A is a diagrammatic view of the dog shown in FIG. 1 .
[0024] FIG. 2A is a perspective view of a receiver used in the inventive pet containment system.
[0025] FIG. 2B is a plan view of the receiver of FIG. 2A mounted on a collar worn by a pet.
[0026] FIG. 3 is a plan view of the casing for a transmitter incorporating the present invention.
[0027] FIG. 4 is a block diagram of an embodiment of the present invention.
[0028] FIG. 5 is a circuit diagram of the embodiment of the present invention shown in FIG. 4 .
DETAILED DESCRIPTION OF THE INVENTION
[0029] With reference to FIGS. 1 through 3 , the basic elements of the inventive pet confinement system are shown. FIGS. 1A, 2A , 2 B and 3 generally show a receiver 10 that is secured to a collar 12 that is worn by a dog D around its neck. The receiver contains two probes 14 and 16 that make contact with the skin of the dog so that when the dog gets too close to an electrified boundary, a shock is created within the receiver 10 and passed through the probes 14 and 16 into the dog as way to alert the dog that behavior such as approaching the fence should not be done. The receiver 10 also contains a charger receptacle 18 that mates with a complementary connection provided in the transmitter 20 , which is the subject of this invention. The receiver 10 contains a light emitting diode (LED) 22 which indicates when the receiver is functioning and an on/off switch 24 for placing the receiver in an on position and in a desired mode of operation. One such receiver that is contemplated to be used in the present invention is that provided in the Woodstream 5140 Fence Free system. The receiver is discussed in greater detail at the Havaheart website having URL: www.havahart.com, the discussion of which is incorporated by reference herein.
[0030] FIG. 1 shows a diagram for the installation of a pet confinement system according to the subject invention. Most often the pet confinement system is used in the context of creating a boundary 100 for providing an area 102 within which a dog D is free to roam. Most often the boundary is set up about a structure such as a house 104 . Frequently, a boundary area 102 contains additional areas such as 106 which are areas where the animal should not roam.
[0031] In its simplest form with reference to FIGS. 1 and 3 , the pet confinement system comprises a wire 110 that is buried in the ground in a loop with the ends of the wire 112 and 114 being connected to a wire pair 116 and 118 that is twisted in the manner shown in FIG. 3 and identified as 120 and terminating in ends 116 and 118 secured to input terminals provided on the transmitter 20 . The twisted wires are used to cancel the magnetic field that normally flows through the wire when it is being used as a single strand to define the boundary 100 . The same concept of the twisted wire can be used such as shown by the use of twisted pair 122 to cancel the field which then makes conductive contact with the wire 124 that surrounds a pool 126 in area 106 . In this way, the boundary 100 is defined about the entire property and the dog is free to roam anywhere within that boundary. At the same time an inner boundary 124 is defined within the boundary 100 to provide an area 106 that the dog is not permitted to enter.
[0032] The transmitter 20 also contains six push-button switches S 1 through S 6 that are used to control the amount of the current passing through the boundary wire 110 . Switch S 6 turns the system on and off and causes an LED 130 to light when the system is on. Switches S 1 through S 5 place the transmitter into a mode where a signal is passed through the wire 110 to generate a magnetic field having a predetermined width. In the present invention, pushing switch S 1 causes the transmitter 20 to emanate a signal that creates a field width with a radius of 1.5 ft. In turn, pushing switch S 2 yields a field width of 2.5 ft. whereas pushing switch S 3 yields a field width of 3.25 ft. Finally, pushing switch S 4 yields a field width of 4.0 ft. and pushing switch S 5 yields a field width of 5.0 ft.
[0033] FIG. 4 shows a general block diagram of the elements that constitute the inventive transmitter 20 . The transmitter contains an input jack 210 which accommodates a connection plug from a portable transformer (not shown) in order to provide an input voltage for the system. Through the use of a full wave bridge rectifier 212 , the input voltage can be AC or DC, but is preferably DC. The rectifier yields a DC voltage, Vcc, that passes through a voltage regulator 214 which has an output port 216 that provides operating voltage to circuit elements within the system. The voltage regulator also has an output 218 connected to a charge jack 220 for mating with the charger receptacle 18 in the receiver 10 in order to charge a rechargeable battery (not shown) housed in the receiver 10 .
[0034] The heart of the inventive transmitter 20 is a microcontroller 300 that provides various control signals on lines 310 to a voltage adjuster 312 . EEPROM 314 is used to program a desired identification code which matches a comparable identification code set in the receiver 10 that is worn by the dog D. When the EEPROM is operating, the identification code (ID) is transmitted to the microcontroller 300 through data lines 316 . This identification code is constantly transmitted to boundary antenna 320 under the direction of controller 300 as will be explained hereinafter so that the receiver is able to detect and pick up the information that is also contained within the signal that carries the ID.
[0035] Also forming part of the invention is the boundary antenna 320 which is made up of a wire that is buried in the ground in the manner shown in FIG. 1 with reference to the wire 110 . This boundary antenna 320 transmits information from the microcontroller 300 that includes the ID along with other information to cause the receiver 10 to respond in different ways. One end of the boundary antenna is connected to a switch 322 that passes through an arrangement of resistors 324 to signal ground 326 . The other end of the boundary antenna is connected to the output of an adjustable voltage regulator 330 . This regulator has an input for receiving an input voltage Vcc of predetermined value from the output of the full wave bridge 212 . The regulator 330 also contains an adjustment port for receiving a signal from the voltage adjuster 312 in order to change the magnitude of the output voltage appearing at the output of the regulator 330 . The inventive circuit also includes an operational amplifier (OP AMP) 340 that is used to amplify a voltage signal appearing on line 342 which represents the voltage passing through resistor arrangement 324 when the switch 322 is on. The voltage signal appearing on line 342 is amplified by OP AMP 342 to a usable value and then placed into the microcontroller and passed through an A-to-D converter housed in the microcontroller. The transmitter also contains a switch array 350 made up of a series of six push button switches that are used to cause the microcontroller 300 to ultimately adjust the current passing through the boundary antenna 320 to yield a magnetic field of desired width appearing around and about wire 110 . Switch S 6 is used to turn the circuit on and off. Switches S 1 through S 5 are used to cause the microcontroller 300 to control the transmitter circuit in order to create a desired boundary field width around wire 110 that defines the boundary antenna 320 .
[0036] Basically, when switch 322 is on, the boundary antenna 320 receives a current that passes through the antenna through the switch and then through the resistor arrangement 324 to signal ground. The flow through the boundary antenna creates a magnetic field around the wire that constitutes the boundary antenna. The OP AMP 340 amplifies the voltage across the resistor arrangement 324 to increase the voltage amplitude to a usable value for conversion by the A-to-D converter in the microcontroller 300 . For each field width requested by switches S 1 through S 5 , there is a unique current flowing through the wire that is the boundary antenna 320 .
[0037] In order to constructively measure the current flowing through the wire, set points are used. A set point is simply an A-to-D converter count which represents the desired loop current for a field width setting. Each of the five field width settings has its own set point. The set points were calculated using a spreadsheet and are based on an amplifier gain of 40. The set points are 54 for a field width of 1.5 ft., 95 for a field width of 2.5 ft., 124 for a field width of 3.25 ft., 149 for a field width of 4.0 ft., and 190 for a field width of 5.0 ft.
[0038] As will be explained in greater detail hereinafter, when a push-button switch is selected, evidencing a desired field width across the wire making up the boundary antenna, the microcontroller 300 puts out a signal on lines 310 into a voltage adjuster 312 made up of resistors and transistor switches. The adjuster, in turn, causes the voltage regulator 330 to put out an output voltage that passes through the boundary antenna 320 . The actual loop current is monitored in the microcontroller and the microcontroller looks to see if the count represents a desired field width. If the count is too low, then the microcontroller causes the voltage adjuster 312 to increase the output voltage from the voltage regulator 330 . This interaction takes place until the microcontroller A-to-D converter reading equals or exceeds the predetermined set point value for a desired field width. At that point, the microcontroller no longer yields signals for changing the voltage output of the voltage regulator and the field width passing through the wire of the boundary antenna is at the predetermined desired value.
[0039] Having covered the general operation of the transmitter, the detailed operation of the circuitry that constitutes the FIG. 4 embodiment of the present invention will now be described with reference to FIG. 5 with like reference numerals denoting like elements to those described in the other figures.
[0040] FIG. 5 is a schematic diagram of a preferred embodiment of the present invention. At the heart of the system is microcontroller 300 . Six push-button switches S 1 -S 6 are connected to the microcontroller 330 . Switches S 2 , S 3 and S 4 share a common connection with pin 15 of controller 300 , whereas, switches S 1 , S 5 and S 6 share a common connection with pin 9 of controller 300 . In turn, the other connections of the switches are as follows: switches S 4 and S 5 are connected to pin 8 ; switches S 3 and S 6 are connected to pin 7 ; and switches S 1 and S 2 are connected to pin 12 .
[0041] EEPROM 314 has pins 1 - 4 connected to ground. The EEPROM also has pin 7 connected to ground. Pin 8 is connected to the output 216 of voltage regulator 214 . Pins 5 and 6 of EEPROM 314 through resistors R 18 and R 19 , respectively, are connected to output 216 which in turn are connected to ground through capacitor C 11 . Pins 5 and 6 are connected to pins 1 and 2 , respectively, of controller 300 .
[0042] With regard to the power supply aspects of the present invention, FIG. 5 shows diodes D 1 -D 4 arranged as a full wave bridge rectifier. DC jack 210 has one conductor 60 connected to node N 1 formed between the cathode of diode D 1 and the anode of diode D 2 and the other conductor 62 connected to node N 2 formed between the cathode of diode D 3 and the anode of diode D 4 . The anodes of diodes D 1 and D 3 are connected to ground. The cathodes of diodes D 2 and D 4 are connected to the input pin 1 of rectifier 214 . Pin 1 of rectifier 214 is also connected to ground through capacitor C 1 .
[0043] Output pin 3 of rectifier 214 is connected to ground through two parallel capacitors C 2 and C 3 . Pin 3 also provide a 5 V DC power source. Pin 2 of rectifier 214 is connected to ground. Pin 3 of rectifier 214 is connected in series with resistor R 16 and LED D 8 to pin 11 of controller 300 . Finally, pin 3 is connected to conductor 70 of charge jack 220 through resistor R 31 . The other conductor 218 of jack 220 is connected to ground.
[0044] Turning now to transistors Q 2 -Q 6 , these transistors have their bases connected to controller 300 in the following way: transistor Q 2 has a base connection to pin 20 of controller 300 in series with resistor R 26 ; transistor Q 3 has a base connection to pin 13 of controller 300 in series with resistor R 25 ; transistor Q 4 has a base connection to pin 4 of controller 300 in series with resistor R 23 ; transistor Q 5 has a base connection to pin 10 of controller 300 in series with resistor R 30 ; and transistor Q 6 has a base connection to pin 6 of controller 300 in series with resistor R 14 .
[0045] The emitters of transistors Q 2 -Q 6 are connected to ground. The bases of transistors Q 2 -Q 6 are connected to pin 1 of the regulator 330 via series resistors R 5 , R 21 , R 22 , R 28 , and R 1 , respectively. Resistor R 4 is connected to ground and pin 1 of regulator 330 .
[0046] Pin 2 of regulator 330 is connected to pin 1 of regulator 330 via resistor R 2 . Pin 2 is also connected to ground via capacitor C 5 and to the anode of diode D 6 . The cathode of diode D 6 is connected to terminal 321 of boundary antenna 320 via series resistor R 3 . Terminal 321 is also connected to ground via transzorb D 5 . In like manner, terminal 323 of boundary antenna 320 is connected to ground via transzorb D 7 . Terminal 323 is connected to ground via resistor R 24 and to the collector of transistor 322 . In turn, transistor has its base connected to pin 14 of controller 300 via resistor R 15 , and its emitter connected to ground via the parallel arrangement of resistors R 6 -R 8 .
[0047] Transzorbs D 5 and D 7 are transient voltage suppressors such as those bearing product number SMBJ 12 A made by Fairchild Semiconductor Corporation, www.fairchildsemi.com. The transzorbs provide protection for the transmitter circuitry from transients caused by lightning strikes.
[0048] Pins 17 and 18 connect to crystal XT 1 and to ground via capacitors C 9 and C 10 , respectively. Pin 16 is connected to voltage source 216 and to ground via capacitor C 8 . Also pin 19 is connected to the cathode of LED D 9 whose anode is connected to voltage source 216 via resistor R 20 . Finally, pin 12 of controller 300 is connected to ground via resistor R 17 .
[0049] The emitter of transistor 322 is connected to pin 3 of OP AMP 340 via resistor R 9 . Pin 2 of OP AMP 340 is connected to ground via resistor R 10 and to pin 1 via resistor R 11 . Pin 5 of OP AMP 340 is connected to ground via capacitor C 7 and to 5 V source 216 . Pin 1 of OP AMP 340 is connected to pin 3 of controller 300 and to ground via resistor R 12 .
[0050] As explained before, the heart of the inventive circuit is the microcontroller 300 . The microcontroller is an eight bit microcontroller developed with low power and high speed CMOS technology. One such controller is that made by Elan Micro Electronics Corp., Hsinchu City, Taiwan and bearing product designation number EM78P458.
[0051] As stated before, six push buttons S 1 through S 6 are connected to the microcontroller 300 to provide controlling inputs. Switch S 6 turns the system on and off. Switches S 1 through S 5 provide an input to cause the microcontroller to adjust the field width around the boundary antenna 320 . The microcontroller 300 executes a program to carry out specific actions based upon which of the buttons is pressed. When a button is pressed, the microcontroller runs a program and outputs analog control signals to the five transistors Q 2 through Q 6 , which are in the voltage adjuster. In a preferred embodiment the transistors are NPN type switching transistors.
[0052] A preferred embodiment of EEPROM 314 bears Model Number AT24C04 made by Atmel Corp., San Jose, Calif., www.atmel.com. The EEPROM is an electrically erasable and programmable read only memory organized as 512 words of eight bit each.
[0053] Light emitting diodes D 8 ( 132 ) and D 9 ( 130 ) are contained on the exterior shell of the transmitter 20 and are used to indicate certain conditions of the transmitter. In particular, LED D 8 lights to indicate that the boundary antenna is connected to the transmitter and operative. LED D 9 indicates whether the transmitter is on or off Both of the LEDs are activated by signals emanating from the microcontroller 300 .
[0054] The voltage regulator 214 in a preferred embodiment bears product designation number LM7805CT and is manufactured by National Semiconductor Corp., www.national.com. Voltage regulator 214 regulates the power to power up the remaining devices in the circuit such as OP AMP 340 , the microcontroller 300 , the EEPROM 314 , and other items in the circuit.
[0055] Looking now at the programmable voltage regulator 330 , this device in a preferred embodiment bears product designation number LM 317 and is made by Motorola, Inc., www.motorola.com-. The output voltage of the regulator designated as V out can be solved by the formula:
V out =1.25v((1+(Variable Resistance/Resistor R 2)).
The variable resistance is determined in the voltage adjuster by which of the transistors Q 2 through Q 6 are conducting in order to selectively place one or more of resistors R 4 , R 5 , R 21 , R 22 , R 1 and R 28 in parallel. As can be seen from FIG. 5 , the formula in its basic form, when all transistors are not conducting, is: 1.25v (1+(R 4 /Resistor R 1 )). This represents the highest voltage output of the voltage regulator 330 .
[0056] By way of example, let's assume that the microcontroller 300 wishes to provide a certain voltage out from the programmable voltage regulator 330 . Further, assume that the desired voltage relies on the parallel arrangement of resistors R 4 , R 22 , and R 28 in voltage adjuster 312 . To accomplish this, the microcontroller puts out activation signals to cause resistors Q 4 and Q 5 to conduct; thus, placing the resistors R 4 , R 22 and R 28 in parallel arrangement and creating an output ratio in order to arrive at the calculation of V out . Through the use of the five transistors Q 2 through Q 6 and the permanent resistor R 4 , thirty-two different values are possible for V out . In this way, for an initial value, all of the transistors are conducting so that all of the resistors are arranged in parallel to produce the lowest V out . Through the output of the opt amp 340 , the ADC rating is read in the microcontroller and compared with a desired reading for a given field width in the manner described above concerning the use of set points.
[0057] As explained before, transistor Q 1 performs two primary functions. First, it is used to complete a path for the boundary antenna and second, to transmit data from the transmitter to the collar worn receiver by making and breaking the loop voltage. This arrangement provides one way communication. This is accomplished by opening and closing the circuit at a specific frequency. In essence, a binary signal is sent to the receiver 10 by the on/off operation of transistor 322 . The output port PWM 2 of controller 300 turns transistor 322 on and off at a specific rate to create the digital signal passing through the loop antenna 320 .
[0058] Transistor 322 can also be used in the second mode for calibration to adjust the current passing through the boundary antenna 320 to produce a magnetic field of a predetermined width. In this way, a desired field width can be created. The field width can be known precisely each time a calibration is accomplished. Whether or not the boundary antenna is connected or is in an open circuit condition can also be detected and in this way, control the lighting of the loop LED D 9 .
[0059] Calibration is carried out under several circumstances. The first is when any button is pressed. The second is when the unit is powered up. The third is at regular preset intervals. In a preferred embodiment, the intervals are every five seconds.
[0060] When entering the calibration phase the desired field width must be known. The user can manually select it by pressing any of the field width buttons ( 1 - 5 ) or by using the default setting when the transmitter is powered up. The microcontroller then goes through the following routine:
1. Set the programmable voltage source to the lowest output voltage (Q 2 - 6 ON). Turn the LOOP LED off. 2. Turn Q 1 ON. This completes the loop circuit that forms the boundary antenna 320 . 3. Take 16 ADC readings and average them. This significantly increases the accuracy of the reading by reducing induced noise picked up by the loop wire from nearby sources. 4. Compare the averaged ADC reading to the set-point: a. If greater than or equal to the set-point the calibration is successful and complete. Go to Step 5. b. Increase the programmable voltage source output voltage to the next higher voltage.
I. Go to Step 3 if all 32 levels have not been tried. II. ERROR—All 32 levels have been tried and the set-point has not been reached. The loop is either broken or not connected. Turn the LOOP LED off.
5. Done! Turn Q 1 off.
[0070] Loop detection is simplified by implementing it in firmware. The loop is either present or not present, based on the existence of loop current. On a periodic basis, perhaps once every five seconds, when data is not being transmitted, the loop can be powered on for a brief instant to determine if loop current is present or not. The loop power would then be turned off by setting Q 1 to the off state, and then normal operation can continue. A calibration phase shall begin if the loop present state changes from not present to present.
[0071] It is to be understood that the present invention is not limited to the illustrated user interfaces or to the order of the user interfaces described herein. Various types and styles of user interfaces may be used in accordance with the present invention without limitation.
[0072] Modifications and variations of the above-described embodiments of the present invention are possible, as appreciated by those skilled in the art in light of the above teachings. It is therefore to be understood that, within the scope of the appended claims and their equivalents, the invention may be practiced otherwise than as specifically described. | 1a
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FIELD OF THE INVENTION
[0001] The present invention relates to a system and a method for transmitting and activating a control data for a programmable personal medical device, in particular for an implantable medical device such as a cardiac pacemaker, defibrillator, or the like. In addition, the present invention relates to such a medical device and a source unit for control data.
BACKGROUND OF THE INVENTION
[0002] A medical device such as a cardiac pacemaker typically receives new control data several times during its operation, with the control data including matters such as changes to the operating parameters of the cardiac pacemaker, software or firmware updates or commands for the cardiac pacemaker, etc. When programming an implant such as a cardiac pacemaker, a programming session may involve the alteration of some parameters and the issuance of associated commands to the implant, such as a request to restart statistics or to begin detection of patient data, and the transmission of the parameters and commands to the implant.
[0003] When a clinical programmer programs the implant in a clinic, a control datum may be transmitted within a few seconds to the implant, with control data being transmitted to the implant in succession. When control data are remotely programmed and transmitted to the implant, the transmission may take as long as several days. In any event, control data are transmitted in succession, i.e., sequentially.
[0004] As more control data are to be transmitted in sequence and as the transmission grows longer, the more probable it is that at least one control datum will be transmitted incorrectly or incompletely. During a long transmission, an interruption of the transmission by a loss of connection can occur. In addition, during such a transmission, a chronological or logical assignment between different items of data may be lost. The control data thus arrive incomplete or corrupted at the implant, which may result in a malfunction of the implant upon an implementation/execution of the control data (e.g., acceptance of the operating parameters or overriding of the firmware). When firmware is updated via remote programming, the problem additionally results that many reprogrammings must be executed, with only one containing the new implant control software. All reprogrammings connected with the update must become active jointly. If all parts are not provided in the implant, the reprogramming may not occur.
SUMMARY OF THE INVENTION
[0005] The invention seeks to provide a system and a method for executing complete and secure transmission of control data, thereby avoiding the problems described above.
[0006] A preferred version of the invention involves a system for transmitting control data for a programmable personal medical device, in particular an implantable medical device, such as a cardiac pacemaker, defibrillator, or the like, having a source unit, a collection unit, and a medical device. The source unit has a data set unit for generating a control data set having a plurality of control data, a check data unit for generating at least one check datum for the control data set, and a transmitting unit for transmitting the control data set and check datum to the collection unit. The collection unit has a receiving unit for receiving the control data set and the check datum, a storage unit for storing the control data set and/or the control data of the control data set, a check unit for checking the integrity of the control data set using the check datum, and a transmitting unit for transmitting the control data to a programmable control unit of the medical device. The medical device has a programmable control unit for controlling functions of the medical device on the basis of the control data. The collection unit is implemented to transmit the control data to the control unit of the medical device only if the integrity of the control data set is established by the check unit. The control unit of the medical device is implemented to execute the control of functions of the medical device on the basis of the control data received from the collection unit.
[0007] The invention also encompasses a method for transmitting control data for a programmable personal medical device, in particular an implantable medical device such as a cardiac pacemaker, defibrillator, or the like, having the following steps:
generating a control data set having a plurality of control data, generating at least one check datum for the control data set, and transmitting control data set and check datum to a collection unit, receiving the control data set, storing the control data set and/or the control data of the control data set, receiving the check datum, checking the integrity of the control data set using the control datum, transmitting the control data to a programmable control unit of the medical device, and executing a control of functions of the medical device on the basis of the control data received from the collection unit,
wherein the step of transmitting the control data to the programmable control unit only occurs if the integrity of the control data set is established during the checking.
[0017] The invention further encompasses a source unit and a personal programmable medical device. The source unit is used to transmit control data for a programmable personal medical device, in particular an implantable medical device such as a cardiac pacemaker, defibrillator, or the like, and includes a data set unit for generating a control data set having a plurality of control data, a check data unit for generating at least one check datum usable for an integrity check of the control data set, and a transmitting unit for transmitting control data set and check datum to a collection unit.
[0018] The programmable personal medical device is particularly an implantable medical device such as a cardiac pacemaker, defibrillator, or the like, and includes a collection unit and a programmable control unit, the collection unit having a receiving unit for receiving a control data set comprising control data and a check datum assigned to the control data set, a storage unit for storing the control data set and/or the control data of the control data set, a check unit for checking an integrity of the control data set using the check datum, and a transmitting unit for transmitting the control data to the programmable control unit of the medical device. The programmable control unit is provided for controlling functions of the medical device on the basis of control data. The collection unit is implemented to transmit the control data to the control unit of the medical device only if the integrity of the control data set is established by the check unit, and the control unit of the medical device is implemented to execute the control of functions of the medical device on the basis of the control data received from the collection unit.
[0019] The invention is based on the insight that in the event of a plurality of associated control data, the use of this control data may only be performed reliably if it is ensured in a suitable manner that all control data are also completely provided. The implant may execute the changes at one stroke if and only if an entire packet has been received. It is important for the safety and reliability of the implementation of the control data that either all changes are executed together, or none at all.
[0020] In one version of the invention, the medical device is an active medical implant. Special safety requirements, which are fulfilled by the present invention, exist for the operational safety in particular for an active medical implant.
[0021] In one version of the invention, the medical device is an implantable cardiac pacemaker or defibrillator-cardioverter. Secure communication of programming data or firmware updates according to the invention is advantageous particularly during operation of a cardiac pacemaker or a defibrillator-cardioverter.
[0022] In one version of the invention, the source unit has a programming device for the preparation of control parameters as control data for the control unit. An operator may prepare control parameters for the control unit in a familiar way, using the programming device known to him, without the control parameters having to be transmitted once again separately to the source unit.
[0023] In one version of the invention, the source unit is implemented to provide a control program for the control unit as the control data, the source unit particularly having a server for providing the control program. If the source unit is equipped with a server, the source unit may be supplied easily with control data by setting a firmware update on the server, for example.
[0024] In one version of the invention, the control data have a control parameter and/or a control program. A control data set may have both control parameters and also control programs, also in combination. In particular, in a firmware update, altered control parameters may also be activated together with the update.
[0025] In one version of the invention, the control data include meta-control data for the control unit for using the control data during the control of functions of the medical device, in particular information in regard to a sequence, a chronological succession, and/or a duration of the use of the control data and/or information in regard to a condition for the use of the control data. In addition to the actual control data, information on the use of the control data is contained in the control data set, which allows greater flexibility of the system according to the invention and better response to operator wishes.
[0026] In one version of the invention, the medical device itself has a collection unit. The collection unit may be situated in the medical device itself, so that the medical device does not require an external collection unit.
[0027] In one version of the invention, a collection unit is situated separately from the medical device and may be coupled to the medical device via a data connection, in particular via a wireless data connection having low range, preferably according to a medical implant communication service specification, the collection unit preferably being situated in a patient device assigned to the medical device. The collection unit is provided outside the medical device and thus checks incoming control data sets independently of the medical device, the checked control data then being transmitted to the medical device.
[0028] It is also possible according to the invention that the collection unit itself in turn functions as a source unit for transmitting the control data to the medical device, the medical device then having a further collection unit itself. Different source and collection units may be provided in a cascade for different communication sections.
[0029] In one version of the invention, the system includes a combination unit having a receiving unit for receiving a first and a second control data set from a source unit, a storage unit for storing the first and the second control data sets and/or the control data of the first and/or second control data set, a check data unit for generating at least one combination check datum for a third control data set comprising the first and the second control data sets, and a transmitting unit for transmitting the third control data set and the combination check datum to the collection unit, the combination unit preferably also having a check unit for checking an integrity of the first and the second control data sets using a first and a second check datum received from the receiving unit, the combination unit being implemented only to transmit the third control data set to the collection unit if an integrity of the first and the second control data sets is established by the check unit. The combination unit includes both functionalities of a source unit and also a collection unit, so that different control data sets, for example, from different source units or in (chronological) succession from one source unit, may be combined into a combined control data set. The combination unit is represented as a type of collection unit in relation to a source unit, while it acts as a source unit in relation to a collection unit.
[0030] In one version of the invention, the check datum includes an identifier establishing an integral control data set, in particular a unique identifier, preferably a checksum and/or a hash value. The generation of a unique value from the control data set represents a simple way to identify and be able to check the control data set. Checksums or hash values which uniquely identify a control data set are especially advantageous, i.e., practically no other control data set results in the same hash value or the same checksum, so that an alteration of the control data set is recognized in any case. Non-unique check data may also be used, if the probability for incorrectly assumed integrity is small enough.
[0031] In one version of the invention, the check datum includes a control data set end signal to indicate a complete transmission of the control data set, preferably in combination with a control data set start signal. Upon a transmission of a signal indicating a start of the control data set and a signal indicating an end of the control data set, it may at least be assumed upon arrival of the control data set end signal that the connection has not been lost during the transmission, because otherwise the end signal would not have arrived. As soon as the end signal indicates the completeness of the control data set, the entire control data set may thus be processed as a whole.
[0032] In one version of the invention, the control data set end signal and the control data set start signal are each provided with an identifier, which allows an assignment of control data set start signal and control data set end signal to one another. An identification of the start and end signals is used for identification and allows, inter alia, different control data sets to be transmitted in parallel without the end and start signals being confused with one another.
[0033] In one version of the invention, the check unit is implemented to transmit a characterization of the control data set and/or the control data forming the control data set to the check data unit, the check data unit generating the check datum on the basis of the characterization and the transmitting unit being implemented for separate transmission of control data set and check datum. One possibility for checking the integrity according to the invention includes a query at the point which has output the control data set, the query appending the required information to the received control data set, so that a comparison between the control data set to be transmitted or transmitted and the received control data set is possible. A transmission of the check datum in the form of a confirmation of the completeness and correctness is performed on the basis of this comparison.
[0034] In one version of the invention, the source unit is implemented to generate and transmit a fourth data set and a fourth check datum having an urgency indicator after a transmission of the first control data set, the collection unit being implemented to interrupt the processing of the first control data set if the collection unit receives the fourth control data set having the urgency indicator. In this case, the transmission of a specially identified control data set, which may also contain a single control datum here, at least suspends the processing of prior control data sets, so that this special control data set may be processed as rapidly as possible in case of emergency and reach its goal, for example.
[0035] In one version of the invention, the collection unit is implemented to abort the processing as an interruption and empty of the storage unit of control data of the first control data set. Upon an interruption of the processing, the processing of the control data set may not only be suspended as a whole, but rather completely aborted, the received control data being removed from the storage unit.
[0036] In one version of the invention, the collection unit is implemented to reassume the processing of the control data set after a processing of the fourth control data set, the control unit being implemented to retain the received first control data set and/or the received control data of the first control data set in addition to the fourth control data set and/or the control data of the fourth control data set. Alternatively (or additionally) to the abort described above, the system is also capable of reassuming the processing in the event of an interruption after processing the interrupting (emergency) control data set.
[0037] Further advantageous versions of the invention result in particular by combination of features of the claims and from the following description of preferred exemplary versions of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0038] The invention is explained in greater detail hereafter on the basis of preferred exemplary versions with reference to the appended figures. In the figures:
[0039] FIG. 1 shows a schematic illustration of an exemplary version of the invention,
[0040] FIG. 2 schematically shows a sequence for preparing a control data set,
[0041] FIGS. 3 a - 3 c show schematic sequences of an exemplary version of the invention, and
[0042] FIGS. 4 a - 4 d show schematic sequences of another exemplary version of the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0043] FIG. 1 shows a schematic illustration of an exemplary version of the invention. The system 10 includes a first and a second source unit 15 , a collection unit 20 , an implant 25 , and a combination unit 30 .
[0044] The first and the second source unit 15 are constructed essentially identically, operate corresponding to one another, and each include a data set unit 35 , a check data unit 40 , a transmitting unit 45 , a programming device 50 , and a server 55 . The collection unit 20 includes a receiving unit 60 , a storage unit 65 , a check unit 70 , and a transmitting unit 75 . The implant 25 includes a programmable control unit 80 and a separate collection unit 20 ′, which is constructed and operates fundamentally like the foregoing collection unit 20 . The combination unit 30 includes a receiving unit 60 ′ similar to the receiving unit 60 of the collection unit 20 , a storage unit 65 ′ similar to the storage unit 65 of the collection unit 20 , a check unit 70 ′ similar to the check unit 70 of the collection unit 20 , a check data unit 40 ′ similar to the check data unit 40 of the source unit(s) 15 , and a transmitting unit 45 ′ similar to the transmitting unit 45 ′ of the source unit(s) 15 .
[0045] A physician prepares control data in the form of control parameters for the implant 25 using the programming device 50 of the source unit 15 . An alternative to this preparation includes the provision of a control data set with a firmware update in the server 55 of the source unit 15 . In any case, the prepared control data are compiled by the data set unit 35 into a control data set, for which the check data unit 40 prepares a checksum as the check datum. The control data set and the check datum are sent to the collection unit 20 via the transmitting unit 45 . Alternatively, the control data set and the check datum may also be sent to the collection unit 20 ′ of the implant 25 or to the combination unit 30 .
[0046] The collection unit 20 receives the control data set and the check datum using the receiving unit 60 and stores the control data from the control data set in the storage unit 65 . The check unit 70 of the collection unit 25 also generates a checksum of the control data set in a way which corresponds to that of the check data unit 40 . If a comparison of the transmitted checksum to the checksum generated in the collection unit results in a correspondence, the integrity of the control data set is thus assumed. The control data are therefore transmitted to the control unit 80 of the implant 25 , where they are implemented.
[0047] The combination unit 30 is designed to accept control data sets and check data from both source units 15 via the receiving unit 60 ′. The control data and/or control data sets are stored in the storage unit 65 ′, the check unit 70 ′ again generating checksums and performing a comparison. In case of a positive result, the control data sets recognized as complete and correct are combined into a joint control data set, a combination check datum for the combination control data set again being generated by the check data unit 40 ′. The combined control data set is transmitted with the combination check datum either to the collection unit 20 or directly to the implant 25 (more precisely its collection unit 20 ′), where the combination control data set and the combination check datum are handled like a control data set and a check datum of the source unit 15 .
[0048] The implant 25 is equipped with a separate collection unit 20 ′, so that it may also directly or indirectly receive control data sets and check data from a source unit 15 or a combination unit 30 and check them for integrity before they are implemented by the control unit 80 .
[0049] FIG. 2 schematically shows an exemplary sequence for preparing a control data set. In step 100 , a control datum for a setting of a first parameter is generated (e.g., parameter 1 →200). In step 105 , a control datum for a setting of a second parameter is generated (e.g., parameter 2 →50). In step 110 , the setting for the second parameter is overwritten (e.g., parameter 2 →100). In step 115 , a control datum for a setting of a third parameter is generated (e.g., parameter 3 →“OFF”). The particular control data are introduced upon their preparation and/or revision into the control data set 200 , which then contains the control data having the desired settings. In step 120 , the termination of the settings is initiated to initiate the transmission of the control data set. In step 125 , the content of the control data set is displayed, so that the user may perform a confirmation in step 130 . In step 135 , the control data set is released for a transmission to an implant.
[0050] FIGS. 3 a - 3 c show schematic sequences of an exemplary version of the invention. FIG. 3 a shows that a control data set 200 is transmitted from a patient device 85 , tuned to the implant 25 , which serves as a relay station to the implant 25 . In the implant 25 , a checksum 205 is calculated from the control data set 200 by a correspondingly programmed CPU or computing unit 90 of the collection unit of the implant 25 . In the event of a correspondence, which is established in step 155 , the predetermined execution of all control data which were contained in the control data set 200 is performed, in step 160 . If the checksums do not correspond, all control data of the control data set 200 are discarded in step 165 .
[0051] FIGS. 4 a - 4 d show schematic sequences of another exemplary version of the invention. The relay station 85 (the patient device) has obtained a firmware update here and transmits it in smaller packets to the implant 25 . For this purpose, the patient device 85 transmits a control data set start signal 210 to the implant 25 ( FIG. 4 a ). It then transmits the firmware update together with further control data such as new control parameters to the implant 25 ( FIGS. 4 b, 4 c ) in packets 215 , 215 ′, whose size and number result through the communication protocol between implant 25 and patient device and the extent of the control data and/or the control data set (of the update). After all packets 215 , 215 ″ have been transmitted, the patient device 65 transmits a control data set end signal 225 to the implant 25 ( FIG. 4 d ). Upon receiving the control data set end signal 225 , the implant assumes that all control data of the control data set 200 have been completely received, because in the event of a communication breakdown between implant 25 and patient device 85 , the control data set end signal would not have arrived. By generating the control data set start and end signals, the patient device 85 at least partially assumes the function of a check data unit and is thus also to be seen as a component of a source unit within the meaning of the invention.
[0052] Upon a transmission of a program (control data) to an implant by remote programming, according to one exemplary version of the invention, a home monitoring service center (HMSC) compiles a data packet having multiple individual changes as in a “shopping basket” and provides the packet with a secure checksum. The implant receives the packet and checks the integrity of the packet on the basis of the checksum. If the packet is intact (the checked checksums correspond), the individual changes contained therein are completely executed. If the packet is incomplete or damaged (the checksum is erroneous), the contained changes are completely discarded, because it cannot be known which individual control data could still possibly be executed in spite of the incompleteness.
[0053] A further exemplary version of the invention relates to the transmission of new firmware to the implant by remote programming. The HMSC sends new implant firmware to a patient device (also called a telex) tuned to the implant. The telex sends a “transaction start” command to the implant. The telex sends a firmware image divided into multiple individual packets to the implant. The telex sends a “transaction end” command to the implant. The implant checks the transmitted firmware on the basis of the checksum upon receipt of the “transaction end” command and activates the new firmware in the event of correctness. If the “transaction end” command is not received, the implant state does not change, and the received parts of the new firmware are discarded (preferably after passage of a specific deadline).
[0054] One exemplary version of the invention relates to an alteration of the implant program using a clinical programmer. On the programming device (programmer), an implant parameter was altered and the program transmitted. Various parameter blocks had to be altered concurrently. Either all alterations are to be executed or none of them. The parameter blocks “SensingBradyCommon” and “BradyModepage” were altered, which are in various positions in the implant. The command “accept program” is to be transmitted, which activates the changes. The command “restart statistics” is to be executed, because after the programming the statistics become inconsistent. The command “detection on” is to be transmitted. The four commands (the alteration of the parameter blocks and the three commands) are compiled into one block (control data set) and transmitted to the implant provided with a checksum. After the completed transmission of the block, the implant checks the checksum and aborts in the event of an erroneous checksum. The parameter blocks “SensingBradyCommon” and “BradyModepage” are assumed at the target position in the implant. The commands “accept program”, “restart statistics”, and “detection on” are executed. The implant transmits a completion acknowledgment to the programming device.
[0055] As an illustration of another exemplary version of the invention, upon transmission of new firmware to the implant by a clinical programmer, the control software of the implant is replaced by a newer version. In addition, the parameter settings are adapted to the new control software and also transmitted to the implant in addition to the new firmware. A firmware update lasts (for example) approximately 3 minutes. During the procedure, the old control software is to be active. After successful transmission, the new control software is activated together with the new parameters at one stroke. A total of (for example) 30 steps must be executed. All steps are transmitted by the programmer into a buffer memory of the implant. The new software and the parameter settings become active at one stroke in the implant with the last step “copy and activate”, if the check of the check data of the transmission of the control data set having the firmware update and the new parameter settings indicates a complete and correctly received control data set.
[0056] The present invention allows the user to execute aftercare via remote programming in a familiar way. He may alter parameters, accept them in a “shopping basket”, alter further parameters (e.g., on another GUI page), also accept them in the “shopping basket”, set an instruction to restart the statistics in the “shopping basket”, and trigger a transmission of the “shopping basket”. The complex reprogrammings combined in the “shopping basket” then occur either completely or not at all. Intermediate states in the implant (half programmed, e.g., due to connection interruption or transmission error) are thus prevented.
[0057] The transmission of a (large and complex) parameter set may preferably be interrupted at any time, so that emergency commands may be transmitted and executed within a short time.
[0058] The described transmission method is generic. Programming may include a sequence of many small blocks and commands. The composition and sequence of the programming may be performed by changes on the HMSC program (remote programming) without altering the implant control software. | 1a
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BACKGROUND OF THE INVENTION
The present invention relates to a combination unit for making tobacco products.
Such combinations are composed of a first machine and a second machine linked one to the other by a transfer unit.
The first and the second machine could consist respectively in a filter maker and a user machine, or alternatively, a cigarette maker capable of forming a single tobacco rod or multiple tobacco rods (two or three), and a filter tip attachment machine, which will combine to make up a cigarette manufacturing line.
Reference is made in the present specification to this second type of combination, albeit implying no limitation.
A typical filter cigarette manufacturing line includes a cigarette maker defining a substantially horizontal first leg, installed in series with at least one filter tip attachment machine comprising a plurality of rollers ordered in such a way as to establish a second leg substantially transverse to the first leg.
The two machines are linked by a transfer unit such as will pick up cigarettes at the outfeed of the first leg and place them in aspirating grooves on the surface of revolution presented by an infeed roller at the start of the second leg.
Manufacturing lines of this type are affected by the drawbacks of being bulky, and of having to rely on transfer units generally unable to handle the high operating speeds of modern cigarette making and filter tip attachment machines, inasmuch as the cigarettes are subjected to notable stresses during the passage from the first to the second machine.
The object of the present invention is to provide a combination unit of compact dimensions, embodied in such a way that the stresses on the cigarettes during their transfer from the first machine to the second will be significantly reduced.
SUMMARY OF THE INVENTION
The stated object is realized according to the invention in a combination unit for manufacturing tobacco products typically of elongated cylindrical appearance, comprising a substantially horizontal first leg identifiable with a first machine, and a second leg identifiable with a second machine, including at least one infeed roller rotatable about an axis extending horizontally and transverse to the second leg.
The first leg and second leg of the combination unit disclosed are arranged substantially parallel one with another and interconnected by a transfer unit rotatable about a substantially vertical axis and comprising a plurality of holder elements such as will carry at least one relative tobacco product from an outfeed end of the first machine along a given transfer path to an infeed end of the second machine.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention will now be described in detail, by way of example, with the aid of the accompanying drawings, in which:
FIG. 1 illustrates a first embodiment of the combination unit according to the invention, viewed schematically and in perspective with certain parts omitted for clarity;
FIG. 2 illustrates a second embodiment of the combination unit according to the invention, viewed schematically and in perspective with certain parts omitted for clarity;
FIG. 3 shows a detail of FIGS. 1 and 2 , viewed schematically in elevation and in section;
FIG. 4 is a schematic plan view of the detail in FIG. 3 , shown with certain parts omitted;
FIG. 5 is a schematic plan view showing a train of gears utilized in the detail of FIG. 3 .
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Referring to FIG. 1 of the drawings, 1 denotes a combination unit, in its entirety, incorporating machines for the manufacture of tobacco products typified by an elongated cylindrical appearance, in particular filter cigarettes.
The unit 1 includes a first machine consisting in a cigarette maker 2 equipped with two tobacco rod processing lines as disclosed in U.S. Pat. Ser. No. 4,418,705, to which reference may be made for a fuller description, and a second machine consisting in a filter tip attachment machine 3 .
The cigarette maker 2 comprises a bed 4 carrying an outfeed beam 5 that coincides in practice with a substantially horizontal leg 6 of the unit 1 , along which two continuous cigarette rods 7 and 8 are caused to advance axially at substantially constant and identical rates of feed toward a rotary cutter head 9 of conventional type. The rods 7 and 8 are divided up by the cutter into respective sticks 10 and 11 each measuring twice the length of a single cigarette.
As discernible from FIGS. 1 , 2 and 3 , the two rods 7 and 8 are made to advance at two different heights, at least along the final part of the beam, and more exactly, the rod 7 on the inboard side of the beam is elevated relative to the other rod 8 .
The filter tip attachment machine 3 comprises a bed 12 surmounted by a vertical bulkhead 13 that extends parallel to the outfeed beam 5 and to the rear of the selfsame beam, as viewed in FIG. 1 . The vertical bulkhead 13 carries a plurality of rollers denoted 14 in their entirety, mounted with axes disposed transversely to the bulkhead 13 and coinciding with a leg 15 of the unit 1 that extends in a direction substantially parallel to that of the leg 6 first mentioned.
16 denotes a transfer unit interconnecting the cigarette maker 2 and the filter tip attachment machine 3 , of which the function is to direct the sticks 10 and 11 singly and in succession from the outfeed end of the one leg 6 , identifiable also as a take-up station denoted A, to an infeed end of the other leg 15 , identifiable also as a release station denoted B and coinciding with an infeed roller 17 of which the axis is denoted 18 . The periphery of the roller 17 in question presents a plurality of aspirating grooves 17 a , familiar in embodiment, each able to accommodate a respective cigarette stick 10 or 11 .
As illustrated in FIGS. 1 and 3 , the transfer unit 16 comprises a cylindrical body 19 of which the axis 20 is vertically disposed. More exactly, it will be seen that the two legs 6 and 15 extend along a direction parallel to the “X” axis of a set of Cartesian coordinates (indicated in FIG. 1 ), whilst the axis 18 of the infeed roller 17 and the axis 20 of the cylindrical body 19 of the transfer unit 16 extend in directions parallel respectively to the “Y” axis and to the “Z” axis.
In particular, and as illustrated in FIGS. 3 , 4 and 5 , the transfer unit 16 incorporates a fixed vertical sleeve 21 centered on the axis 20 of the cylindrical body 19 , anchored at the bottom end to a mounting denoted 22 and accommodating a coaxially aligned shaft 23 .
This same vertical shaft 23 is power driven from the bottom end by a further shaft 24 , disposed at right angles, to which it is coupled by way of a bevel gear pair 25 - 26 .
Keyed onto the top end of the sleeve 21 is the fixed sun gear 27 of an epicyclic train, denoted 28 in its entirety ( FIG. 5 ), which also includes a planet carrier 29 concentric with the sun gear 27 , and a plurality of planet gears 30 mounted freely to the planet carrier 29 and coupled to the sun gear 27 by way of intermediate idle gears 31 .
It will be seen in FIG. 5 that the transmission ratio between the sun gear 27 and the single planet gears 30 is 1:1.
The transfer unit 1 comprises a plurality of holder elements 32 each associated with a relative planet gear 30 and including a plate 33 of which the upwardly directed surface presents two parallel grooves 34 and 35 set at different heights, for reasons that will become apparent. The plate 33 is centered on a vertical axis 36 offset from the axis of rotation 37 of the planet gear 30 .
More exactly, referring to FIGS. 3 and 4 , the planet gear 30 is keyed to a tubular portion 38 extending downward from a hollow block 39 that carries the holder element 32 .
The tubular portion 38 houses a first shaft 40 centered on and rotatable about the planet axis 37 , of which a first top end carries a first gear 41 meshing by way of an idle gear 42 (see FIG. 4 ) with a further gear 43 carried by the bottom end of a second shaft 44 coaxial with the axis 36 of the plate 33 and connected to the holder element 32 at its top end.
The first shaft 40 is connected at the bottom end to a cam and rocker mechanism, denoted 45 in its entirety, comprising an element 46 with two arms 47 and 48 which occupy a common plane and are arranged substantially in a Vee formation with the vertex of the Vee keyed to the shaft 40 .
The cam and rocker mechanism 45 further comprises respective following rollers denoted 49 and 50 , the one mounted underslung to the arm denoted 47 , the other mounted overslung to the arm denoted 48 .
Finally, the mechanism 45 comprises cam means 51 that consist in a cylindrical body 52 associated rigidly with the sleeve 21 , presenting a lower first profile 53 positioned to interact with one following roller 49 , and an upper second profile 54 positioned to interact with the other following roller 50 .
The two cam profiles 53 and 54 are offset one from another and from the axis 20 of the sun gear, their geometry and placement being such that the single holder elements 32 will be caused to pivot on the relative axes 36 as the planet carrier 29 rotates about the sun gear.
Operationally, the cam and rocker mechanism 45 combines with the first and second shafts 40 and 44 , with the first gear 41 , and with the gears denoted 42 and 43 , establishing means by which to control the axial orientation of the cigarette sticks 10 and 11 .
Referring finally to FIG. 3 , the two grooves 34 and 35 presented by the plate 33 of the holder element 32 are embodied in conventional manner with suction holes arranged along the bottom surface and connected to a source of negative pressure likewise conventional in embodiment (not illustrated) by way of ducts 56 passing through portions of the second shaft 44 and of the hollow block 39 .
In practical application, the transfer unit 16 will be positioned below the outfeed beam 5 of the cigarette maker 2 and the infeed roller 17 of the filter tip attachment machine 3 , with the infeed roller 17 rotating tangentially at its lowest point to the horizontal plane occupied by the beam 5 .
The transfer unit 16 operates in such a manner as to direct the single holder elements 32 through a trajectory extending from a position at the take-up station A, below the outfeed beam 5 , to a position at the release station B beneath the roller 17 .
To reiterate, the grooves 34 and 35 of the single holder elements 32 are set at different heights so that the two sticks 10 and 11 can be taken up at the two dissimilar elevations aforementioned, and transferred to two contiguous grooves 17 a of the infeed roller 17 at different heights, coinciding with those of the grooves 34 and 35 presented by the plate 33 .
As discernible from FIG. 4 , and in accordance with standard practice, the cut cigarette sticks 10 and 11 are taken up from the beam 5 at the one station A advancing at a given pitch denoted p 1 , and released to the other station B spaced apart at a reduced pitch p 2 ; pitch p 1 might be 128 mm, for example, and pitch p 2 could be 38 mm, equivalent to the distance separating the two cigarette rods 7 and 8 .
The transfer unit 16 is designed to bring about a corresponding reduction in speed of the sticks 10 and 11 , which are taken up from the first station A at a higher tangential velocity substantially equal to the linear velocity of the rods 7 and 8 , and then released to the second station B at a lower tangential velocity equal to the angular velocity at the periphery of the infeed roller 17 serving the filter tip attachment machine 3 . In effect, it will be seen from FIG. 4 that the second shaft 44 supporting the holder element 32 is at a maximum distance D 1 from the axis 20 of the cylindrical body 19 when passing through the take-up station 4 , and at a minimum distance D 2 from this same axis 20 when passing through the release station B. It will be seen also from the schematic representation of FIG. 5 that the positions of maximum and minimum distance, diametrically opposed on either side of the sun gear 27 , are assumed by the shaft 44 as a result of the relative planet gear 30 rotating 180° about its axis 37 when the planet carrier 29 is set in motion around the sun axis 20 .
Observing FIG. 4 , it will be seen that the trajectory followed by each of the second shafts 44 carrying a respective holder element 32 appears as a circumference denoted C, flattened slightly in the neighborhood of the release station B.
Referring to the foregoing description of the embodiment illustrated in FIG. 1 , where the two legs 6 and 15 are disposed substantially parallel with one another and in the same plane, the single holder elements 32 describe an arc 57 of 180° in passing from the take-up station A to the release station B.
In the course of this same rotation, the means controlling the axial orientation of the sticks 10 and 11 will cause each pair of sticks to pass from a position at the take-up station A in which the two axes are parallel with the first leg 6 , to a position at the release station B in which the same two axes are rotated through 90° and parallel with the axis 18 of the infeed roller 17 of the filter tip attachment machine 3 , hence transverse to the second leg 15 .
More exactly, as the planet carrier rotates about the sun axis 20 , the interaction of the following rollers 49 and 50 with the two cam profiles 53 and 54 will cause the element 46 with the two arms to rotate clockwise, as viewed in FIG. 4 .
This same angular movement is accompanied by a rotation of the first shaft 40 about the relative axis 37 , also of the first gear 41 and, by way of the corresponding idle gear 42 and intermediate gear 43 , of the second shaft 44 carrying the holder element 32 , likewise about the relative axis 36 .
One of the advantages of the transfer unit 16 disclosed is that the reduction in pitch from p 1 to p 2 can be brought about along an arc of 180°, and therefore in a time substantially twice as long as the time taken by right angle units typical of the prior art.
Accordingly, the deceleration of the advancing sticks 10 and 11 is brought about more gradually, and the stresses acting on the selfsame sticks are thus significantly reduced.
Finally, it will be seen that the element 46 with two arms could be replaced by an element with just one arm and a relative following roller positioned to engage a relative single cam profile, albeit the solution shown in FIG. 4 offers the advantage of greater precision in that it is a positive acting mechanism able to eliminate backlash.
As illustrated in FIG. 2 , moreover, the filter tip attachment machine 3 might present a second leg, in this instance denoted 15 a , extending in a direction opposite to that illustrated in FIG. 1 . | 1a
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CROSS-REFERENCE TO RELATED APPLICATIONS
The present application is a continuation of U.S. patent application Ser. No. 14/012,161, filed Aug. 28, 2013, which is a continuation of U.S. patent application Ser. No. 13/952,982, filed Jul. 29, 2013, which claims priority benefit of U.S. Provisional Patent App. No. 61/798,540, filed on Mar. 15, 2013, and U.S. patent application Ser. No. 14/012,161 claims priority benefit of U.S. Provisional Patent App. No. 61/798,540, filed on Mar. 15, 2013.
Any and all applications for which a foreign or domestic priority claim is identified in the Application Data Sheet as filed with the present application are hereby incorporated by reference under 37 C.F.R. §1.57.
FIELD
The present disclosure generally relates to devices, systems, methods for making, and methods for use in thrombectomy. Several embodiments relate to systems and methods for providing novel approaches for stroke treatment.
BACKGROUND
Stroke is the leading cause of long term disability in the United States and the second leading cause of death worldwide with over 4.4 million deaths in a year (1999). There are over 795,000 new strokes every year in the United States. Around 85% of all strokes are acute ischemic strokes caused from a blockage in a blood vessel or a blood clot occluding a blood vessel. In 1996, the FDA approved a thrombolytic drug to dissolve blood clots called recombinant tissue plasminogen activator (r-tpa). Despite practice guidelines from multiple national organizations stating the intravenous r-tpa is the standard of care for patients with acute ischemic stroke within 3 hours from symptom onset, only 3-4% of patients with acute ischemic stroke received this drug in the United States. Unlike intravenous r-tpa, catheter-based therapies for mechanical thrombectomy can be used for up to 8 hours or beyond from acute ischemic stroke symptom onset and could benefit more people. With advances in regional stroke networks, there are more and more stroke patients who are getting access to intra-arterial thrombolysis and therapies, and are as high as 21.6%.
SUMMARY
Blood clots can range from 5 mm to greater than 55 mm. In addition, blood clots can extend from one vessel diameter to another vessel diameter. There is clearly an unmet need currently for a mechanical thrombectomy device that is gentle and safe on the fragile human blood vessels, that can be customized to the length of the clot or clot burden using the same device by the operator, that can be visualized with ease under X-ray fluoroscopy, that can reach the smallest of human blood vessels, that can be compatible with torsional rasping of the clot, and/or have bonding zones or attachment points that are strong even between dissimilar metals or alloys to avoid the risk of any fracture points, as well as have flexible delivery systems that have good proximal support and good distal flexibility. Several embodiments of the invention provide one or more of the advantages above. In some embodiments, all of the advantages above are provided.
In several embodiments, the device is particularly beneficial because it includes one or more of the following advantages: (i) adapted for and gentle on the fragile blood vessels instead of an expansile laser-cut stent based mechanical thrombectomy device; (ii) tapered to mimic the tapering of the human blood vessels thereby allowing for the use of a single tapered device to remove blood clots extending across different tapering blood vessel diameters; (iii) allows for flexibility during deployment and retrieval in tortuous human blood vessels thereby allowing for longer usable lengths of the device; (iv) comprises a long usable length can be customized to the length of the clot or the clot burden without having to use multiple devices to remove the clot in piece meal; (v) a textile structure based mechanical thrombectomy device allows for torsional rasping of the textile structure around the blood clot to entrap the clot and retrieve it; (vi) allows for filtering distal emboli or debris that may be released; (vii) employs processes to bond the textile structure and the delivery system allow for bonding of dissimilar metals or alloys; (viii) comprises an inlay bonding approach of the textile structure with the delivery system, which allows for a low overall profile and outer diameter of the mechanical thrombectomy device in the collapsed configuration to be less than e.g., 0.0125 inches (0.317 mm); (ix) low overall profile and outer diameter of the mechanical thrombectomy device in the collapsed configuration allows for the device to be deployed with a microcatheter that has an inner lumen diameter of e.g., 0.014 inch or greater (0.355 mm); (x) patterns of radio-opaque filaments or wires to achieve maximal radio-opacity and visibility for the operator during X-ray fluoroscopy; (xi) multiple transition points for the laser-cut delivery system or hypotube, which allows for distal flexibility and proximal support as well as supports the ability to perform torsional rasping of the clot; and/or (xii) the laser-cut hypotube with multiple transition points is incorporated as the core braid for the wall of the microcatheter, which allows for distal flexibility and proximal support for allowing the safe and effective deployment of the textile structure based mechanical thrombectomy device.
Various embodiments of the present invention are shown in the figures and described in detail below.
BRIEF DESCRIPTION OF DRAWINGS
FIG. 1 is a schematic diagram illustrating the 2D view of one of the embodiments with a spherical tapered textile structure.
FIG. 2 is a schematic diagram illustrating the 3D perspective view of one of the embodiments with a spherical tapered textile structure.
FIG. 3 is a schematic diagram illustrating the 2D view of one of the embodiments with an oblong tapered textile structure.
FIG. 4 is a schematic diagram illustrating the 3D perspective view of one of the embodiments with an oblong tapered textile structure.
FIG. 5 is a schematic diagram illustrating the 2D view of one of the embodiments with a spherical and oblong interspersed tapered textile structure.
FIG. 6 is a schematic diagram illustrating the 2D view of one of the embodiments with a spherical non-tapered textile structure.
FIG. 7 is a schematic diagram illustrating the 2D view of one of the embodiments with an oblong non-tapered textile structure.
FIG. 8 is a schematic diagram illustrating the 2D view of one of the embodiments with a spherical and oblong interspersed non-tapered textile structure.
FIG. 9 is a schematic diagram illustrating the 2D view of one of the embodiments with cylindrical wide-mouthed distal tip textile structure.
FIG. 10 is a schematic diagram illustrating the 2D view of one of the embodiments with a cylindrical narrow-mouthed distal tip textile structure.
FIG. 11 is a schematic diagram illustrating the 2D view of one of the embodiments with a cylindrical narrow-mouthed distal tip with a spherical or oblong distal filter textile structure.
FIG. 12 is a schematic diagram illustrating the 2D view of one of the embodiments with a cylindrical narrow-mouthed distal tip with a spherical distal and proximal filter textile structure.
FIG. 13 is a schematic diagram illustrating the 2D view of one of the embodiments with a cylindrical narrow-mouthed distal tip with an oblong distal and proximal filter textile structure.
FIG. 14A is a schematic diagram illustrating the wires positioned on the yarn to develop a biomedical textile structure in one of the embodiments.
FIG. 14B is a schematic diagram illustrating the braid carrier set up mechanism for the position of the wires on the yarn to develop a biomedical textile structure in one of the embodiments.
FIG. 15A is a photograph illustrating the wires being braided into a biomedical textile structure on the yarn in one of the embodiments.
FIG. 15B is a photograph illustrating the wires being knitted into a biomedical textile structure in one of the embodiments.
FIG. 15C is a photograph illustrating the wires being woven into a biomedical textile structure in one of the embodiments.
FIG. 16 is a photograph illustrating the primary tubular shape set textile structure in one of the embodiments.
FIG. 17 is a schematic diagram illustrating the primary shape setting into the necessary geometries needed to develop the shape-set textile structures in one of the embodiments.
FIG. 18 is a photograph illustrating the mandrel used for braiding on the yarn that is then used for primary shape setting into the necessary geometries needed in one of the embodiments.
FIG. 19 is a photograph illustrating secondary shape setting into the necessary geometries needed to develop the shape-set textile structure in one of the embodiments.
FIG. 20 is an X-ray photograph illustrating one of the embodiments where there is grouping of multiple radio-opaque filaments or wires together to form an inter-twining thick band for maximal radio-opacity during fluoroscopy.
FIG. 21 is an X-ray photograph illustrating single filaments inter-twined to provide radio-opacity during fluoroscopy in one of the embodiments.
FIG. 22 is an X-ray photograph illustrating double filaments inter-twined to provide radio-opacity during fluoroscopy in one of the embodiments.
FIG. 23 is a photograph illustrating the need for post-processing of the free end of the textile structure to keep the filaments or wires from fraying in one of the embodiments.
FIG. 24 is a schematic diagram illustrating the appearance of the free end of the textile structure after laser cutting the free end to keep the filaments or wires from fraying in one of the embodiments.
FIG. 25 is a schematic diagram illustrating the inlay bonding approach between the shape-set textile structure and the delivery system using solder in one of the embodiments.
FIG. 26 is a schematic diagram illustrating the overall ratio of the cross-sectional area between the filaments or wires of the textile structure and the bonding agent in one of the embodiments.
FIG. 27A is a schematic diagram illustrating the inlay bonding approach between the shape-set textile structure and delivery system using epoxy agents in one of the embodiments.
FIG. 27B is a photograph illustrating the inlay bonding approach between the shape-set textile structure and delivery system using epoxy agents in one of the embodiments.
FIG. 28 is a schematic diagram illustrating the inlay bonding approach between the shape-set textile structure and delivery system using a pinched ring as well as a bonding agent in one of the embodiments.
FIG. 29 is a schematic diagram illustrating the inlay bonding approach between the shape-set textile structure and delivery system using a pinched tube as well as a bonding agent in one of the embodiments.
FIG. 30 is a schematic diagram illustrating the overlay bonding approach between the proximal neck of the shape-set textile structure and the distal end of the delivery system using solder in one of the embodiments.
FIG. 31 is a schematic diagram illustrating the overlay bonding approach between the proximal neck of the shape-set textile structure and the distal end of the delivery system using epoxy in one of the embodiments.
FIG. 32 is a schematic diagram illustrating the overlay bonding approach between the proximal neck of the shape-set textile structure and the non-laser cut distal tip of the delivery system using epoxy in one of the embodiments.
FIG. 33 is a schematic diagram illustrating the overlay bonding approach between the proximal neck of the shape-set textile structure and the distal end of the delivery system using epoxy and heat shrink tubing in one of the embodiments.
FIG. 34 is a schematic diagram illustrating the overlay bonding approach between the distal neck of the shape-set textile structure and the distal end of the delivery system using bonding agent in one of the embodiments.
FIG. 35 is a photography illustrating the angled flexible laser-cut hypotube delivery system in one of the embodiments.
FIG. 36 is a schematic diagram illustrating dimensions for laser-cut Pattern A in one of the embodiments.
FIG. 37 is a schematic diagram illustrating dimensions for laser-cut Pattern B in one of the embodiments.
FIG. 38 is a schematic diagram illustrating the directional stagger of laser-cut Pattern A and Pattern B in one of the embodiments.
FIG. 39 is a schematic diagram illustrating the interspersed laser-cut Pattern A and B in one of the embodiments.
FIG. 40 is a schematic diagram illustrating the interspersed laser-cut Pattern A and B with the inter-pattern stagger in one of the embodiments.
FIG. 41 is a schematic diagram illustrating the edges of the kerf in the angled laser-cut delivery system or hypotube are rounded or sharp in one of the embodiments.
FIG. 42 is a schematic diagram illustrating the flexible transition points in the laser-cut pattern of the hypotube in one of the embodiments.
FIG. 43 is a photograph illustrating the degree of angled laser-cut and the degree of uncut in the angled laser-cut delivery system or hypotube in one of the embodiments.
FIG. 44 is a schematic diagram illustrating the horizontal laser-cut delivery system in one of the embodiments.
FIG. 45 is a schematic diagram illustrating the edges of the kerf in the horizontal laser-cut delivery system or hypotube are rounded or sharp in one of the embodiments.
FIG. 46 is a photograph illustrating the degree of horizontal laser-cut and the degree of uncut in the horizontal laser-cut delivery system or hypotube in one of the embodiments.
FIG. 47 is a schematic diagram illustrating a hybrid delivery system with the filaments or wires that are braided together like a hypotube in one of the embodiments.
FIG. 48 is a schematic diagram illustrating a thrombus or blood clot in the right middle cerebral artery causing an acute ischemic stroke noted during angiography with a guide catheter or a shuttle or a balloon guide catheter positioned in the right internal carotid artery in one of the embodiments.
FIG. 49 is a schematic diagram illustrating a standard microcatheter being advanced across the thrombus or blood clot in the right middle cerebral artery over a microwire in one of the embodiments.
FIG. 50 is a photograph illustrating the shape-set textile structure based mechanical thrombectomy device in one of the embodiments.
DRAWINGS—REFERENCE NUMERALS
Part numbers for the Figures are listed below
Part
Number
Description
1
Distal Tip
5
Extra small spherical bulbs (d = 3 mm)
10
Small spherical bulbs (d = 3.5 mm)
15
Medium spherical bulbs (d = 4 mm)
20
Large spherical bulbs (d = 4.5 mm)
25
Proximal Marker band
30
Delivery System/Hypotube
35
Extra small vessel segment
40
Small vessel segment
45
Medium vessel segment
50
Large vessel segment
55
Usable length
60
Proximal marker to distal tip length
65
Narrow Distal Neck
70
Wide Distal Neck
75
Extra Small oblong bulbs
80
Small oblong bulbs
85
Medium oblong bulbs
90
Large oblong bulbs
95
Narrow neck between bulbs
100
Non-tapered spherical bulbs (diameter = 1-30 mm)
105
Non-tapered oblong bulbs (diameter = 1-30 mm)
110
Proximal neck
115
Cylindrical shape-set structure
120
Distal marker band
125
Distal spherical filter (diameter = 1-30 mm)
130
Proximal spherical filter (diameter = 1-30 mm)
135
Distal oblong filter (diameter = 1-30 mm)
140
Proximal oblong filter (diameter = 1-30 mm)
145
Yarn Wheel
150
Spindle
155
Filament of textile structure
160
Preform point
165
Textile structure
170
Direction of rotation of yarn wheel
175
Cylindrical mandrel
190
Laser cut free end of the textile structure
195
Lead free solder with flux 2 or 3
200
Epoxy glue
205
Any type of bonding agent - solder, epoxy glue etc.
210
Pinched Ring
215
Pinched cylinder
220
Heat Shrink PET tube
225
Overlay bonding zone
230
Uncut bonding zone
235
Hypotube through cross-section of textile structure
240
Distal to distal overlay bonding zone
245
Kerf Width
250
Strut Width
251
Strut Width 2
252
Strut Width 3
253
Strut Width 4
255
Laser cut length
260
Anchor point distance (gap between 2 kerfs on same row)
265
Delivery system wall thickness
270
Step 1 of diagonal stagger distance between two rows of laser
cuts of the same pattern
275
Step 2 of diagonal stagger distance between two rows of laser
cuts of the same pattern
280
Direction of pattern A laser cut
285
Direction of pattern B laser cut
295
Length of delivery system
300
Inner diameter circumference of delivery system
305
Outer diameter circumference of delivery system
310
Direction of folding delivery system (Compressing expanded
view into cylindrical view of delivery system)
315
Inter-pattern stagger distance between rows
320
Laser cut pattern A
330
Laser cut pattern A and B interspersed
335
Rounded kerf edge
340
Square or sharp kerf edge
345
wires of delivery system
350
Bonding zone of textile structure to delivery system
355
bonding agent for filaments of delivery system
360
Extra small pitches (Kerf width plus strut width)
365
Small pitches (Kerf width plus strut width)
370
Medium pitches (Kerf width plus strut width)
375
Large pitches (Kerf width plus strut width)
580
Guide catheter
590
Microcatheter
600
Microwire
650
Blood clot or Clot burden
DETAILED DESCRIPTION
FIG. 1 is a schematic diagram that illustrates a two-dimensional front view of one of the embodiments with a spherical tapered textile structure. It has three components in one of the embodiments: a shape-set textile structure, a bonding zone at the region of the proximal marker band, and a delivery system or hypotube.
The shape-set tapered textile structure in several embodiments has a distal tip, that in the expanded configuration has an outer diameter of less than e.g., 0.017 inches (0.43 mm) and in the collapsed configuration has an outer diameter of less than e.g., 0.0125 inches (0.317 mm) In several embodiments, the expanded configuration of the tip has a diameter in the range of about 0.35-0.65 mm (e.g., 0.40-0.45 mm) In several embodiments, the collapsed configuration has a diameter in the range of about 0.1-0.34 mm (e.g., 0.25-0.33 mm) In some embodiments, for larger vessels, the expanded configuration has a diameter in the range of about 1-40 mm and a diameter in the range of about 0.5-10 mm in a collapsed configuration. In some embodiments, the ratio of the expanded configuration to the collapsed configuration is 1.2:1-10:1. In several embodiments, the distal neck is narrow and has similar outer diameter in the expanded and collapsed configuration as the distal tip. The distal neck has a length that ranges from about 1-5 mm in one of the embodiments.
In several embodiments, there are a total of 10 spherical bulbs in one of the embodiments with varying diameters in the expanded configuration and in the collapsed configuration has an outer diameter of less than e.g., 0.0125 inches (0.317 mm) In several embodiments, the expanded configuration of the bulbs has a diameter in the range of about 1-6 mm (e.g., 3-4.5 mm) In several embodiments, the collapsed configuration has a diameter in the range of about 0.1-0.9 mm (e.g., 0.25-0.5 mm) In some embodiments, for larger vessels, the expanded configuration has a diameter in the range of about 5-40 mm and a diameter in the range of about 0.5-5 mm in a collapsed configuration. In some embodiments, the ratio of the expanded configuration to the collapsed configuration is 1.2:1-10:1.
In some embodiments, the varying outer diameters of the 10 spherical bulbs in the expanded configuration are as follows in one of the embodiments: The distal three extra-small spherical bulbs have an outer diameter (e.g., d=3 mm) in the expanded configuration and corresponds to the extra-small vessel segments such as the M2 segments of the middle cerebral artery, the next three small spherical bulbs have an outer diameter (e.g., d=3.5 mm) in the expanded configuration and corresponds to the smaller vessel segments such as the distal M1 segment of the middle cerebral artery, the next two medium spherical bulbs have an outer diameter (e.g., d=4 mm) in the expanded configuration and corresponds to the medium vessel segments such as the proximal M1 segment of the middle cerebral artery, and the proximal two large spherical bulbs have an outer diameter (d=4.5 mm) in the expanded configuration that corresponds to the large vessel segments such as the distal supra-clinoid segment of the internal carotid artery. This tapered configuration of the shape-set textile structure allows for adequate and safe deployment of the device across blood vessels with multiple diameters. Although specific diameter numbers are provided in this paragraph, other embodiments include diameters that are +/−5, 10, 15, or 20%.
In some embodiments, 10 bulbs are used. However, in other embodiments, 1-9 bulbs or 11-30 (or more) bulbs may be used. In some embodiments, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 bulbs are used. In some conditions, for example in the leg, where clots can be up 20-40 cm, 40-60 bulbs may be used. In some embodiments, 1 bulb is used for every 0.2-5 cm (e.g., about 0.5-2 cm).
In several embodiments, bulbs of various sizes and/or shapes are provided on a single elongate support structure (such as a neck, tube, spindle, spine, rod, backbone, etc.). The elongate support structure may be hollow, filled or partially hollow. The elongate support structure may have a length in the range of about 1-20 cm (e.g., about 4-8 cm, 5-10 cm, etc). In larger vessels (e.g., outside the brain) the length can be about 20-50 cm. The diameter or width of the elongate support structure is in the range of about 0.35-0.65 mm (e.g., 0.40-0.45 mm) in an expanded configuration and in the range of about 0.1-0.34 mm (e.g., 0.25-0.33 mm) in the collapsed configuration. In some embodiments, for larger vessels, the expanded configuration of the elongate support structure has a diameter in the range of about 1-40 mm (e.g., 5-20 mm) and a diameter in the range of about 0.5-10 mm (e.g., 1-2 mm) in a collapsed configuration. Wall thickness of the elongate support structure are, in some embodiments, ranges from about 0.01-4 mm (e.g., about 0.02-1 mm 0.02-0.05 mm, e.g., 0.025 mm) The elongate support structure may be braided, knitted or weaved with two or more strands (e.g., about 12-120 strands, 12-96 strands, 48 strands) in some embodiments. The pattern, in some embodiments, is one-over-one-under-two, one-over-one-under-one, two-over-two-under-two, etc. In some embodiments, the braid angle is in the range of about 45-179 degrees (e.g., about 130-160 degrees, 151 degrees). The picks (or pixels) per inch (PPI) range from about 50-300 PPI (e.g., about 150-190 PPI, e.g., 171 PPI). In some embodiments, increased outward expansile force and/or compression resistance is provided by a higher braid angle and/or higher PPI. In some embodiments, the force/resistance (e.g., radial force) is in a range sufficient to expand a target vessel in the range of about 0%-30%. In some embodiments, the total diameter size of the treatment device is 0.5 mm-1.5 mm greater than the target vessel diameter. In some embodiments, the total diameter size of the treatment device is oversized by 10-50% with respect to the target vessel diameter. The elongate support structure may be made of shape memory alloys (e.g., nickel titanium). In some embodiments, the elongate support structure is about 50-95% (e.g., 75%) nickel titanium and about 5-50% (e.g., 25%) platinum iridium or platinum tungsten or combinations thereof. The radio-opaque portions can be spaced or clustered to increase visibility under x-ray. For example, a thick band pattern may be used which can include 1-12 radio-opaque strands (e.g., filaments, wires, etc.) that are wound adjacently with one another. In several embodiments, the bulbs are integral with the elongate support structure. In other embodiments, the bulbs are coupled (fixably or reversibly coupled) to the elongate support structure.
For example, bulbs size (with respect to the outer diameter in an expanded configuration) is about 0.5-3 mm (e.g., 3 mm), about 3.1-3.9 mm (e.g., 3.5 mm), about 4-4.4 mm (e.g., 4 mm), and about 4.5-7.5 mm (e.g., 4.5 mm) are provided. In some embodiments, the bulbs are sized in the range of about 1 mm-80 mm (e.g., 2 mm-12 mm) Bulbs in range of 4-10 mm may be particular beneficial for larger clots and/or vessels (e.g., in the leg). The sizes above are reduced by 1.3-10 times in the collapsed configuration. In some embodiments, the collapsed configuration of the bulbs is about 50-80% of the inner diameter of the delivery catheter (e.g., microcatheter). In some embodiments, each consecutive bulb is larger than the other. In other embodiments, two sizes are used in an alternate pattern. In yet other embodiments, three or more sizes are used in a series, and each series is repeated two, three, four, five, six, seven, or more times. As an example, if a series of three sizes is alternated, twenty-one bulbs are used. In some embodiments, larger bulbs may be used at the ends, while smaller bulbs are used in the middle. Bulbs may be smaller at the ends and larger in the middle.
Various bulb shapes may be used according to several embodiments, including spherical, oblong, egg, and elliptical (e.g., with respect to top view, side-view and/or cross-section). Square, rectangular and diamond-shapes (e.g., with respect to top view, side-view and/or cross-section) are used in some embodiments. Spiral, twisted, or helical bulbs are provided in some embodiments. For example, sphere-like bulbs and oblong bulbs may be used in a single strand. In some embodiments, shapes are alternated. In yet other embodiments, three or more shapes are used in a series, and each series is repeated two, three, four, five, six, seven, or more times. In some embodiments, bulbs of a first shape may be used at the ends, while bulbs of a second shape are used in the middle. Bulbs may be a first shape at the ends and a second shape in the middle, or vice versa.
The positioning of the bulbs may be beneficial for certain vessel sizes and/or clot locations, material, and/or sizes. Bulbs may be touching (e.g., contiguous) or non-touching. A single strand may include bulbs that are both touching and non-touching. In several embodiments, a strand includes bulbs that are all non-touching and/or are spaced apart by one or more spacers. These spacers may be of the same or different material than the bulbs. The spacers may also be shaped differently than the bulbs. The spacers may comprise, be embedded with or coated by markers or other visualization aids (such as radio-opaque portions).
The bulbs may be separated by distances of about 0.1 to 50 mm, including, but not limited to, about 0.5-1, 1-2, 2-3, 3-4, 4-5, 5-8, 8-10, 10-12, 12-15, 15-25, 25-35, and 35-50 mm apart, including overlapping ranges thereof. The spaces between all the bulbs in one strand may be constant. Alternatively, the spacing between two or more (or all) of the bulbs may be different. In some embodiments, some bulbs are spaced the same distance from one another, while other bulbs have different spacing.
FIG. 2 is a schematic diagram illustrating the 3D perspective view of one of the embodiments with a spherical tapered textile structure.
FIG. 3 is a schematic diagram illustrating the 2D view of one of the embodiments with an oblong tapered textile structure.
FIG. 4 is a schematic diagram illustrating the 3D perspective view of one of the embodiments with an oblong tapered textile structure.
FIG. 5 is a schematic diagram illustrating the 2D view of one of the embodiments with a spherical and oblong interspersed tapered textile structure.
FIG. 6 is a schematic diagram illustrating the 2D view of one of the embodiments with a spherical non-tapered textile structure.
FIG. 7 is a schematic diagram illustrating the 2D view of one of the embodiments with an oblong non-tapered textile structure.
FIG. 8 is a schematic diagram illustrating the 2D view of one of the embodiments with a spherical and oblong interspersed non-tapered textile structure.
FIG. 9 is a schematic diagram illustrating the 2D view of one of the embodiments with cylindrical wide-mouthed distal tip textile structure.
FIG. 10 is a schematic diagram illustrating the 2D view of one of the embodiments with a cylindrical narrow-mouthed distal tip textile structure.
FIG. 11 is a schematic diagram illustrating the 2D view of one of the embodiments with a cylindrical narrow-mouthed distal tip with a spherical or oblong distal filter textile structure.
FIG. 12 is a schematic diagram illustrating the 2D view of one of the embodiments with a cylindrical narrow-mouthed distal tip with a spherical distal and proximal filter textile structure.
FIG. 13 is a schematic diagram illustrating the 2D view of one of the embodiments with a cylindrical narrow-mouthed distal tip with an oblong distal and proximal filter textile structure.
FIG. 14A is a schematic diagram illustrating the wires positioned on the yarn to develop a biomedical textile structure in one of the embodiments.
FIG. 14B is a schematic diagram illustrating the braid carrier set up mechanism for the position of the wires on the yarn to develop a biomedical textile structure in one of the embodiments.
FIG. 15A is a photograph illustrating the wires being braided into a biomedical textile structure on the yarn in one of the embodiments. FIG. 15B is a photograph illustrating the wires being knitted into a biomedical textile structure in one of the embodiments. FIG. 15C is a photograph illustrating the wires being woven into a biomedical textile structure in one of the embodiments.
FIG. 16 is a photograph illustrating the primary tubular shape set textile structure in one of the embodiments.
FIG. 17 is a schematic diagram illustrating the primary shape setting into the necessary geometries needed to develop the shape-set textile structures in one of the embodiments.
FIG. 18 is a photograph illustrating the mandrel used for braiding on the yarn that is then used for primary shape setting into the necessary geometries needed in one of the embodiments.
FIG. 19 is a photograph illustrating secondary shape setting into the necessary geometries needed to develop the shape-set textile structure in one of the embodiments.
FIG. 20 is an X-ray photograph illustrating one of the embodiments where there is grouping of multiple radio-opaque filaments or wires together to form an inter-twining thick band for maximal radio-opacity during fluoroscopy.
Radio-opaque materials, metals or alloys, including but not limited to iridium, platinum, tantalum, gold, palladium, tungsten, tin, silver, titanium, nickel, zirconium, rhenium, bismuth, molybdenum, or combinations of the above etc. to enable visibility during interventional procedures.
FIG. 21 is an X-ray photograph illustrating single filaments inter-twined to provide radio-opacity during fluoroscopy in one of the embodiments.
FIG. 22 is an X-ray photograph illustrating double filaments inter-twined to provide radio-opacity during fluoroscopy in one of the embodiments.
FIG. 23 is a photograph illustrating the need for post-processing of the free end of the textile structure to keep the filaments or wires from fraying in one of the embodiments. Post-processing of the free end of the textile structure (e.g., the elongate support structure and the bulbs) in some of the embodiments includes dip coating, spray coating, sandwich welding the free end using radio-opaque marker bands. Radio-opaque marker band materials, metals or alloys, including but not limited to iridium, platinum, tantalum, gold, palladium, tungsten, tin, silver, titanium, nickel, zirconium, rhenium, bismuth, molybdenum, or combinations of the above etc. to enable visibility during interventional procedures. In some of the embodiments, radio-opaque marker bands can be sandwich welded to the free end of the textile structure (e.g., the elongate support structure and the bulbs), butt welded to the distal end of the delivery system/hypotube, bonded or soldered to the delivery system or hypotube at regular intervals or laser welded into the kerfs created in the laser cut pattern at regular intervals to help measure a clot length, such radio-opaque markers at regular intervals may be separated by distances of about 0.1 to 50 mm, including, but not limited to, about 0.5-1, 1-2, 2-3, 3-4, 4-5, 5-8, 8-10, 10-12, 12-15, 15-25, 25-35, and 35-50 mm apart, including overlapping ranges thereof.
The dip coating or spray coating may comprise a biomedical polymer, e.g., silicone, polyurethane, polyethylene (Rexell™ made by Huntsman), polypropylene, polyester (Hytril™ made by Dupont), poly tetra fluoro-ethylene (PTFE), polyvinyl chloride (PVC), polyamides (Durethan™ made by Bayer), polycarbonate (Corethane™ made by Corvita Corp), or polyethylene-terephthalate. The dip coating or spray coating may further comprise a radio-opaque material, e.g., particles of tantalum, particles of gold, other radio-opaque agents, e.g., barium sulfate, tungsten powder, bismuth subcarbonate, bismuth oxychloride, iodine containing agents such as iohexol (Omnipaque™ Amersham Health).
FIG. 24 is a schematic diagram illustrating the appearance of the free end of the textile structure (e.g., the elongate support structure and the bulbs) after laser cutting the free end to keep the filaments or wires from fraying in one of the embodiments.
FIG. 25 is a schematic diagram illustrating the inlay bonding approach between the shape-set textile structure (e.g., the elongate support structure and the bulbs) and the delivery system (e.g., a hypotube, wire or multi-filament hybrid) using solder in one of the embodiments. The solder may be a silver-based lead free solder in some embodiments. The shape-set textile structure may be substantially or fully oxide free when bonding the shape-set textile structure to the delivery system when using such solder.
FIG. 26 is a schematic diagram illustrating the overall ratio of the cross-sectional area between the filaments or wires of the textile structure (e.g., the elongate support structure and the bulbs) and the bonding agent in one of the embodiments.
FIG. 27A is a schematic diagram illustrating the inlay bonding approach between the shape-set textile structure and delivery system using epoxy agents in one of the embodiments. FIG. 27B is a photograph illustrating the inlay bonding approach between the shape-set textile structure and delivery system using epoxy agents in one of the embodiments.
FIG. 28 is a schematic diagram illustrating the inlay bonding approach between the shape-set textile structure (e.g., the elongate support structure and the bulbs) and delivery system using a pinched ring as well as a bonding agent in one of the embodiments.
FIG. 29 is a schematic diagram illustrating the inlay bonding approach between the shape-set textile structure (e.g., the elongate support structure and the bulbs) and delivery system (e.g., a hypotube, wire or multi-filament hybrid) using a pinched tube as well as a bonding agent in one of the embodiments. In some of the embodiments, inlay bonding approach includes laser welding, laser butt welding, laser rivet welding, and mechanical crimping of a flared distal end of the hypotube on the inlayed proximal neck of the textile structure (e.g., the elongate support structure and the bulbs).
FIG. 30 is a schematic diagram illustrating the overlay bonding approach between the proximal neck of the shape-set textile structure (e.g., the elongate support structure and the bulbs) and the distal end of the delivery system (e.g., a hypotube, wire or multi-filament hybrid) using solder in one of the embodiments.
FIG. 31 is a schematic diagram illustrating the overlay bonding approach between the proximal neck of the shape-set textile structure (e.g., the elongate support structure and the bulbs) and the distal end of the delivery system (e.g., a hypotube, wire or multi-filament hybrid) using epoxy in one of the embodiments.
FIG. 32 is a schematic diagram illustrating the overlay bonding approach between the proximal neck of the shape-set textile structure (e.g., the elongate support structure and the bulbs) and the non-laser cut distal tip of the delivery system (e.g., a hypotube, wire or multi-filament hybrid) using epoxy in one of the embodiments.
FIG. 33 is a schematic diagram illustrating the overlay bonding approach between the proximal neck of the shape-set textile structure (e.g., the elongate support structure and the bulbs) and the distal end of the delivery system (e.g., a hypotube, wire or multi-filament hybrid) using epoxy and heat shrink tubing in one of the embodiments.
FIG. 34 is a schematic diagram illustrating the overlay bonding approach between the distal neck of the shape-set textile structure (e.g., the elongate support structure and the bulbs) and the distal end of the delivery system (e.g., a hypotube, wire or multi-filament hybrid) using bonding agent in one of the embodiments. In some of the embodiments, overlay bonding approach includes laser welding, laser butt welding, laser rivet welding, and mechanical crimping of a flared distal end of the hypotube on the inlayed proximal neck of the textile structure (e.g., the elongate support structure and the bulbs).
FIG. 35 is a photography illustrating the angled flexible laser-cut hypotube delivery system in one of the embodiments.
Various components (e.g., the elongate support structure, the bulbs, the sheath or the delivery system such as the hypotube) may be made up of materials that are biocompatible or surface treated to produce biocompatibility. Suitable materials include e.g., platinum, titanium, nickel, chromium, cobalt, tantalum, tungsten, iron, manganese, molybdenum, and alloys thereof including nitinol, chromium cobalt, stainless steel, etc. Suitable materials also include combinations of metals and alloys. Suitable materials also include polymers such as polylactic acid (PLA), polyglycolic acid (PGA), polyclycoloc-lactic acid (PLGA), polycaprolactone (PCL), polyorthoesters, polyanhydrides, and copolymers thereof. In some embodiments, the thrombectomy device is made of nitinol and platinum tungsten.
FIG. 36 is a schematic diagram illustrating dimensions for laser-cut Pattern A in one of the embodiments.
FIG. 37 is a schematic diagram illustrating dimensions for laser-cut Pattern B in one of the embodiments.
FIG. 38 is a schematic diagram illustrating the directional stagger of laser-cut Pattern A and Pattern B in one of the embodiments.
FIG. 39 is a schematic diagram illustrating the interspersed laser-cut Pattern A and B in one of the embodiments.
FIG. 40 is a schematic diagram illustrating the interspersed laser-cut Pattern A and B with the inter-pattern stagger in one of the embodiments.
FIG. 41 is a schematic diagram illustrating the edges of the kerf in the angled laser-cut delivery system or hypotube are rounded or sharp in one of the embodiments.
FIG. 42 is a schematic diagram illustrating the flexible transition points in the laser-cut pattern of the hypotube in one of the embodiments.
FIG. 43 is a photograph illustrating the degree of angled laser-cut and the degree of uncut in the angled laser-cut delivery system or hypotube in one of the embodiments.
FIG. 44 is a schematic diagram illustrating the horizontal laser-cut delivery system in one of the embodiments.
FIG. 45 is a schematic diagram illustrating the edges of the kerf in the horizontal laser-cut delivery system or hypotube are rounded or sharp in one of the embodiments.
FIG. 46 is a photograph illustrating the degree of horizontal laser-cut and the degree of uncut in the horizontal laser-cut delivery system or hypotube in one of the embodiments.
FIG. 47 is a schematic diagram illustrating a hybrid delivery system with the filaments or wires that are braided together like a hypotube in one of the embodiments.
FIG. 48 is a schematic diagram illustrating a thrombus or blood clot in the right middle cerebral artery causing an acute ischemic stroke noted during angiography with a guide catheter or a shuttle or a balloon guide catheter positioned in the right internal carotid artery in one of the embodiments.
FIG. 49 is a schematic diagram illustrating a catheter (e.g., microcatheter) being advanced across the thrombus or blood clot in the right middle cerebral artery over a microwire in one of the embodiments. The microwire is then removed and the mechanical thrombectomy device is advanced through the hub of the microcatheter via an introducer sheath that is protective encasing for the flexible delivery system. In several embodiments, the catheter (e.g., microcatheter) is reinforced with the laser cut hypotube so as to, in one embodiment, inherit the maneuverability advantages of the hypotube (e.g., to facilitate proximal support and distal flexibility). In some embodiments, a catheter with varying pitches is used. For example, the pitch from the distal end to the proximal end varies as follows: about 0.005 inch, 0.01 inch, 0.02 inch, 0.04 inch, 0.08 inch and 0.16 inch. In some embodiments, the pitch from the distal end to the proximal end varies as follows: about 0.005 inch for the distal most 20%, 0.01 inch for the next 15%, 0.02 inch for the next 15%, 0.04 inch for the next 15%, 0.08 inch for the next 15%, and 0.16 inch for the next (or proximal-most) 20%.
The introducer sheath may comprise a biomedical polymer, e.g., silicone, polyurethane, polyethylene (Rexell™ made by Huntsman), polypropylene, polyester (Hytril™ made by Dupont), poly tetra fluoro-ethylene (PTFE), polyvinyl chloride (PVC), polyamides (Durethan™ made by Bayer), polycarbonate (Corethane™ made by Corvita Corp), or polyethylene-terephthalate. Combinations of two or more of these materials may also be used.
The microcatheter may comprise a biomedical polymer, e.g., silicone, polyurethane, polyethylene (Rexell™ made by Huntsman), polypropylene, polyester (Hytril™ made by Dupont), poly tetra fluoro-ethylene (PTFE), polyvinyl chloride (PVC), polyamides (Durethan™ made by Bayer), polycarbonate (Corethane™ made by Corvita Corp), or polyethylene-terephthalate. Combinations of two or more of these materials may also be used.
FIG. 50 is a photograph illustrating the shape-set textile structure based mechanical thrombectomy device in one of the embodiments.
In several embodiments, the devices described herein can be used in the brain. In some embodiments, vasculature in the periphery can be treated. In some embodiments, coronary vessels are treated. Abdominal aorta and branches are treated in several embodiments.
In some embodiments, a subject having a clot is identified. An access catheter is advanced over a guidewire to a vessel proximate or containing the clot. The guidewire may be removed at this stage. A microcatheter is advanced over a microwire, but stop before or at the clot. The microwire then crosses the clot by 0.5-5 mm (e.g., slices through the center of the clot). The microcatheter is then advanced over the microwire to cross the clot. The microwire is then removed or retracted. The thrombectomy device (the elongate support structure with the bulbs bonded to a delivery system, such as a hypotube, wire or multi-filament wire/hypotube device), as disclosed in several embodiments herein is positioned within an introducer sheath, and together are advanced through the hub of the microcatheter. The thrombectomy device is then advanced through the microcatheter, and the introducer sheath is removed. The thrombectomy device is advanced until it is at the tip of the microcatheter (which is beyond the clot). The thrombectomy device is kept in position, and the microcatheter is retracted (e.g., unsleeved, unsheathed) until the thrombectomy device is expanded. The length of retraction is related to length of the clot in one embodiment (e.g., the microcatheter is retracted to or before the proximal end of the clot). The thrombectomy device is torqued (e.g., in a counterclockwise motion) to facilitate torsional rasping (e.g., rotationally scraping), thereby allowing the bulb(s) to entrap the clot, and collect any debris (emboli). The sticky portions of the clot, which can be attached to the endothelium wall, can be removed by the torqueing motion. The non-laser cut braided nature of the bulbs facilaite gentle entrapment of the clot without perforating the blood vessel. In one embodiment, a 360 degree rotation on the proximal end results in a distal rotation that is less than 360 degrees (e.g., 90-180 degrees). In several embodiments, the rotational force from the proximal end to the distal is not 1:1. Instead the ratio is 1:0.75, 1:0.5 or 1:0.25. This non-1:1 ratio, in some embodiments, is beneficial because it provides a gentle rotation that reduces the risk that the blood vessel is rotated, displaced, disrupted or perforated. In several embodiments, if one bulb cannot fully entrap the clot, another bulb (whether it is the same or different in size and/or shape) will be able to further entrap the clot. In some embodiments, the undulations (e.g., the hills and valleys created by the bulbs and support structure) facilitate clot entrapment. Undulation is also provided at a micro level by the braiding pattern. This dual-undulating pattern enhances scraping and entrapment in several embodiments. The clot, once entrapped or captured by the bulbs, can then be removed as the thrombectomy device is removed from the subject. The thrombectomy device is removed as follows in some embodiments: the microcatheter and the delivery system (e.g., hypotube) are retracted into the tip of the guide catheter while negative suction is applied (e.g., with a syringe) at the level of the guide catheter and also while the microcatheter is retracted at a similar rate such that the microcatheter does not generally recapture any expanded portion of the thrombectomy device or expand (or expose) additional portions of the thrombectomy device. In other words, unexpanded bulbs remain unexpanded and expanded bulbs remain expanded until they are retracted into the guide catheter. Suction can be applied for about 5-30 seconds using a 30-90 cc syringe. The steps above need not be performed in the order recited.
The following references are herein incorporated by reference: (1) Sarti C, Rastenyte D, Cepaitis Z, Tuomilehto J. International trends in mortality from stroke, 1968 to 1994. Stroke. 2000; 31:1588-1601; (2) Wolf P A, D'Agostino R B. Epidemiology of Stroke. In: Barnett H J M, Mohr J P, Stein B M, Yatsu F, eds. Stroke: Pathophysiology, Diagnosis, and Management. 3rd ed. New York, N.Y.: Churchill Livingstone; 1998:6-7; (3) Adams H P, Jr., Adams R J, Brott T, del Zoppo G J, Furlan A, Goldstein L B, Grubb R L, Higashida R, Kidwell C, Kwiatkowski T G, Marler J R, Hademenos G J. Guidelines for the early management of patients with ischemic stroke: A scientific statement from the Stroke Council of the American Stroke Association. Stroke. 2003; 34:1056-1083; (4) Rymer M M, Thrutchley D E. Organizing regional networks to increase acute stroke intervention. Neurol Res. 2005; 27:59-16; and (5) Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, Pessin M, Ahuja A, Callahan F, Clark W M, Silver F, Rivera F. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. Jama. 1999; 282:2003-2011.
While the invention is susceptible to various modifications, and alternative forms, specific examples thereof have been shown in the drawings and are herein described in detail. It should be understood, however, that the invention is not to be limited to the particular forms or methods disclosed, but to the contrary, the invention is to cover all modifications, equivalents and alternatives falling within the spirit and scope of the various embodiments described and the appended claims. The ranges disclosed herein also encompass any and all overlap, sub-ranges, and combinations thereof. Language such as “up to,” “at least,” “greater than,” “less than,” “between,” and the like includes the number recited. Numbers preceded by a term such as “about” or “approximately” include the recited numbers. For example, “about 3 mm” includes “3 mm.” | 1a
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RELATED APPLICATIONS
This is a continuation application of copending International Patent Application PCT/EP2008/005867 which was filed on Jul. 17, 2008 and published in English, and claims priority of European Patent Application 07014576.8 filed on Jul. 25, 2007. The entire contents of these priority applications are fully incorporated herein by reference.
BACKGROUND OF THE INVENTION
The invention relates to an application device for applying a dispensable material that is stored in a cavity of some kind of a receptacle. More particularly, the material may be a liquid, semi-liquid, pasty or powdered material preferably used for medical, diagnostic, cosmetic or dental applications. The application device comprises a closed state and an open state. It may be configured as an injection device configured for single or multiple use and having a closed state and an open state.
From US 2005/0215952 A1 an application device configured as a single-use syringe is known which comprises:
a tubular receptacle enclosing a cavity for receiving a liquid; a bung made of an elastic material being held at a first longitudinal end of the tubular receptacle and comprising a through channel that is fluidly connected with the cavity; a holder engaging the bung; and a needle secured within the holder and comprising a delivery duct fluidly connected with the through channel.
The known syringe includes a tubular receptacle provided with sealingly closing-off elements delimiting a chamber, intended to be filled with a liquid, and having a liquid-delivery duct opening into the chamber, a needle-carrying base having a duct for supplying a liquid to the needle and being axially movable between a retracted position in which the delivery duct is closed-off, and an advanced injection position in which it allows the liquid to flow out of the chamber to the needle, a cap having a shape adapted to cover the base and provided with elements for detachable connection to the tubular receptacle, axial-stop elements arranged so as to keep the base in its closing-off position when the latter is covered by the cap, and axial stop elements arranged so as to limit the axial displacement travel of the base, once the cap is removed.
The known device suffers from several draw-backs: First of all the opening and closing system of the syringe relies on clips made of hard plastic material that engage recesses provided on the holder. Reliability of the working of these clips is based on plastic molded parts and relative tolerances between these parts.
Also the basic principle of this syringe for moving from the closed state to the open state is based on a sliding seal. There is the potential risk of a blocking of the seal after extended storage time. If the axial movement is impeded or blocked in some way, then there is the risk that the syringe may not be activated to allow an injection of the stored liquid to a patient.
There is a variety of other so-called “dry needle” application devices, comprising a tubular receptacle containing the liquid to be injected and closed off by a membrane, and a double-point needle which can be displaced axially relative to the tubular receptacle so as to pierce the membrane at the moment of injection. (DE 2 055 840; U.S. Pat. No. 4,720,285; WO 96/013171).
The provision of a membrane seal poses a complication of the manufacturing process. In addition, there is always a necessary activation movement either by twisting of the cap or by an axial displacement of the part penetrating the membrane.
Again, there is the risk of blocking of the penetrating needle so that the syringe may not be activated. Further there is the risk of generating particles as well.
SUMMARY OF THE INVENTION
In view of this it is a first object of the invention to disclose an improved application device for applying a material stored within a cavity which is easy to manufacture and can be conveniently and reliably be activated for use.
It is a second object of the invention to disclose an improved application device for applying a material which is suitable for long-term storage the material stored within the application device.
It is a third object of the invention to disclose an improved application device which can be used as ready-to-use syringe filled with a medical material.
It is a forth object of the invention to disclose an improved application device that can be used as a ready-to-use syringe filled with a medical material that avoids leakage after long-term storage.
It is a fifth object of the invention to disclose an improved method for manufacturing an application device that is prefilled with a material to be applied.
According to the invention these and other objects of the invention are achieved by an application device for applying a dispensable material, the application device having a closed state and an open state and comprising:
an elastic part made of an elastic material and having a through channel being configured for engaging a cavity of a receptacle; a holder comprising a support for receiving a dispensing means fluidly connected with the through channel; and a pinch seal sealing the through channel when being in said closed state.
The object is fully achieved in this way.
Namely, the sealing is effected in a very simple way.
If possibly after extended storage time there should occur some sticking within the through channel so that the pinch seal is permanently blocked, it may be opened by exerting a pressure.
Alternatively, or in addition, the internal surface of the through channel of the elastic said elastic part may comprise a coating made of a material preventing sticking of the internal surface and interaction with any dispensable material filled into the cavity of the receptacle. This coating may, e.g. be a parylene or PTFE coating.
So there is no risk that the application device cannot be transferred into its open state even after extended storage life.
According to a preferred embodiment of the invention a cap is fitted onto a peripheral portion of the holder for compressing the holder at least partially to effect the pinch-seal. Further, the cap may comprise an end portion that at least partially fits into the collar, in particular into a hollow tubular portion of the collar.
These features help to facilitate a long-term sealing of a material obtained within the cavity of the receptacle. While the cap may consist of a material that may be subject to creeping during long-term storage, such possible creeping is prevented by the collar that may consist of a more stable material.
According to a further feature of the invention the elastic part comprises a peripheral flange resting against an end portion of the receptacle, the peripheral flange being sealed against said end portion by the holder which at least partially encloses the peripheral flange and secures it to the end portion of the receptacle.
Thus the application device includes an integrated sealing of the cavity of the receptacle with the delivery means or needle connected thereto.
According to a preferred embodiment of the invention the receptacle is configured as a syringe barrel, cartridge, vial, bottle or bag.
According to a further embodiment of the invention the dispensing means is configured as a needle or as a coupling, in particular as a Luer-Lock thread, for attaching a part.
So the dispensing means may preferably be coupled to a needle so as to allow an injection of the material stored within the cavity into a patient or into an animal, or to allow a direction into any other part attached by some sort of coupling such as a Luer-Lock thread, a bayonet type connector etc.
According to a further development of the invention the elastic part is configured as a bung at least partially received within the holder.
This allows for a simple design and easy activation or deactivation of the pinch seal.
According to a further embodiment of the invention the application device further comprises:
a receptacle enclosing a cavity for receiving a dispensable material; a bung made of an elastic material being held at a first longitudinal end of the receptacle and comprising the through channel that is fluidly connected with the cavity; a holder engaging the bung; and a needle secured within the holder and comprising a delivery duct fluidly connected with the through channel.
In this way the application device is configured as a syringe.
According to a further development of the invention the application device further comprises:
a removable cap supported on a peripheral portion of the holder when being in the closed state; wherein the cap, when being in the closed state, compresses the peripheral portion of the holder at least partially, thereby effecting the pinch seal; and wherein the pinch seal of the through channel is released, when the cap is removed, thereby allowing delivery of the dispensable material from the cavity through the through channel to the dispensing means, in particular through a delivery duct to a tip of a needle.
Thus the application device may be configured as a ready-to-use prefilled injection syringe.
According to this design the pinch seal can be effected in a very simple way by compressing the bung with the cap when resting on a peripheral portion of the holder so that the through channel extending through the bung is fully blocked. When the syringe shall be made ready for use, only the cap must be taken off, thereby transferring the syringe into the open state. Upon removal of the cap the pressure exerted by the cap on the bung is released so that the bung flexes outwardly under its own elastic force thereby freeing the through channel.
In addition, since the pinch seal is merely effected by compressing the elastic bung by the cap being supported on a peripheral portion of the holder, the operation of the syringe is not influenced by any clip tolerances, and activation of the syringe can be effected very reliably.
According to a further development of the invention the holder comprises at least one flexible arm that is pressed by the cap against the bung to generate a pinch seal of the through channel when being in the closed state.
This feature allows a very effective sealing of the through channel, since the flexible arm allows to generate a high pressure on the bung so as to effect a good pinch seal.
According to a further development of this design the at least one flexible arm is biased to the outside so as to release the pinch seal upon removal of the cap.
In this way an easy release of the pinch seal is effected upon removal of the cap. So the flexible arm allows to generate an effective pinch seal when being in the closed state and to reliably transition into the open state under its own biasing force.
Preferably the holder is made of a hard plastic material that generates a biasing force on the at least one flexible arm when pressed into the closed state.
In this way no additional biasing means, such as a spring means, is necessary to effect the desired biasing force.
The bung may preferably be made of a polypropylene, a thermo plastic elastomer (TPE), silicone rubber (LSR) or a different rubber type material.
Such a material provides the desired resilience to effect a good pinch seal in the compressed state and to release the pinch seal upon release of the outer pressure. Also this material can easily be molded into the desired shape.
According to a further development of the invention the tubular receptacle comprises a tubular extension being connected to the reminder of the tubular receptacle by a neck portion, wherein the holder comprises a hollow tubular portion that is mated to the tubular extension and comprises an inner rim portion protruding to the inside and engaging the neck portion for securing the holder on the tubular extension.
This allows for a simple and reliable design.
According to a further development of this design a collar is fitted onto the periphery of the hollow tubular portion for locking the inner rim portion onto the neck portion.
This allows for a simple assembly and a reliable securement of the holder on the tubular extension of the tubular receptacle.
According to a further development of the invention the bung comprises a peripheral flange being secured within the hollow tubular portion of the holder abutting the tubular extension of the receptacle.
Thereby reliable design and safe seal is facilitated.
The cap is preferably made from a rigid material, preferably from a hard plastic material.
This design allows an easy manufacture by molding and, in addition, provides sufficient rigidity to effect the necessary pressure for the pinch seal when being seated on the peripheral part of the holder.
According to a further development of the invention the cavity of the tubular receptacle is filled with a liquid which is sealed by a piston that is displaceable within the tubular receptacle by a piston rod.
In this way the single-use application device is filled with the desired liquid that can be expelled from the tip in the usual manner by exerting pressure on the piston rod for advancing the piston within the tubular receptacle.
According to a further embodiment of the invention the application device comprises a plurality of pinch seals coupled to different dispensable materials allowing a mixing of the materials after transfer of the pinch seals into the open state.
Thus a series of pinch seals may be used to seal of different dispensable materials and to effect a mixing of the materials when the pinch seals are transferred into the open state.
The object of the invention is further solved by a method of manufacturing an application device having a closed state at an end an open state, the method comprising the following steps:
providing a receptacle enclosing a cavity for receiving a liquid; attaching a bung made of an elastic material to the receptacle so that a through channel extending through the bung is fluidly connected with the cavity; providing a holder comprising a support for receiving a dispensing means fluidly connected with the through channel; attaching the holder to the bung so that the bung is at least partially enclosed from the outside and that the dispensing means is fluidly connected with said through channel; fitting a collar onto an end portion of the receptacle; providing a removable cap; attaching the cap onto a peripheral portion of the holder thereby pressing at least a portion of the holder onto the bung, thereby generating a pinch seal of the through channel; and securing an end portion of the cap within the collar.
Such a pre-manufactured application device may be filled with a drug material by a drug manufacturer by filling the cavity with the liquid, pasty or powdered material and sealing the filled cavity to the outside by inserting a piston held displaceably within the tubular cavity at an end of a piston rod. The application device is suitable for long-term storage of materials, such as drug materials.
The holder may support an injection needle or some kind of coupling such as a Luer-Lock thread or a bayonet-type connection.
Prior to filling the application device may be sterilized either in an assembled state or in a pre-assembled (open) state.
It is understood that the features of the invention mentioned above and those yet to be explained below can be used not only in the respective combinations indicated, but also in other combinations or in isolation, without leaving the scope of the present invention.
BRIEF DESCRIPTION OF THE DRAWINGS
Other features and advantages of the invention will become apparent from a preferred embodiment of the invention which will be described hereafter with reference to the drawings which are of merely exemplary nature without limiting the scope of the invention and in which:
FIG. 1 shows a perspective view of an application device according to the invention;
FIG. 2 shows an enlarged longitudinal partial section of the application device according to FIG. 1 in the region of the cap and the adjoining longitudinal end of the tubular receptacle, shown in the closed state with the cap attached; and
FIG. 3 shows the application device of FIG. 2 in its open state, after removal of the cap.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
In FIG. 1 a single-use application device according to the invention is shown in perspective view and depicted in total with reference numeral 10 .
The application device 10 comprises a tubular receptacle 12 which is configured as a glass cylinder, having a first longitudinal end 13 and a second longitudinal end 14 and enclosing a cavity 15 that can be filled with a liquid. The cavity 15 is sealed to the outside by a piston 18 held at the end of a piston rod 20 and sealed against the interior wall of the cavity 15 by suitable sealing rings (not shown).
The application device 10 is shown in FIG. 1 in its closed state in which the cavity 15 is sealed against a needle supported on the first tubular end 13 of the tubular receptacle 12 and surrounded by a collar 24 and an attached cap 22 .
For transferring the application device 10 from its closed state shown in FIG. 1 to an open state in which a liquid can be injected through the needle 32 shown in FIGS. 2 and 3 , merely the cap 22 needs to be removed and thereafter the piston 22 can be advanced within the cavity 15 by pressing the end of the piston rod 20 with one finger while holding the tubular receptacle 12 at a gripping flange 16 provided on the second longitudinal end 14 with two fingers.
The details of the application device that allow a sealing of the cavity 15 against the needle 32 when being in its closed (or “dry”) state and for transferring the application device into its open state in which liquid stored within the cavity 15 can be injected through a tip 38 of the needle 32 will be explained hereinafter with reference to FIGS. 2 and 3 .
According to FIG. 2 the tubular receptacle 12 comprises a tubular extension 45 having a smaller diameter than the reminder of the tubular receptacle 12 and being connected to the remainder of the tubular receptacle 12 by a neck portion 44 defining a circumferential recess. Held within the inner wall of the tubular extension 45 is a bung 46 made of a polypropylene material or from TPE. The bung is of generally cylindrical shape resting with a peripheral flange 50 against the end surface of the tubular extension 45 and having a central through channel 48 that opens into the cavity 15 at one end and opens into a delivery duct 36 of the needle 32 at the other end.
In FIG. 3 the bung 46 is shown in its released state so that the central through channel 48 is not blocked by a pinch seal effected in the closed state shown in FIG. 2 .
A holder 26 preferably made of a hard but elastic plastic material is attached onto the outer surface of the bung 46 and comprises an enlarged portion 40 having a larger outer diameter with a hollow tubular portion 41 that is fitted onto the peripheral flange 50 of the bung 46 and onto the tubular extension 45 of the tubular receptacle 12 , thereby pressing the peripheral flange 50 of the bung 46 against the tubular extension of the receptacle 12 . To effect a proper securement, the enlarged portion 40 comprises an inner rim portion 42 at its end remote from the needle 32 engaging the neck portion 44 of the tubular receptacle 12 . To finally secure the holder 26 against removal from the tubular receptacle 12 , in addition, a collar 24 is pressed onto the peripheral wall of the enlarged portion 40 using a press fit and rests against a rim portion protruding outwardly at the end of the enlarged portion 40 .
The needle 32 , usually made of stainless steel is fitted into a central opening 28 of the holder 26 and secured by an adhesive 30 or by another means so that the inner end of the needle 32 rests about flush with the through channel 48 of the bung 46 .
The holder 26 at one side comprises a flexible arm 34 extending from a portion near the inner end of the needle 32 and having a free end remote from the needle 32 . The flexible arm 34 has a cross section of a wedged shape having a larger thickness at its free end than at its other end that is connected to the remainder of the holder 26 . The holder 26 is made from a hard but elastic plastic material that allows to bias the flexible arm 34 into the position shown in FIG. 3 so that the bung 46 is not compressed in the open state indicated by numeral 10 ′ in FIG. 3 .
For transferring the application device into a closed state in which the central through channel 48 of the bung 46 is sealed by the pinch seal 52 as shown in FIG. 2 , the cap 22 needs to be attached on the holder 26 . The cap 22 is inserted onto a peripheral portion of the holder 26 resting with its end within a slot provided between the peripheral portion of the holder 26 and the collar 54 and abutting against the enlarged portion 40 of the holder 26 . In this closed state shown in FIG. 2 the flexible arm 34 is pressed by the cap 22 to the inside against the bung 46 thereby effecting the pinch seal 52 of the through channel 48 , whereby the through channel 48 is effectively blocked.
This closed state shown in FIG. 2 is the ready-to-use state of the application device filled for instance with a medical drug by a drug manufacturer. The liquid containing the drug solution within cavity 15 is sealed against the needle 32 by the pinch seal 52 . When the application device needs to be used, merely the cap 22 is pulled off from the holder 26 while holding the application device at the tubular receptacle 12 . Once the cap 22 is removed, as shown in FIG. 3 , the flexible arm 34 flexes to the outside under its own bias thereby releasing the central through channel 48 so that the drug solution contained in cavity 15 may then ejected out of the needle tip 38 by advancing the piston rod 20 thereby expelling the drug solution through the needle tip 38 .
In case after a long storage period there should be some tendency of sticking between the two adjacent parts of the inner wall of the bung 46 effecting the pinch seal 52 , the pressure generated by advancing the piston 18 into the cavity 15 will effectively remove any potential blockage of the pinch seal 52 .
Alternatively, or in addition, the inner wall surface of the bung may comprise a coating (not shown) that is made from a material that prevents sticking and that prevents interaction with any drug material. Such a coating may, e.g. consist of parylene of PTFE (polytretrafluorethylene). This leads to a very reliable design. | 1a
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BACKGROUND OF THE INVENTION
[0001] The invention relates to a tendon fixation anchor.
[0002] In the reconstruction of ligaments and tendons of the musculoskeletal system in the human or animal body, it is necessary to fasten the tendon transplant on the bone. This is particularly the case with the reconstruction of the front and rear cruciate ligaments in the knee joint. The criteria for an anatomically and functionally suitable fastening or fixation are a high resistance to being torn out, a fixation close to the joint and a minimization of the necessary tendon length. The minimization of the tendon length is therefore desirable since the necessary tendons are often taken from the body, whereby functional limitations at the related body parts occur. Inasmuch as this is concerned, it is desirable to remove as few tendons as possible.
BRIEF SUMMARY OF THE INVENTION
[0003] With regard to these problems, it is an object of the invention to permit an improved fastening of tendons on the bone, which is secure and simultaneously renders possible a fixation close to the joint, with a minimized tendon length.
[0004] This object is achieved according to the present invention by a tendon fixation anchor which is designed for being received in a bone channel and comprises at least one first through-hole, which extends transversely to an insertion direction, in which the tendon fixation anchor can be inserted into a bone channel, through which first through-hole tendons to be fastened can be led.
[0005] Preferred embodiments of the invention are set forth in the subsequent description as well as the attached figures.
[0006] The tendon fixation anchor according to an embodiment of the invention is in particular suitable for the fastening of tendons in the reconstruction of the cruciate ligament, in particular for the fastening on the femoral side.
[0007] The tendon fixation anchor according to the invention is thus designed such that, for the fixation of a tendon, it can be inserted into a channel formed previously in the bone, i.e. in particular into a bore formed in the bone, and fixes the tendon in the inside of the bone channel. According to the invention, by way of the tendon fixation anchor, it is now rendered possible to carry out the fixation of the tendons in the bone, since the tendon fixation anchor is designed such that it can be inserted into the channel formed in the bone or into the bore formed in the bone. The required tendon length can now be shortened since the tendon can now be fixed directly in the bone (close to the joint).
[0008] The tendon fixation anchor according to the invention is designed such that it comprises a through-hole extending transversely to the insertion direction. The insertion direction is thereby the longitudinal direction of the bone channel or of the bore in the bone, into which channel or bore the tendon fixation anchor is inserted. The tendon fixation anchor with a retracted tendon is thereby pulled into the bone channel from one end. The first through-hole in the fixation anchor serves for fastening the tendon on the anchor. This is effected by way of the tendon being led through this through-hole before the insertion of the fixation anchor into the bone channel.
[0009] Subsequently, the tendon is pulled through the bone channel, and thus the fixation anchor is pulled into the bone channel. The tendon thereby preferably jams or clamps behind a projection formed in the bone channel or an abutment shoulder, which is formed in the bone channel and on which the fixation anchor comes to bear. This means that for this, the bone channel is designed such that it has a cross-sectional change, i.e. a region with a greater cross section, which receives the fixation anchor, and a connecting region with a smaller cross section, through which the tendon then extends further through the bone. Due to the fact that the tendon is led through the through-hole, it can be turned over once on the fixation anchor and thus embraces or wraps the fixation anchor.
[0010] Preferably, the tendon fixation anchor is designed as one part or in a single-piece manner. Moreover, it usefully comprises no moving parts. Preferably, the tendon fixation anchor comprises a second through-hole which is designed for receiving a suture for fastening a tendon pulled through the first through-hole. The tendon can be sewn on the fixation anchor by way of this second through-hole, for example by a suture being led through the second hole and around an outer side of the fixation anchor and simultaneously being led through the tendon. Thereby, the seam does not need to resist the tensions forces which occur later in the joint, since the tendon with the fixation anchor is clamped or jammed in the bone channel, but serves mainly for fixing the tendon on the fixation anchor on inserting the fixation anchor into the bone channel.
[0011] The second through-hole extends preferably parallel to the first through-hole. Thus the tendon can be led along via the second through-hole, so that a suture led through the second through-hole can extend transversely to the extension direction of the tendon through this tendon.
[0012] Further preferably, the second through-hole has a smaller, in particular significantly smaller, diameter than the first through-hole. The second through-hole only needs to be so large in diameter that a suture can be led once or several times through this hole, while the first through-hole must be so large that a tendon or a complete tendon bundle, which is to be fastened as a transplant on the bone, can be led through this through-hole. This means the first through-hole with regard to its diameter is selected such that it can receive the tendon transplant.
[0013] The second through-hole in the insertion direction preferably lies in front of the first through-hole. The insertion of the tendon fixation anchor into the bone channel is preferably effected in a manner such that the tendon is pulled through the bone channel, wherein the fixation anchor is previously fastened on the end of the tendon, and then with the tendon is pulled into the bone channel, where it then jams and/or comes to bear on a projection in the bone channel and thus fixes the tendon. If the second through-hole is situated in front of the first through-hole in the insertion direction, then the tendon which is led through the first through-hole extends past the second through-hole, so that a suture can be led through the second through-hole transversely through the tendon, in order to fasten this on the fixation anchor.
[0014] The tendon fixation anchor according to the invention further preferably comprises two diametrically opposed, first peripheral surface sections which are designed as bearing-contact surfaces for bearing on the peripheral wall of a bone channel. In particular, these first peripheral surface sections are preferably shaped such that they can come to bear on the inner wall of the bone channel or of a bore formed in the bone, in a large-surfaced manner. For this, the peripheral surface sections preferably have a shape, in particular a curvature which corresponds to the shape or curvature of the inner wall of the bone channel. The first through-hole, seen in the insertion direction, preferably lies in an axial section of the fixation anchor in which the peripheral surface sections, which come to bear on the bone, are formed.
[0015] For this purpose, the first peripheral surface sections are further preferably curved about a common longitudinal axis extending in the insertion direction. This means the peripheral surface sections seen in cross section form sections of a circle extending about the longitudinal axis. Here, the radius of curvature is preferably selected such that it corresponds essentially to the inner diameter of the bone channel, into which the tendon fixation anchor is to be inserted, or is slightly smaller than the radius of the bone channel. Since the bone channel, as described above, is usually formed by way of drilling, it usually has a circular cross section. With the described design of the peripheral surface sections, these can thus come to bear on the circular inner surface of the bone channel. The two peripheral surface sections thereby preferably form the outer peripheral sections of the fixation anchor, i.e. those peripheral surfaces which have the maximal outer diameter.
[0016] The tendon fixation anchor is fixed in the bone channel transversely to the insertion direction in the bone channel, preferably without play, by way of the bearing contact of these peripheral surface sections on the inner surfaces of the bone channel. Since the tendon fixation anchor further preferably has a greater length in the insertion direction than in the diameter direction between the two first peripheral surface sections, moreover, one prevents the tendon fixation anchor from being able to rotate in the bone channel about an axis extending transversely to the insertion direction.
[0017] Further preferably, two second peripheral surface sections, which are diametrically opposite one another, are situated between the mentioned first peripheral surface sections in the peripheral direction. These second peripheral surface sections thus in the peripheral direction connect the first peripheral sections to one another. The first through-hole and, optionally, the second through-hole extend between these second peripheral sections in the diametric direction with respect to the longitudinal axis of the fixation anchor, i.e. its insertion direction.
[0018] Thus, the tendon to be fastened is preferably led via these second peripheral surface sections in a direction parallel to the insertion direction or longitudinal axis of the fixation anchor and then led through the first through-hole and led back again on the opposite, second peripheral surface sections, so that this tendon, led through the first through-hole, wraps the fixation anchor. On inserting the fixation anchor into the bone channel, the tendon can then be clamped between the second peripheral surface sections and the inner wall of the bone channel.
[0019] The second peripheral surface sections are preferably designed in a planar manner. Thus, seen in a cross-sectional plane, they extend essentially in a chord-like manner to the arcs formed by the first peripheral surface sections. Thus, further preferably, the diametric distance between the two second peripheral surface sections is smaller than the diametric distance between the two first peripheral surface sections. Since as described, the bone channel is usually designed with a circular cross section, in each case a free space remains between the second peripheral surface sections and the oppositely lying inner wall of the bone channel, on inserting the fixation anchor into the bone channel. The tendon can be led through this free space.
[0020] The free space however is preferably dimensioned such that, with a fixation anchor inserted completely into the bone channel, the tendon is clamped between the second peripheral surface of the fixation anchor and the surrounding wall of the bone channel. This means that the diametrical distance between the second peripheral surface sections is preferably selected such that it is smaller than the diameter of the bone channel by an amount which is smaller than double the thickness of the tendon transplant to be received.
[0021] Particularly preferably, the tendon fixation anchor is designed such that its diameter tapers in the insertion direction. This is particularly the diameter between the previously described first peripheral surface sections. This means that these first peripheral surface sections thus form sections of a cone. The fixation anchor thus tapers in a cone-shaped manner in the insertion direction. This simplifies the introduction into the bone channel.
[0022] Moreover, a secure jamming in the bone channel can be achieved, in particular if the bone channel is conically shaped in the corresponding direction. Thus, the distance between the peripheral surfaces of the fixation anchor, in particular the first peripheral sections of the fixation anchor and the inner peripheral surfaces of the bone channel, can reduce on inserting the fixation anchor into the bone channel, until the fixation anchor comes to bear on the inner periphery of the bone channel preferably without play, and is thus securely clamped in the inside of the bone channel.
[0023] The tendon fixation anchor according to the invention permits a new type of method for the fixation of a tendon with the reconstruction of ligaments and tendons of the musculoskeletal system, in particular for fastening a tendon transplant with cruciate ligament reconstruction.
[0024] First, a bone channel or a bore is introduced into the bone, in which the tendon transplant is to be fastened. This bone is preferably the femur. The bone channel is thus formed by way of special instruments such that it obtains a bottle-neck shape. This means that the bone channel comprises at least two sections with a differently large cross section or diameter, wherein the section with the smaller cross section or diameter faces the joint. The section with the larger cross section or diameter is designed for receiving a tendon fixation anchor according to the preceding description.
[0025] In particular, the bone channel in this region has a shape and a diameter which are matched to the tendon fixation anchor or its outer shape, such that the tendon fixation anchor can clamp itself into the bone channel. Thereby, it comes to bear in particular on the bearing-contact shoulder which is formed by the cross-sectional reduction, on the inner periphery of the bone channel and is thus fixed in the bone. This contact shoulder in the bone channel is thus designed such that it is situated as close as possible to the joint, but the remaining web on the inner periphery of the bone channel in the extension direction of the bone channel has such a thickness that it is adequately stable, in order to be able to accommodate the forces exerted by the fixation anchor.
[0026] Next, the transplant is led by a loop through the first through-hole of the fixation anchor and then is fixed by a holding suture, which is led through the second through-hole, on the tendon fixation anchor. The holding suture thereby extends preferably on both sides of the fixation anchor in each case through the region of the tendon which is situated there, and then in a spaced manner, once again through the tendon, so that it then runs on the outer side of the fixation anchor to its diametrically opposite side. This means that the holding suture wraps round the fixation anchor.
[0027] Subsequently, the tendon fixation anchor together with the tendon transplant which is fastened thereon is then inserted into the bone channel in the later pulling direction which forms the insertion direction. The tendon fixation anchor then clamps itself or jams close to the entry of the bone channel to the joint, on the bearing-contact shoulder which is formed there by the cross-sectional reduction. The tendon transplant is also clamped between this bearing-contact shoulder or this web and the fixation anchor.
[0028] Thus, this remaining bony (cortical) web on the inner periphery of the bone channel, at the exit opening of the bone channel which faces the joint, serves as a barrier to the joint side and ensures an extremely tear-resistant connection in the loading direction of the transplant. The transplant length can be shortened by way of this fastening of the tendon transplant which is very close to the joint, compared to a fastening on the rear side of the bone.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
[0029] The foregoing summary, as well as the following detailed description of the invention, will be better understood when read in conjunction with the appended drawings. For the purpose of illustrating the invention, there are shown in the drawings embodiments which are presently preferred. It should be understood, however, that the invention is not limited to the precise arrangements and instrumentalities shown. In the drawings:
[0030] FIG. 1 is a schematic lateral view of a knee joint;
[0031] FIG. 2 is a top perspective view of a fixation anchor according to an embodiment of the invention;
[0032] FIG. 3 is a lateral view of the fixation anchor according to FIG. 2 ; and
[0033] FIG. 4 is a sectional view of a bone channel with the inserted fixation anchor.
DETAILED DESCRIPTION OF THE INVENTION
[0034] FIG. 1 schematically shows the knee joint with a tibia T and femur F, between which a cruciate ligament (tendon) transplant TT is arranged. The tendon transplant TT extends with its femoral end FI into a bone channel 2 in the femur and with its tibial end TI into a bone channel 4 in the tibia T. The bone channels 2 and 4 each extend from the joint sides 6 and 8 of the femur and tibia, respectively, to the respective rear sides of the bone. This means that they are designed as through-channels or through-holes.
[0035] In the shown embodiment, the fastening of the tendon transplant TT in the bone channel 2 in the femur is effected with the help of a fixation anchor 10 , which is inserted into the inside of the bone channel 2 . In this manner, the tendon transplant TT at its femoral end FI does not need to extend through the complete bone channel, but has a necessary length LF in the bone channel 2 , which is shorter than the bone channel 2 .
[0036] FIGS. 2 and 3 show the fixation anchor in detail. The fixation anchor 10 is designed as a cone with two flattened, diametrically oppositely lying peripheral surface sections 12 . These peripheral surface sections 12 , as second peripheral surface sections, lie between the two peripheral surface sections 14 which are arranged in a diametrically opposite manner. The first peripheral surface sections 14 form sections of the outer peripheral surface of a cone and are curved about the longitudinal axis X of the fixation anchor 10 . The diameter or radius of curvature reduces in the insertion direction E, which runs in the direction of the longitudinal axis X of the fixation anchor 10 .
[0037] The fixation anchor 10 comprises a first through-hole 16 extending normally to the longitudinal axis X between the second peripheral surface sections 12 . The through-hole 16 is designed for receiving the transplant TT and has a diameter which is selected so large that the tendon transplant TT can extend through the through-hole 16 . The first through-hole 16 has a maximal diameter which is slightly smaller than the maximum distance of the first peripheral surface sections 14 in the diametric direction. Preferably, the diameter of the through-hole 16 is larger than the minimal distance of the first peripheral surface sections 14 in the diametric direction, i.e. larger than the smallest diameter of the fixation anchor 10 between the two first peripheral surface sections 14 at the tapered end of the cone. Thus, the diameter of the through-hole 16 can be just as large or larger than the smallest diameter of the bone channel 2 .
[0038] The diameter of the bone channel 2 can also be designed such that it is adapted to the thickness of the tendon bundle or tendon transplant TT which is to be received, i.e. the bone channel 2 only needs to be designed insignificantly larger than the thickness of the tendon transplant TT, so that it does not lead to a weakening of the bone.
[0039] A second through-hole 18 extends between the second peripheral surface sections 12 , in a manner parallel to the first through-hole 16 and spaced from it in the insertion direction E. This second through-hole serves for receiving a suture for the fixation of the tendon transplant TT on the fixation anchor 10 .
[0040] FIG. 4 shows that the end 20 of the fixation anchor 10 , which is at the rear in the insertion direction E, is designed in a curved manner, wherein the curved surface of the rear end 20 extends essentially concentrically to the middle axis of the first through-hole 16 .
[0041] As is to be seen in FIG. 4 , the bone channel 2 in the femur is designed in the manner of a bottle neck. This means that the bone channel 2 has a first section 22 with a larger diameter and a second section 24 with a smaller diameter, wherein the second section 24 is adjacent the joint side 6 of the femur F. The second section 24 with the smaller diameter thus forms a cross-sectional reduction with a bearing-contact shoulder 26 . The second section 24 in the extension direction of the bone channel 2 is designed in a very short manner compared to the first section 22 , so that it merely forms a web which projects radially inwardly form the peripheral wall of the bone channel 2 and is adjacent the joint side 6 , i.e. on the end of the bone channel 2 which faces the joint. The inner cross section or the inner diameter of the section 24 is smaller than the smallest diameter of the fixation anchor 10 between the first peripheral surface sections 14 defining the cone surfaces. The greatest distance or diameter of the fixation anchor 10 between the first peripheral surface sections 14 , as is to be seen in FIG. 4 , corresponds essentially to the inner diameter of the first section 22 of the bone channel 2 .
[0042] Before inserting the fixation anchor 10 into the bone channel 2 , the tendon transplant TT is led in the manner of a loop through the first through-hole 16 of the fixation anchor 10 , so that the tendon transplant TT bears on the two second peripheral surface sections 12 of the fixation anchor 10 . There, the tendon transplant TT is fixed with the help of a suture 28 which is led through the second through-hole 18 of the fixation anchor 10 and around its side 30 which is at the front in the insertion direction.
[0043] Subsequently, the tendon is pulled in the insertion direction E through the bone channel 2 and thus moves the end of the tendon transplant TT with the fixation anchor 10 from the side which is away from the joint, into the bone channel 2 , until the fixation anchor 10 comes to bear in a clamping manner on the bearing-contact shoulder 26 , which is defined by the section 24 which is smaller in diameter. Then the tendon transplant TT is also clamped between the fixation anchor 10 and the inner wall of the bone channel 2 , in this region, so that a secure fixation is achieved here.
[0044] It will be appreciated by those skilled in the art that changes could be made to the embodiments described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the particular embodiments disclosed, but it is intended to cover modifications within the spirit and scope of the present invention as defined by the appended claims. | 1a
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BACKGROUND
This invention relates to uterine fibroid treatment.
Cellular proliferation and differentiation in uterine tissue is considered to be regulated by ovarian steroids as fibroids appear in the reproductive years and regress after the menopause. Uterine fibroids are most commonly treated by surgery, usually by full or partial hysterectomy, although removal of individual fibroids (myomectomy) is also undertaken at rather greater risk on women who have not completed child bearing. As far as medical treatment is concerned, agonist analogues of LHRH (luteinizing hormone-releasing hormone) such as Buserilin (GnRH analogue) have been employed to suppress oestrogen-progesterone as fibroids are ovarian steroid dependent. Such medical treatments, however, suffer from a variety of side effects such as predisposition to osteopetrosis and are not recommended for long term use.
SUMMARY
It is an object of the present invention to provide an alternative medical treatment for uterine fibroids which, it is believed, may have potential for use in situations where the above-mentioned medical treatments are inadvisable.
The present invention is based on the discoveries by the present inventor that angiotensin II (Type II) receptor (AT 2 ) is highly expressed in fibroid tissue compared to normal myometrium (see attached FIGS. 1(A) to 1(E)), and that angiotensin II stimulates myometrial cell proliferation (see FIGS. 3(A) and 3(B).
The present invention, in a first aspect, resides in the use of an angiotensin-converting enzyme (ACE) inhibitor for the manufacture of a medicament for the treatment of uterine fibroids.
The present invention, in a second aspect, resides in the use of an angiotensin II-receptor antagonist for the manufacture of a medicament for the treatment of uterine fibroids.
The present invention, in a third aspect, resides in the use of a renin inhibitor for the manufacture of a medicament for the treatment of uterine fibroids. In this connection, it is to be appreciated that, in the renin-angiotensin system (RAS), renin synthesized by the kidneys and secreted into the circulation cleaves the decapeptide angiotensin I from angiotensinogen. Angiotensin I is converted by ACE to the octapeptide angiotensin II which is the biologically active hormone. Accordingly, the use of a renin inhibitor will also have the effect of inhibiting angiotensin II.
In a fourth aspect, the present invention resides in the use of an angiotensin II receptor (AT 1 and/or AT 2 ) expression inhibitor (including an antisense oligonucleotide directed against the angiotensin II receptor (AT 1 and/or AT 2 ) expression gene) in the manufacture of a medicament for the treatment of fibroids.
With regard to said first aspect of the present invention, namely the use of an ACE inhibitor to suppress angiotensin II expression, it is considered that any ACE inhibitor can potentially be used, including those which are known and which have been used or proposed to be used for ACE inhibition in the treatment of hypertension and congestive heart failure.
For example, ACE inhibitors such as Captopril (very soluble in water) and Enalapril (CAS 75847-73-3) (sparingly soluble in water) have relatively few side effects and are very effective in the treatment of hypertension.
Other ACE inhibitors which may be suitable are:
Benazepril,
Ramipril,
Lisinopril,
Imidapril 6366A (CAS 89371-44-8) (Arzneim. Forsch./Drug Res., September 1992, 42(9), pages 1109-14),
N-[8-amino-1(S)-carboxyoctyl]-L-alanyl-L-proline (AB-47, CAS 120008-53-9)
Pimobendan (CAS 118428-36-7) (Arzneim. Forsch./Drug Res. 43(1) No. 2a, 1993, pages 233-235), and
antisense oligonucleotides directed against the ACE gene or against genes for other enzymes in the renin-angiotensin system.
With regard to angiotensin II receptor antagonists, it is considered that suitable antagonists can be found amongst the following:
Saralasin,
Losartan (DuP753) (CAS 124750-99-8),
PD 123177,
CGP 42112A,
BIBS 39,
BIBS 222,
Sar-Ile-Ang II,
Sar-Thr-Ang II,
Sar-Ala-Ang II,
Sar-Val-Ala-Ang II,
Sar-O-Me-Tyr-Ang II
(see Arzneim. Forsch./Drug Res., 43(1) No. 2a (1993), pages 214-246).
As far as renin inhibitors are concerned, it is considered that suitable renin inhibitors may be:
Remikiren (R o 42-5892, CAS 126371-83-3)
[N-(pyridyl-3-propionyl)-phenylalanyl-histidyl-(3S,4S) ACHPA-isoleucylamino]-2-methyl-2-dihydroxy-1,3-propane (Arzneim. Forsch./Drug Res., Feb 1993 43(2A), pages 255-259).
Other renin inhibitors may be C1-992 (J. Pharmacol. Exp. Ther., 268:372-9, 1994); non-peptide renin inhibitors containing 2-(((3-phenylpropyl)phosphoryl)oxy)alkanoic acid moieties as P 2 -P 3 replacements (J. Med. Chem. 37:486-97, 1994) and antisense oligonucleotides directed against the renin-expression gene.
The ACE inhibitor, angiotensin II-receptor antagonist (e.g. Saralasin, Losartan or PD 123177) or an angiotensin II receptor (AT 1 and/or AT 2 ) expression inhibitor (including an antisense oligonucleotide directed against the angiotensin II receptor (AT 1 and/or AT 2 ) expression gene) may be used concomitantly or sequentially with a gonadotropin-releasing hormone agonist (GnRH--A) such as Buserelin or Goserelin in the treatment of uterine fibroids to reduce the size thereof.
Accordingly, the present invention further resides in the use of an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II-receptor antagonist for the manufacture of a medicament for the treatment of uterine fibroids, concomitantly or sequentially with gonadotropin-releasing hormone agonist (GnRH--A) such as Buserelin or Goserelin.
The present invention also resides in the concomitant or sequential use of (a) an ACE inhibitor (e.g. Ramipril, Lisinopril or Enalapril), or an angiotensin II-receptor antagonist (e.g. Saralasin, Losartan or PD 123177) with (b) a gonadotropin-releasing hormone agonist (GnRH--A) such as Buserelin or Goserelin in a method of the treating uterine fibroids.
Such use may comprise administration of a medicament comprising a mixture of (a) and (b), or administration of a medicament containing (a) and a medicament containing (b) either concomitantly or sequentially. Medicament (a) may be administered before medicament (b) or vice versa.
BRIEF DESCRIPTION OF THE DRAWINGS
FIGS. 1A-1E: Autoradiograms of the distribution of [ 125 I]-angiotensin II binding to adjacent sections (20 μm) of the human non-pregnant myometrium containing a fibroid. (A) Total binding; (B) binding in the presence of the AT 1 receptor selective ligand DuP753 (1.0 μM); (C) binding in the presence of the AT 2 receptor selective ligand PD123177 (1.0 μM); (D) binding in the presence of DuP753 (1.0 μM) plus PD 123177 (1.0 μM); (E) binding in the presence of unlabeled angiotensin II (0.1 nM). In FIGS. 1A-1E, dark regions indicate high densities of labeled receptors.
FIGS. 2A-2J: Autoradiograms of the distribution of 125 I-angiotensin II binding to adjacent sections of the human non-pregnant myometrium and fibroid. (A) Total binding; (B) binding in the presence of the AT 1 receptor selective ligand DuP753 (1.0 μM); (C) binding in the presence of the AT 2 receptor selective ligand PD123177 (1.0 μM); (D) binding in the presence of DuP753 (1.0 μM) plus PD123177 (1.0 μM); (E) binding in the presence of unlabeled angiotensin II (AngII, 0.1 nM); (F) binding in the presence of unlabeled angiotensin I (AngI, 0.1 nM); (G) binding in the presence of unlabeled angiotensin III (AngIII, 0.1 nM); (H) binding in the presence of unlabeled Sar-Thr-angiotensin II (0.1 nM); (I) binding in the presence of unlabeled Amino-Phe-angiotensin II (0.1 nM); (J) binding in the presence of unlabeled Sar-Ala-angiotensin II (0.1 nM). In FIGS. 2A-2J, dark regions indicate high densities of labeled receptors.
FIGS. 3A-3B: Effect of angiotensin II and an AT, receptor ligand on angiotensin II-induced myometrial cell proliferation. (A) Effect of angiotensin II on myometrial cell proliferation; (B) effect of AT 1 receptor ligand DuP753 on angiotensin II-induced myometrial cell proliferation.
FIG. 4: Effect of an ACE inhibitor on cell proliferation.
FIG. 5: Effect of an AT receptor antagonist on angiotensin II-mediated cell growth.
DETAILED DESCRIPTION OF THE INVENTION
The present invention will now be described in further detail.
Materials and Methods
Materials
[ 125 I]Angiotensin II (2200 Ci/mmol) was purchased from Amersham International Plc (Amersham, Berks U.K.). Angiotensin II, saralasin and other reagents unless otherwise specified were purchased from Sigma Chemical Co. (Poole, Dorset, U.K.). Basic fibroblast growth factor (bFGF) was purchased from RD Systems (Minneapolis, U.S.A). Losartan (DuP753; (2-n-butyl-4-chloro-5-hydroxymethyl-1-[2-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole) and PD123177 (1-(4-amino-3-methylphenyl)-methyl-5-diphenyl-acetyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-C]pyridine-6-carboxylic acid) were from DuPont Merck Pharmaceuticals and kindly provided by Dr. N. M. Barnes, University of Birmingham. Components for the culture medium were obtained from Flow Laboratories (High Wycombe, Berks., U.K.).
Source of Tissue
Myometrium was collected from women undergoing total abdominal hysterectomy. Patients selected had no apparent endocrinological problems and no local organic pathologies. All tissues were obtained from 20-48 year old women with a history of regular menstrual cycles. None of the patients had taken any hormonal medication for at least 3 months before the surgery. The tissue was rinsed in sterile saline and rapidly frozen over dry-ice, wrapped in Parafilm to prevent dehydration and stored at -70° C. until they were sectioned for receptor autoradiographic studies.
Preparation of Tissue Sections
Frozen myometrium and fibroid tissues were surrounded in embedding medium (OCT compound, Miles Scientific) before 20 μm sections were cut using a cryostat (-15 to -1 9° C.) and thaw mounted onto gelatin-coated glass slides for receptor autoradiographic studies. Sections were stored (less than 2 week) desiccated at -80° C. until used.
Myometrial Cell Preparation
Tissue samples were placed into sterile calcium and magnesium-free HBSS containing penicillin (100 U/ml) and streptomycin (100 μg/ml) for transfer to the laboratory. Myometrial cells were isolated by collagenase digestion. Briefly, myometrium was finely chopped and incubated in HBSS containing 1 mg/ml collagenase IA, 20 mM Hepes, 100 U/L penicillin, 100 μg/ml streptomycin and 5 μg/ml fungizone at 37° C. until the cells were dispersed. Myometrial cells were obtained by centrifugation for 15 minutes at 400 g over 60% Percoll and the cells washed with HBSS. Myometrial cells were characterised by their ability to respond to oxytocin and staining for actin.
[ 125 I]Angiotensin II Autoradiography
Slide mounted human myometrial/fibroid sections were removed from storage and allowed approximately 30 min to equilibrate to room temperature. To reduce endogenous levels of angiotensin II in the tissue, the sections were preincubated for 60 min in incubation buffer (mM; sodium chloride, 150; sodium dihydrogen phosphate, 50; magnesium chloride, 10; ethyleneglycol-bis-(β-amino-ethyl ether)-N,N'-tetra-acetic acid, 5 and 0.4% w/v bovine serum albumin, pH 7.4) at 25° C. The slides were then incubated in incubation buffer which contained 0.1 nM [ 125 I ]angiotensin II in the absence (total binding) or presence of competing compound (either 1.0 μm unlabelled angiotensin II, 1.0 μM DuP753, 1.0 μm PD123177 or 1.0 μm DuP753 plus 1.0 μm PD123177) for 60 min at 25° C. Immediately following incubation, the tissue sections were washed in ice-cold incubation buffer for 2 min and dipped (1 s) in ice-cold distilled water to remove buffer salts. The sections were rapidly dried in a stream of cold dry air and exposed to Hyperfilm-[ 3 H] (Amersham International) in X-ray cassettes together with [ 125 I] standards (Amersham International) for 10 days. Autoradiographic films were developed in Kodak LX 24 developer (5 min) and Kodak Unifix (5 min) and were quantitated by reference to [ 125 I] standards (fmol/mg tissue; Amersham) using image analysis.
Cell Culture and Cell Proliferation Studies
Cells were maintained in 175 cm 2 flasks in Dulbecco's modified Eagle's medium (DMEM) containing 10% (v/v) fetal calf serum (FCS), 1% L-glutamine, 20 mM Hepes and 1% antibiotic-antimycotic mixture (10,000 U penicillin, 10 μg streptomycin, and 25 μg ml -1 fungizone) at 37° C. in a humidified atmosphere of air/CO 2 (19:1) until 95% confluent. Thereafter, the cells were trypsinised, washed and re-plated at a density of 10×10 3 cells per well in 24-well plates in 1 ml of DMEM with 10% FCS for the proliferation studies. After 24 hrs, the medium was removed and replaced with serum-free DMEM. After a further 24 hrs, the experiments were initiated on quiescent monolayers of myometrial cells. To the serum-starved myometrial cells was added either angiotensin II (0.1 μm or 1.0 μm) in the presence or absence of 1% FCS or bFGF (20 ng/ml) or FCS (1%) alone or DuP753 with or without angiotensin II (0.1 μM) and cell growth measured at day 4 and day 6 by counting cell numbers in a Coulter counter as described below. The corresponding medium was replaced every 24 hrs with fresh medium.
Calibration of the Coulter Counter
Calibration of the Coulter counter was achieved by counting the myometrium cell suspension at reduced aperture size ranging from 0 to 32. A calibration curve was constructed from the cell counts on the function of the aperture size, and the aperture size corresponding to the middle point of the plateau part of the calibration curve was used for the cell counting. The aperture size used for myometrium cell counting was 16.
Counting of the Myometrium Cells
At defined time-points, the growth media was removed and the cells were washed with 1 ml of isotonic saline (0.9% sodium chloride), followed by the addition of 1 ml of 10 mM HEPES buffer containing 1.5 mM magnesium chloride, and 2 drops of Zap-oglobin (Coulter Electronics Ltd., Luton, Beds., UK) containing 2.5% acetic acid to each well. The 24-well plate was allowed to incubate at 37° C. for 10 min. After which, the suspended cells were pipetted up and down to disperse the cell clusters. The cell suspension was then added to 9 ml of counting solution containing 0.9% sodium chloride and 0.5% formalin in a Coulter counter container. Each well was washed three times with the counting solution from the same container and effluent collected in the same container. The number of cells in each well was counted at the aperture size of 16 on the Coulter counter (Coulter Electronics Ltd., Luton, Beds U.K.). Three readings were taken for each well and a mean value of the three readings obtained. The mean (±SD) value of cell counts from the triplicate wells was calculated.
Results and Discussion
Expression of Angiotensin II Receptor Subtypes
With the development of non-peptide angiotensin II receptor (AT) antagonists, attention has focused on the AT receptor as a target to pharmacologically manipulate the renin-angiotensin system. Using quantitative receptor autoradiography, we have pharmacologically characterised the presence of AT 2 receptors on non-pregnant myometrium and fibroids (FIG. 1). Dark regions indicate high density of labelled receptors. It is clear from the FIG. 1 that the fibroid region contains a higher density of angiotensin II receptors than normal myometrium. FIG. 1(A) to 1(E) are autoradiograms of the distribution of [ 125 I]angiotensin II binding to adjacent sections (20 μm) of the human non-pregnant myometrium containing a fibroid. In FIG. 1(A), total binding of such labelled angiotensin II is illustrated. FIG. 1(B) shows binding in the presence of the AT 1 receptor selective ligand DuP753 (1.0 μm). FIG. 1(C) shows binding in the presence of the AT 2 receptor selective ligand PD123177 (1.0 μm). FIG. 1(D) shows binding in the presence of DuP753 (1.0 μM) plus PD123177 (1.0 μM). FIG. 1(E) shows binding in the presence of unlabelled angiotensin II (0.1 nM). Dark regions indicate high densities of labelled receptors. The difference in density between FIGS. 1(A) and 1(B) represents AT 1 receptor specific binding. This receptor subtype is weakly expressed in myometrium. The difference in density between FIGS. 1(A) and 1(C) represents AT 2 receptor specific binding. The fibroid region in FIG. 1(C) shows a lower AT receptor expression than the same region in FIG. 1(B), thus indicating that the fibroid has predominantly AT 2 type receptors. The fibroid had a higher density of angiotensin II receptors than normal myometrium. The difference between FIG. 1(A) and 1(D) represents specific AT 1 plus AT 2 receptor-density, and the difference between FIG. 1(D) and 1(E) represents a newly discovered, non-AT 1 /non-AT 2 angiotensin II recognition site. The intensity of expression of such non-AT 1 /non-AT 2 angiotensin II recognition site in the fibroid tissue only disappears in the presence of cold angiotensin II (1 μM), thus indicating that this is an additional high affinity angiotensin II recognition site. This newly discovered site is pharmacologically distinct from known AT receptor subtypes, and Sar-Thr-angiotensin II and Sar-Ala-angiotensin II can selectively displace [ 125 I]angiotensin II from this site (FIG. 2).
Angiotensin II-induced Myometrial Cell Proliferation
The results of growth experiments are given in attached FIG. 3(A) and 3(B) which are graphs plotting mean cell count against time in days. It will be seen from FIG. 3(A) that the presence of angiotensin II (0.1 μM) in culture medium has a significant effect on myometrial cell growth and that after six days in culture there is approximately a 100% increase in myometrial cell proliferation compared to cells in culture medium devoid of angiotensin II. It is also interesting to note that the angiotensin II-induced response is comparable to that induced by a classic growth factor such as bFGF (Table 1).
TABLE 1______________________________________ Days 0 day (+/-SD) 4 days (+/-SD) 6 days (+/-SD)______________________________________Control (1% FCS) 65.83 +/- 1.52 127.00 +/- 12.53 146.33 +/- 16.22 Ag II (0.1 μM 64.33 +/- 2.73 167.33 +/- 21.55 333.67 +/- 7.51 in 1% FCS) bFGF (20 ng/ml 63.90 +/- 1.88 167.33 +/- 25.11 307.33 +/- 49.69 in 1% FCS)______________________________________
In addition, angiotensin II receptor antagonists blocked the effect of angiotensin II on cell proliferation. It can be seen in FIG. 3(B) as an example that DuP753 inhibits the effects of angiotensin II on cell proliferation. Preliminary data also shows that PD177123 also inhibits angiotensin II-mediated cell growth. Consequently, it is reasonable to infer that reduction of the level of angiotensin II or blocking of the high affinity angiotensin II binding sites in the fibroid will lead to a reduction in, or inhibition of, fibroid growth.
Patient Treatment Regimes
The invention proposes to treat patients in one of the following ways:
(1) By oral administration of the drug and this may be the preferred method of treatment.
(2) intravaginal administration using a vaginal ring
(3) adding drug via a intrauterine device
(4) directly at the site of the tumour using an ultrasound directed local injection into the fibroid (as some of these compounds are water soluble, they could be placed in an oil-based solution and then injected so as to give slow release of the active drug).
(5) as a pellet inserted directly at the site of the tumour using the long-acting near-zero order releasing system with the aid of laproscopy.
As discussed above, FIGS. 1A-1E are different autoradiograms of the distribution of [ 125 I]-angiotensin II binding to adjacent sections (20 μm) of the human non-pregnant myometrium containing a fibroid. The difference in density between (A) and (B) represents AT 1 receptor specific binding (this receptor subtype is not detected in myometrium); difference in density between (A) and (C) represents AT 2 receptor specific binding; difference between (A) and (D) represents specific AT 1 plus AT 2 receptor density and the difference between (D) and (E) represents the newly discovered, non-AT 1 /non AT 2 angiotensin II recognition site. Note the intensity of expression of such non-AT 1 /non-AT 2 angiotensin II recognition site in the fibroid tissue which only disappears in the presence of cold angiotensin II suggesting that the fibroid expresses high levels of the binding site.
As discussed above, FIGS. 2A-2J are different autoradiograms of the distribution of [ 125 I]angiotensin II binding to adjacent sections (20 μm) of the human non-pregnant myometrium (Myo) and fibroid (Fib).
As discussed above, FIG. 3(A) illutrates the effect of angiotensin II on myometrial cell proliferation. Myometrium cells were maintained in Dulbecco's modified Eagle's medium (MD) with 10% (v/v) FCS, containing 1% L-glutamine, 20 mM HEPES and 1% antibiotic-antimycotic mixture (10,000 U penicillin, 10 mg streptomycin) at 37° C. in a humidified atmosphere of air/CO 2 (19:1) until 95% confluent. For the proliferation studies, the cells were plated at a density of 10×10 3 cells per well in 24 well plates in 1 ml of DMEM with 10% FCS. After 24 hrs the medium was removed and replaced with serum-free DMEM. After a further 24 hrs, the experiment was initiated on quiescent monolayers of myometrial cells. To each of the wells in triplicate was added 1 ml of angiotensin II (0.1 μM) or DMEM alone, in the presence or absence of 1% FCS. The cell growth was measured at day 4 and day 6 by counting cell numbers in a Coulter Counter. Each point represents the mean ± sem of triplicate determinations from a single experiment, typical of three others.
As discussed above, FIG. 3(B) illustrates the effect of AT 1 receptor ligand (DuP753) on angiotensin II-induced myometrial cell proliferation.
Myometrium cells were maintained in Dulbecco's modified Eagle's medium (MD) with 10% (v/v) FCS, containing 1% L-glutamine, 20 mM HEPES and 1% antibiotic-antimycotic mixture (10,000 U penicillin, 10 mg streptomycin) at 37° C. in a humidified atmosphere of air/CO 2 (19:1) until 95% confluent. For the proliferation studies, the cells were plated at a density of 10×10 3 cells per well in 24 well plates in 1 ml of DMEM with 10% FCS. After 24 hrs the medium was removed and replaced with serum-free DMEM. After a further 24 hrs, the experiment was initiated on quiescent monolayers of myometrial cells. To each of the wells, in triplicate, was added 1 ml of 1% FCS as control or angiotensin II (0.1 μM), or DuP753 (1 μM) or DuP753 plus angiotensin II (0.1 μM) in the presence of 1% FCS. The cell growth was measured at day 4 and day 6 by counting cell numbers in a Coulter Counter. Each point represents the mean ± sem of triplicate determinations from a single experiment, typical of three others.
A further series of experiments were conducted as described below:
Immunocytochemistry
Serial 3 μm sections of formalin-fixed, paraffin-embedded tissue were used for immunohistochemistry. Sections were de-paraffinized by incubation for 5 min with Histoclear and hydrated through methanol to water. Endogenous peroxidase activity was quenched by 0.3% (v/v) hydrogen peroxide in methanol for 10 minutes. The primary antibodies were rabbit polyclonal antibodies raised against the human renin, angiotensin converting enzyme, ANG1, ANG II and AT 1 receptor. Non-immune goat serum (10% in 0.01 mol/l PBS, pH 7.2) was used as a dilution of the primary antibody to reduce non-specific binding. Amplification of the primary antibody reaction was achieved using a goat anti-rabbit secondary antibody (diluted 1:200 in 0.01 mol/l PBS, pH 7.2) for 30 min followed by a complex of streptavidin (Dako Ltd, Bucks, UK) and biotinylated peroxidase (Dako Ltd, Bucks, UK). Finally, the binding was visualised by the addition of 0.5 mg/ml diaminobenzidine (Sigma Chemical Co. Ltd, Poole, Dorset, UK) and 0.01% hydrogen peroxide in 0.01 mmol/l PBS to the antigen-antibody complex. Between each step the sections were washed in 3×200 ml of 0.1% (v/v) polyoxylene-10-oleoyl-ether in 0.01 mmol/l PBS, pH 7.2, over a period of 15 min. All incubations of antisera were carried out at room temperature in a wet chamber mounted on a rocking tray which ensures a movement of antiserum over the whole section. The sections were counterstained with Mayers Haematoxylin, dehydrated and mounted.
Results
Using the immunocytochemistry described above, the primary antibodies raised against renin, angiotensin converting enzyme, angiotensin I and angiotensin II were used to show that the components of the renin-angiotensin system (RAS) are expressed in myometrium and fibroids. This suggests that there is local RAS within the tissue itself, further supporting the functional studies. In addition, immunoreactive AT 1 receptor protein was localised in myometrial smooth muscle cells and around the blood vessels, indicating that myometrium and fibroid tissues contain AT 1 receptors in addition to AT 2 receptors which were clearly identified using autoradiography results. Evidence also indicates that there is intense vascularization around the uterine fibroid and also within the fibroids as QBN10 (a marker of endothelial cells) intense endothelial cell staining in immunohistochemical sections.
Cell Culture and Measurement of [ 3 H]-thymidine Incorporation
Myometrial cells prepared as described previously were resuspended in culture medium containing DMEM supplemented with 10% (v/v) FCS, 10 mM L-glutamine, 20 mM hepes, 100 U/mi penicillin and 100/μg/ml streptomycin in 24 well plates at a density of approximately 250×10 3 cells per well and maintained at 37° C. in a humidified atmosphere of air/CO 2 (19:1).
DNA synthesis was assayed by measuring [ 3 H]-thymidine incorporation into DNA. Subconfluent myometrial cells were made quiescent by incubation with serum-free medium for 48 h, the medium being replaced with serum-free medium containing 0.2% (w/v) bovine serum albumin (BSA) and [ 3 H]-thymidine (0.2 μCi/well). The cells were further incubated for 48 h in the presence of angiotensin-converting enzyme (ACE) inhibitor (0.1 and 1.0 mM Captopril, hatched and solid columns respectively) or angiotensin II (100 nM AgII, crossed column). The medium was then removed and the cells incubated with 10% cold trichloroacetic acid TCA) at 4° C. for 15 min. TCA-precipitated material was redissolved in 0.2 M NaOH and the radioactivity determined by liquid scintillation counting in a β-scintillation analyser. Positive and negative controls for proliferation were established by incubating cells with 10% fetal calf serum (square column) and by growth in the absence of the agonist in serum-free medium (open column).
Results
As shown in FIG. 4, DNA synthesis was reduced by almost 50% of control (open column--0% FCS) in the presence of ACE inhibitor. This suggests that myometrial cells have the capacity to generate endogenous angiotensin II which promotes myometrial cell growth. Use of ACE inhibitors will reduce the ability of these cells to proliferate.
In another series of experiments, using the procedures described above in relation to FIGS. 3A and 3B, the results as shown in FIG. 4B were obtained. As FIG. 5 shows, angiotensin II-mediated cell proliferation is significantly inhibited when the cells are incubated with 1.00 μM of DuP753 or PD123177 or/and DuP753 plus PD123177. This suggests that in myometrial cells, angiotensin II stimulates cells proliferation via AT 1 or AT 2 receptor subtype.
Method of Treatment and Drug Administration
EXAMPLE
Treatment with Angiotensin Converting Enzyme Inhibitor Ramipril.
Start patient on 2.5 mg once daily for one week. Increase dose to 5 mg once daily for 12 weeks then increase dose to 10 mg for a further 12 weeks. Monitor size of fibroid and continue at this dose until fibroids fibroid/uterus reduces in size by 50%. Reduce dose to 5 mg once daily for as long as required. Drug may be orally administered. | 1a
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This invention was made with government support under CA 24872 and GM 31459 awarded by the National Institutes of Health. The government has certain rights in the invention.
BACKGROUND OF THE INVENTION
The invention herein describes a method of facilitating the entry of drugs into cells at pharmokinetically useful levels and also a method of targeting drugs to specific organelles within the cell. This lipid/drug conjugate targeting invention embodies an advance over other drug targeting methods because through this method, intracellular drug concentrations may reach levels which are orders of magnitude higher than those achieved otherwise. Furthermore, it refines the drug delivery process by allowing therapeutic agents to be directed to certain intracellular structures. This technology is appropriate for use with antiviral and antineoplastic drugs because it has been observed that both virally infected and neoplastic cells have an altered intracellular organelle morphology.
Numerous methods for enhancing the activity and specificity of antiviral and antineoplastic drug action have been proposed. In general, the desired result is to increase both the efficiency and specificity of the therapeutic agent. One method of achieving this result has been receptor targeting. This method involves linking the therapeutic agent to a ligand which has an affinity for a receptor expressed on the desired target cell. Treatment by this method results in the drug adhering to the target cell through the ligand receptor complex and exerting its therapeutic effects directly on the cell.
One drawback of receptor targeting lies in the finite number of receptors on target cells. It has been estimated that the maximum number of receptors on a cell is approximately one million (Darnell, Lodish and Baltimore, Molecular Cell Biology (1986)). Thus, there is a maximum binding of one million drug ligand complexes to any given cell. Furthermore, the maximum number of specific receptors is much lower, for example, for a specific steroid, there are between ten thousand and one hundred thousand. Id. Thus, attempts at receptor targeting wherein the drug is conjugated with a ligand specific for a single receptor type will result in a maximum binding of less than about one hundred thousand conjugates per cell.
In response to the deficiencies encountered with receptor targeting, investigators have looked for other methods of delivering therapeutic agents at concentrations higher than those achievable through the receptor targeting process. Experiments suggested that lipids have selective affinities for specific biological membranes.
The selective association of certain lipids with specific biological membranes provided a possible avenue of drug targeting. In light of this possibility, researchers have attempted to target drugs by conjugating them with cholesterol. Unfortunately, these attempts have met with disappointing results. Remy et al., 1962, J. Org. Chem. 27:2491-2500. Mukhergee, K. L., Heidelberger, C., 1962, Cancer Research 22:815-22. Brewster, M. E., et al., Improved delivery through biological membranes. XXXL: Solubilization and stabilization of an estradiol chemical delivery system by modified beta-cyclodextrins, J. Pharm. Sci. 77:981-985, have had some success with carrying estradiol to the brain using pyridinium salts as carriers.
Another attempt at cell targeting through the use of lipids was made by Rahman et al., 1982, Life Sci. 31:2061-71. These investigators found that liposomes which contained galactolipid as part of the lipid appeared to have a higher affinity for parenchymal cells than liposomes which lacked galactolipid. These researchers suggested that this finding might have utility in drug targeting.
An additional challenge in designing an appropriate drug delivery scheme is to include within the drug conjugate a functionality which could either accelerate or reduce the rate at which the drug is released upon arrival at the desired site. Such a functionality would be especially valuable if it allowed differential rates of drug release.
BRIEF SUMMARY OF THE INVENTION
The present invention is directed to an improved method for drug delivery. This drug delivery system achieves site specific drug delivery through conjugating the drug with a lipid carrier. This invention also has the specific advantage of facilitating the entry of drugs into cells via a lipid carrier, allowing intracellular drug concentrations to attain levels higher than the levels achievable by other methods. As disclosed herein, the invention comprehends a lipid drug conjugate wherein the lipid will selectively associate with certain biological membranes, and facilitate intracellular drug localization. The lipid may be conjugated to the drug through use of a spacer, which may act to release the drug from the lipid, target the conjugate to the cell, incorporate the drug into a viral envelope, or perform other functions to maximize the effectiveness of the drug.
This type of conjugate has numerous advantages. First, this invention will allow the entry of drugs into cells at a pharmokinetical rate not currently possible with many potentially useful antiviral and antineoplastic drugs. Second, in comparison to receptor specific drug targeting this method will not require specific receptors. Third, it is believed that a therapeutic ratio between normal and either virally infected or neoplastic cells will be obtained as a result of greater cell sensitivity due to the presence of already compromised organelles, such as the golgi. Fourth, in contrast to tradional attempts to target drugs to specific cells, this method may target drugs to intracellular compartments and organelles. Fifth, these compounds may be incorporated into the viral envelope directly modifying its lipid composition, which could influence infectivity. Sixth, this invention incorporates a spacer region which can be varied and may allow a pharmacologically relevant rate of drug release from lipids.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 depicts the synthetic scheme put forth in Example 1.
FIG. 2 depicts the synthetic scheme put forth in Example 2.
FIG. 3 depicts the synthetic scheme put forth in Example 3.
FIG. 4 depicts the synthetic scheme put forth in Example 4.
FIG. 5 depicts the synthetic scheme put forth in Example 5.
FIG. 6 depicts the synthetic scheme put forth in Example 6.
FIG. 7 depicts the synthetic scheme put forth in Example 7.
FIG. 8 depicts the synthetic scheme put forth in Example 8.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention provides a method for facilitating drug entry into cells and for delivering drugs selectively to intracellular organelles. This is achieved by conjugating the desired therapeutic agent to a lipid carrier and administering this conjugate by standard techniques, including topical application.
The activity of these conjugates can be further refined by attaching the lipid carrier to a therapeutic agent through a spacer group having a first and a second end. Specifically, this is achieved through first linking the lipid to the first end of the spacer group through a linker functional group. In such a case, the therapeutic agent is then bound to a second end of the spacer group through a second linker functional group. This lipid/spacer/drug conjugate will provide enhanced flexibility and versatility in targeting drug delivery and in facilitating drug release upon reaching the target site.
Experimentally, it was found that the distribution of fluorescent ceramide is markedly different in neoplastic and virally infected cell lines as compared to "normal" cells. The marked difference in the distribution of fluorescent ceramide suggests that the neoplastic and virally infected cells have compromised golgi. Cells with compromised golgi could be made more susceptible to inactivation by treating them with ceramide linked to therapeutic agents which would direct them within the cell to the golgi.
A drug, as used herein, will be defined as including, but not necessarily limited to any anti-viral, antineoplastic drug. For the purposes of this application, compound 8, as referred to herein, is defined as the HIV1 protease inhibitor identified as compound 8 in Dreyer, G. B., et. al., Inhibition of Human Immunodeficiency Virus 1 Protease Inhibitor In Vitro. Rational design of substrate analog inhibitors PNAS Vol. 86, pp. 9752-56, Dec. 1986.
A lipid carrier, as defined herein will be taken to mean any lipid having an affinity for, or capable of crossing, a biological membrane, including but not limited to ceramide, phophotidyl choline, phosphatidic acid, estrogen, ether lipids, sphingomyelin or other sphingolipids.
A linker functional group is defined as any functional group for covalently binding the lipid carrier or therapeutic agent to the spacer group. These groups can be designated either "weak" or "strong" based on the stability of the covalent bond which the linker functional group will form between the spacer and either the lipid carrier or the drug. The weak functionalities include, but are not limited to phosphoramide, phosphoester, carbonate, amide, carboxyl-phosphoryl anhydride, ester and thioester. The strong functionalities include, but are not limited to ether, thioether, amine, amide and ester. The use of a strong linker functional group between the spacer group and the drug will decrease the rate at which the drug will be released at the target site, whereas the use of a weak linker functional group between the spacer group and the drug may act to facilitate release of the drug at the target site. Enzymatic release is another possibility, however, the rate of release of the drug would not necessarily be correlated with bond strength.
A spacer group may be broadly defined as any chemical group designed to facilitate the attachment of the drug/lipid conjugates to a target cell and/or the release of the drug at the desired target site. Such spacers may, facilitate enzymatic release at certain intracellular sites. Some spacers may simply present an "unhindered inhibitor," still linked to the carrier-spacer conjugate, to a target enzyme. Spacer groups, as described herein, include, but are not limited to aminohexanoic acid, polyglycine, polyamides, polyethylenes, and short functionalized polymers having a carbon backbone which is one to about twelve carbon molecules in length. Throughout the description of the examples, it will be assumed that all intermediate compounds will be isolated using standard methods.
EXAMPLE 1
An antiviral compound consisting of sphingosine conjugated to compound 8. Sphingosine is reacted with 1,3 Bis(trimethylsilyl)urea as described in W. Verbloom et al., 1981, Synthesis 807 to give a trimethyl silyl derivative of sphingosine. The sphingosine derivative is then conjugated with compound 8 in which the terminal amine is covered by a tBoc protecting group in the presence of diethyl azodicarboxylate (DEAD) and triphenyl phosphine as described in Y. Kishimoto, (1975), Chemistry and Physics of Lipids, 15:33-36. The sphingosine/compound 8 conjugate is then reacted in the presence of pyridine hydrofluoride as described in Matsuura, S. et al., (1976): J. Chem. Soc.-Chem. Communications, pg. 451., to remove the tBoc protecting group, to give compound 8 covalently bound to sphingosine through an amide bond.
EXAMPLE 2
An antiviral compound consisting of ceramide conjugated to a first end of a polyglycine spacer through an ester linker functional group, wherein enzyme inhibitor compound 8 is conjugated through an amide linker functional group to a second end of the polyglycine spacer. Polyglycine, as used in this example, has both a carboxy terminus and an amino terminus, the amino terminus being protected by a t-Boc group. Polyglycine is conjugated through its carboxy terminus to ceramide forming an ester linkage, as described in Anderson et al., 1963, J. Chem. Soc.-Chem. Communications, 85:3039. The resulting compound is further conjugated through the amino terminus of the polyglycine residue. Compound 8 has a carboxy terminus and an amino terminus. In this example the amino terminus is protected by a t-Boc protecting group. The conjugation takes place between the amino terminus of the polyglycine and the carboxy terminus of the HIV-1 protease inhibitor. This reaction is carried out in the presence of DEAD and triphenyl phosphine according to the method of Y. Kishimoto, (1975), Chemistry and Physics of Lipids, 15:33-36. The amino terminus of the HIV-1 protease inhibitor residue is deprotected according to the method of Matsuura, S. et al, 1976, J. Chem. Soc.-Chem. Communications, pg. 451.
EXAMPLE 3
An antiviral compound consisting of ceramide conjugated to AZT-monophosphate. Ceramide is reacted with AZT-monophosphate in the presence of dicyclohexylcarbodiimide as described in Smith, M. and Khorana, G.(1958), J.A.C.S. 80:1141 to yield ceramide conjugated through a phosphodiester bond to AZT-monophosphate.
EXAMPLE 4
An antineoplastic compound wherein sphingosine is conjugated through a phosphodiester bond to 5-fluorodeoxyuridine. Sphingosine is reacted with 5-fluorodeoxyuridine in the presence of dichlorophenyl phosphate according to the method of Baer 1955, Can. J. Biochem. Phys. 34:288, to yield sphingosine conjugated to 5-fluorodeoxyuridine through a phosphodiester bond.
EXAMPLE 5
An antiviral compound wherein ceramide is first conjugated to a first end of an oligomer 3 hydroxy propanoic acid spacer through an ester functional group, and wherein AZT is conjugated to a second end of said polyester spacer through a phosphodiester bond. First a polyester spacer is obtained, having a carboxyl at a first end and a triphenylmethyl group esterified to a second end. This spacer is conjugated to ceramide at its first end through an ester functional linker group according to the method of Anderson et al., 1963, J.A.C.S., 85:3039. This compound is then conjugated through the second end of the spacer compound to AZT monophosphate by means of a phosphodiester bond according to the method of Baer 1955, Can. J. Biochem. Phys. 34:288. In this antiviral compound, the bond breakage between the spacer and the drug would be slow in the absence of a phosphohydrolase.
EXAMPLE 6
An antiviral compound wherein phosphatidic acid, phosphatidyl choline, phophatidyl glycerol or phosphatidyl ethanolamine is linked through a phosphoester linker functional group to AZT. Phosphatidic acid, phosphatidyl choline, phophatidyl glycerol or phosphatidyl ethanolamine is conjugated to azido deoxythymidine according to the method of Baer et al., 1955.
EXAMPLE 7
An antiviral compound wherein ceramide is conjugated through an ester functional group to a first end of a polyglycine spacer, and wherein AZT is conjugated through a phosphoester functional group to a second end of the polyglycine spacer. Ceramide is first conjugated through an ester functional group to a first end of a polyglycine spacer (as described in Example 2). The ceramide-polyglycine compound is then conjugated through a phosphoester bond to a second end of the polyglycine spacer to AZT monophosphate according to the method of Paul, R., and Anderson, G. W., 1960, J.A.C.S. 82:4596.
EXAMPLE 8
An antiviral compound wherein aminohexanoyl sphingosine is conjugated to AZT. Aminohexanoyl sphingosine is conjugated with AZT monophophoimidazole according to the method of Paul, R., and Anderson, G. W., 1960, J.A.C.S. 82:4596 to yield aminohexanoyl sphingosine conjugated to AZT through a phophoramide bond. | 1a
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CROSS-REFERENCE TO RELATED APPLICATIONS
Pursuant to 35 U.S.C. § 119(e), this application claims the benefit of U.S. Provisional Patent Application No. 60/127,459, entitled Heeling Apparatus and Method , filed Apr. 1, 1999, and named Roger R. Adams as inventor, which is hereby incorporated by reference for all purposes.
TECHNICAL FIELD OF THE INVENTION
This invention relates in general to the field of footwear and active sports and more particularly to a heeling apparatus and method.
BACKGROUND OF THE INVENTION
Action or extreme sports include various sports such as, for example, skateboarding, snow boarding, in-line skating, rock climbing, and skydiving. Most action or extreme sports require expensive and cumbersome equipment that can only be used in select and, often, limited areas. Because these select and limited areas are not convenient to most people, these activities can only be enjoyed at select times. This results in a substantial investment in equipment that is only used sporadically, when large blocks of time are available to travel to such select and limited areas available for the activity. Because of these limitations and inconveniences, many times interest in the activity wanes.
SUMMARY OF THE INVENTION
The present invention presents the rare opportunity to create an entirely new sport and activity with mass appeal that does not suffer from the disadvantages, limitations, and problems mentioned above. From the foregoing it may be appreciated that a need has arisen for a heeling apparatus and related methods to create the foundation for a new action or extreme sport that can be pursued in many locations and conditions without the need for a large investment in equipment.
According to one aspect of the present invention, a heeling apparatus is provided that includes a footwear having an opening in a sole, such as the heel portion of the sole, to receive a wheel assembly, and a wheel assembly positioned in the opening of the sole of the footwear. The wheel assembly may include an axle, a wheel mounted on the axle, and a mounting structure operable to support the axle. In alternative embodiments, the wheel assembly includes only the wheel mounted on the axle without the need for the mounting structure. In other embodiments, the mounting structure is integrated or included as part of the opening in the sole of the footwear.
According to another aspect of the present invention a wheel/axle assembly for use in a wheel assembly of a heeling apparatus is provided that includes a wheel, a first bearing, a second bearing, and an axle. The wheel has an axle opening, a first annular recess on a first side of the wheel that surrounds the axle opening on the first side, and a second annular recess on a second side of the wheel that surrounds the axle opening on the second side. The first bearing is positioned in the first annular recess on the first side of the wheel, and the second bearing is positioned in the second annular recess on the second side of the wheel. The axle is positioned within the axle opening of the wheel such that the wheel is rotatably coupled to the axle through the first bearing and the second bearing.
According to yet another aspect of the present invention, a method for using a heeling apparatus on a surface is provided that includes running on a surface by using a forefoot portion of a sole of the heeling apparatus to contact the surface, and rolling on the surface with a wheel of the heeling apparatus extended below the bottom of the sole through an opening in the sole by using a wheel of the heeling apparatus to contact the surface.
According to a still further aspect of the present invention, a method for making a heeling apparatus is provided that includes providing a footwear that includes a sole, forming an opening in the sole of the footwear that extends to a bottom surface of the sole, and positioning a wheel assembly in the opening of the sole of the footwear.
The present invention provides a profusion of technical advantages that include the capability of the heeling apparatus to function as normal, comfortable footwear for walking, and even running, and to function as rolling footwear, which may be referred to only herein as “heeling.”
Another technical advantage of the present invention includes the capability to implement the invention using virtually any available footwear such as, for example, conventional shoes, boots, dress shoes, loafers, sandals, slippers, bindings, and the like. Conventional footwear may be incorporated into a heeling apparatus by, preferably, forming or cutting an opening in the heel portion of the sole of such conventional footwear. Thus, the present invention may be implemented using conventional footwear that appears externally, during normal use, as conventional footwear. This allows the present invention to be practiced as a “stealth” or “covert” activity because, from external appearances, it is being performed using conventional footwear. In a preferred embodiment of the present invention, the sole of conventional athletic shoes may be used in the present invention without the need to design awkward looking thick soled shoes to house the wheel.
A further technical advantage of the present invention includes the capability to implement the present invention with other active sport accessories such as in a grind show, such as the grind show made by SOAP, which also provides grinding or sliding functionality.
Yet another technical advantage includes the capability to use the present invention to enjoyably obtain an overall aerobic workout.
Still yet another technical advantage of the present invention includes the capability of enhanced control for turning and maneuvering, while still providing durability, reliability, and mechanical strength. The present invention provides this durability and reliability in harsh environments and with heavy and demanding use, including the capability to withstand the forces of jumps, spins and maneuvers of all kinds.
Another technical advantage includes capability of removable wheels and axles so that bearings may be easily changed and maintained and so that different types of wheels, bearings, and axles may be used as desired by the user and as dictated by the conditions.
In yet a further technical advantage of the present invention includes a wheel/axle assembly that can be easily inserted or removed from a wheel assembly or mounting structure, such as by using a friction fit. In other embodiments, the wheel assembly, or heeling apparatus, includes the capability of a retractable wheel. This allows a user to quickly and conveniently convert from using the heeling apparatus as normal footwear into using the heeling apparatus for “heeling.” The wheel is moved from a retracted position in the sole or heel of the heeling apparatus to an extended position where at least a portion of the wheel is exposed below the sole for rolling. The retractable wheel may be implemented using any number of designs and/or configurations such as a king pin arrangement, a dual position arrangement using a collapsible axle, a hinged arrangement, or even a spring arrangement.
Other technical advantages are readily apparent to one skilled in the art from the following figures, description, and claims.
BRIEF DESCRIPTION OF THE DRAWINGS
For a more complete understanding of the present invention and the advantages thereof, reference is now made to the following brief description, taken in connection with the accompanying drawings and detailed description, wherein like reference numerals represent like parts, in which:
FIG. 1 is a side view that illustrates a heeling apparatus implemented using an athletic shoe according to one embodiment of the present invention;
FIGS. 2A and 2B are bottom views that illustrate two embodiments of a sole of the heeling apparatus with openings in the sole;
FIGS. 3A and 3B are bottom views of the two embodiments of the sole as shown in FIGS. 2A and 2B and illustrate a wheel in each of the openings of the soles;
FIG. 4 is a perspective view that illustrates a wheel rotatably mounted to an axle, which also may be referred to as a wheel/axle assembly, for use in a wheel assembly according to one embodiment of the present invention;
FIG. 5 is a perspective view that illustrates a mounting structure for use with a wheel rotatably mounted to an axle, as illustrated in FIG. 4, to form a wheel assembly;
FIG. 6 is a bottom view that illustrates a wheel assembly that includes the wheel rotatably mounted on the axle as shown in FIG. 4 and the mounting structure of FIG. 5;
FIG. 7 is a side view that illustrates the wheel assembly positioned above and through the opening in a footwear to form a heeling apparatus;
FIGS. 8A, 8 B, 8 C, and 8 D are profile views of various wheels that illustrate the surface profile of these wheels that may used in various embodiments of the present invention;
FIG. 9 is a perspective view that illustrates a mounting structure of another embodiment for use in a wheel assembly of a heeling apparatus;
FIG. 10 is a perspective view that illustrates a wheel assembly that uses yet another embodiment for use in a heeling apparatus;
FIG. 11 is a side, partial cutaway view that illustrates one embodiment of a heeling apparatus that illustrates the wheel assembly provided in the sole of the heeling apparatus and the opening in the sole not extending completely through the sole;
FIG. 12 is a side view of another embodiment that illustrates the heeling apparatus of the present invention with a removable wheel cover positioned to cover the wheel and the opening in the sole;
FIG. 13 is a bottom view that illustrates another embodiment of the present invention with a spherical ball serving as a wheel and positioned in a mounting structure in an opening in the heel portion of the sole;
FIG. 14 is a perspective view that illustrates a “heeler” using the present invention to “heel”;
FIG. 15 is a perspective view that illustrates a wheel rotatably mounted to an axle, which also may be referred to as a wheel/axle assembly, similar to FIG. 4;
FIG. 16 is a cutaway view that illustrates a collapsible axle of the wheel/axle assembly of FIG. 15 implemented as a spring loaded collapsible axle;
FIG. 17 is a perspective view that illustrates another mounting structure for use with the wheel/axle assembly and the collapsible axle, as illustrated in FIG. 15 and FIG. 16, to form a wheel assembly;
FIG. 18 is a side, cutaway view that illustrates a wheel assembly positioned through an opening in a sole that illustrates one embodiment of an axle that couples to the mounting structure to provide a retractable wheel using an assembly that may be referred to as a king pin arrangement;
FIG. 19 is a bottom view that illustrates the wheel assembly of FIG. 18 that further illustrates the dual king pin arrangement;
FIG. 20 is a side view that illustrates one member of the mounting structure that further illustrates the coupling of the axle to the mounting structure using the dual king pin arrangement; and
FIG. 21 is a breakaway and perspective view that illustrates a two piece wheel that includes an inner core and an outer tire and that may be used in the present invention.
DETAILED DESCRIPTION OF THE INVENTION
It should be understood at the outset that although an exemplary implementation of the present invention is illustrated below, the present invention may be implemented using any number of techniques, materials, designs, and configurations whether currently known or in existence. The present invention should in no way be limited to the exemplary implementations, drawings, and techniques illustrated below, including the exemplary designs and implementations illustrated and described herein.
It should be understood at the outset that although exemplary implementations of the present invention are illustrated below, the present invention may be implemented using any number of mechanisms, arrangements, structures, and/or techniques. Thus, the present invention should in no way be construed to be limited to the exemplary implementations, drawings, and techniques illustrated and described herein.
FIG. 1 is a side view of a heeling apparatus 10 implemented using an athletic shoe 12 according to one embodiment of the present invention. The heeling apparatus 10 preferably includes a wheel assembly provided in an opening in the heel portion of the sole of a footwear. For example the athletic shoe 12 includes an opening in the bottom of a heel portion 18 of a sole 14 with a wheel assembly provided in the hole such that a wheel 16 extends below the bottom of the sole 14 . The wheel assembly preferably includes at least one wheel, such as the wheel 16 , rotatably mounted on an axle (not illustrated in FIG. 1 ). The wheel 16 mounted on the axle is preferably positioned in the opening of the sole 14 through a mounting structure (not illustrated in FIG. 1) that is operable to support the axle such that a portion of the wheel 16 extends below the heel portion 18 of the sole 14 .
The amount or length of the portion of the wheel 16 that extends below the bottom of the sole 14 , as defined by a distance 24 , will preferably be less than the diameter of the wheel 16 . The distance 24 , however, may be greater than, less than, or equal to the diameter of the wheel 16 .
The athletic shoe 12 , as is true of most footwear, may be generally described as having the sole 14 and an upper part 26 . The upper part 26 may be constructed of virtually any material such as, for example, leather, plastic, or canvas. The sole 14 may include three parts: ( 1 ) an inner sole or insole (not illustrated in FIG. 1 ); ( 2 ) a midsole 28 ; and ( 3 ) an outer sole or outsole 30 . The insole may provide added cushion and may or may not be removable. In some embodiments, the insole may include a removable portion, such as a DR. SCHOLL'S insole, and a portion that remains attached to the athletic shoe 12 . The outsole 30 will preferably be made of a durable material, such as rubber, and may have a textured surface, such as with knobbies, to provide added traction. The midsole 28 will generally be constructed of a soft or “cushiony” material and will generally be thicker than the insole and the outsole 30 . In some embodiments, however, the sole 14 will comprise only one part, such as the leather sole of a loafer. In other embodiments, the sole 14 may include a separate heel block or object that elevates the footwear, such as the heel of a leather wingtip dress shoe. This heel block or object may be considered to be part of the heel portion 18 of the sole 14 . It should be understood that the present invention may be implemented in virtually any footwear, irrespective of the design or the make-up of the sole 14 . Various styles of footwear and methods of making footwear are known in the art and are known by one of ordinary skill in the art. For example, U.S. Pat. Nos.: 4,245,406, 5,319,869, 5,384,973, 5,396,675, 5,572,804, 5,595,004, and 5,885,500, which are hereby incorporated by reference for all purposes, provide various background information regarding various footwear and methods of making footwear.
In most footwear, including the athletic shoe 12 , the sole 14 may also be divided into three portions or regions: ( 1 ) the heel portion 18 , ( 2 ) an arch portion 20 , and ( 3 ) a forefoot portion 22 , as illustrated in FIG. 1 . It should be understood that the heel portion 18 , the arch portion 20 , and the forefoot portion 22 of the sole 14 are incapable of being exactly defined and located, and that such portions vary from one footwear type to another. Thus, the location, the boundaries between, and the size of the heel portion 18 , the arch portion 20 , and the forefoot portion 22 of the sole 14 are only rough approximations.
It should also be understood that although the position of the opening in the bottom of the sole 14 , and hence also the wheel 16 , is preferably located in the heel portion 18 of the sole 14 , such an opening may also be located at the boundary of the heel portion 18 and the arch portion 20 , at the arch portion 20 , or at virtually any other location on the sole 14 . The opening in the bottom of the sole 14 may extend entirely through the sole 14 , e.g., through the outsole, the midsole and the insole, or only partially through the sole 14 , e.g., through the outsole, and a portion or all of the midsole.
The wheel 16 may be constructed or made of virtually any known or available material such as, for example, a urethane, a plastic, a polymer, a metal, an alloy, a wood, a rubber, a composite material, and the like. This may include, for example, aluminum, titanium, steel, and a resin. Preferably, the material will be durable, provide quiet performance, and will provide a “soft” or “cushioning” feel. In one embodiment, the wheel 16 may be implemented as one or more precision bearings such that the precision bearing serves as the wheel 16 itself. In yet another embodiment, the wheel assembly may include a spring or suspension such as, for example, a leaf spring, to provide additional cushion or suspension when the wheel 16 contacts a surface and a force is applied to the athletic shoe 12 in the direction of the surface, such as when a someone is wearing and walking in the heeling apparatus 10 . The spring is preferably provided as part of the mounting structure of the wheel assembly. In still another embodiment, the wheel 16 is provided as a two piece wheel with an inner core, such as a hard inner core, such as a hard inner core, surrounded by an outer tire, such as a urethane tire.
Depending on the desired implementation, the wheel 16 and the axle may be removable from the wheel assembly. In such a case, a removable cover may be provided in the opening in the sole 14 to cover the opening so that debris and dirt does not enter the opening. The removable cover may be provided in virtually any available configuration readily ascertainable by one of ordinary skill in the art. In one embodiment of the removable cover, an axle portion of the removable cover fits and/or couples to the mounting structure in the same or similar manner that the axle in which the wheel 16 is mounted fits and/or couples to the mounting structure of the wheel assembly. A tool may also be provided to facilitate the removal of the axle and wheel 16 . This tool will, preferably, be small and multifunctional to provide any other possible adjustments to the heeling apparatus 10 , such as a screw driver, a wrench, and the like. In other embodiments of the heeling apparatus 10 , the wheel 16 may be retractable into the opening in the sole 14 . In this manner, the wheel 16 may be retracted into the sole 14 and, thus, will not extend below the bottom of the sole 14 . This allows the heeling apparatus 10 to function just like ordinary footwear, such as the athletic shoe 12 .
In one embodiment of the present invention, the wheel assembly does not include an axle, and, arguably, not a mounting structure, and the wheel 16 is provided as a sphere, such as a stainless steel ball bearing, that is rotatably positioned in the opening in the bottom of the heel portion 18 of the sole 14 , one embodiment of which is shown in FIG. 13 . In another embodiment, the wheel assembly comprises an axle positioned completely through or partially through the heel portion 18 of the sole 14 such that the sole 14 supports the axle and the wheel is rotatably mounted on the axle in the opening of the sole 14 . In this manner, the need for the mounting structure is eliminated.
In operation, a person wearing the heeling apparatus 10 may either walk normally or roll on the wheel 16 by lifting or raising the sole 14 so that only or almost only the wheel 16 contacts a surface. This action may be referred to as “HEELING” or to “HEEL.” The wheel 16 , depending on the desired implementation of the present invention, may be removed or retracted to a position such that the wheel 16 does not extend below the bottom of the sole 14 . This, generally, will result in the heeling apparatus 10 performing like an associated footwear. When the wheel 16 is removed or retracted, a removable cover may be placed over the opening in the bottom of the sole 14 to prevent debris from entering the opening and potentially damaging the wheel assembly. In still other embodiments, a removable cover may be placed over the wheel 16 while a portion of the wheel 16 remains extended below the bottom of the sole 14 to assist with walking, an example of this is illustrated in FIG. 12 .
It should be understood, however, that even if the wheel 16 is not removed or retracted as just described, the user may still comfortably walk and run, even with the wheel 16 extended. This generally occurs because the distance 24 can be minimal, which provides a unique “stealth” or “covert” aspect to heeling. This also results in the wheel rolling the opening or hole in the sole 14 of the heeling apparatus 10 . In one embodiment, the distance 24 is less than the radius of the wheel 16 , which results in most of the wheel residing within the opening of the sole 14 .
FIGS. 2A and 2B are bottom views of two embodiments of the sole 14 of the heeling apparatus 10 . In particular, the outsole 30 or bottom of the sole 14 is illustrated in FIG. 2A with an opening 40 in the heel portion 18 of the sole 14 . In the embodiment illustrated, the opening 40 is provided in a square or rectangular configuration. The opening 40 , however, may be provided in virtually any configuration, such as, for example, a circular or an elliptical configuration.
As mentioned previously, the opening 40 may extend partially or completely through the sole 14 . The opening 40 may be provided through a heel block or object. Further, the opening 40 be positioned in, near, or in a combination of the heel portion 18 , the arch portion 20 , and the forefoot portion 22 .
FIG. 2B illustrates a second embodiment as to the placement and configuration of the opening 40 . The outsole 30 is illustrated with an opening 40 A and an opening 40 B in the heel portion 18 of the sole 14 . In this manner, one or more wheels, including one or more axles, may be positioned in both the opening 40 A and 40 B.
FIGS. 3A and 3B are bottom views of the two embodiments of the sole 14 as shown in FIGS. 2A and 2B and illustrate a wheel in each of the openings of the soles. This includes a wheel 42 positioned in the opening 40 in FIG. 3A and a wheel 42 A and a wheel 42 B in the openings 40 A and 40 B, respectively, of FIG. 3 B.
The wheel 42 and the wheels 42 A and 42 B are illustrated as cylindrical wheels. These wheels, however, may be provided in virtually any available configuration. Further, one or more wheels may be positioned in each opening.
FIG. 3A further illustrates other elements of the wheel assembly that include a first member 48 and a second member 54 of a mounting structure that is used to removably couple with an axle 50 . The axle 50 extends through the wheel 42 such that the wheel 42 is rotatably coupled or mounted to the axle 50 . This preferably involves the use of precision bearings, such as high performance precision bearings, provided in a recess, such as an annular recess, on either side of the wheel 42 . A first precision bearing 56 and a second precision bearing 58 may be ABEC grade precision bearings and are illustrated with hidden lines and positioned in the first recess and second recess of the wheel 42 . In alternative embodiment, loose ball bearings may be used.
The axle 50 may be made of any material that provides suitable physical characteristics, such as strength and weight, to name a few. The axle 50 is preferably made of hardened steel, is cylindrical in shape, each end is rounded, and is removably coupled with a first member 48 and a second member 54 , respectively, of the mounting structure. The removable coupling between each end of the axle 50 and the first member 48 and the second member 54 may be achieved by any known or available mechanism. In a preferred embodiment, a sphere or a ball bearing, preferably using a moveable spring and/or a screw bias, is used to contact and exert a side wall force between one or members of the mounting structure and the axle 50 .
It should also be noted that because the weight of the user of the heeling apparatus 10 will exert a significant downward force and the ground or surface will exert an equal force upward, the axle 50 , and, hence, the wheel 42 will generally be forced into place. Only when the heel is raised from a surface will any force or friction be required to keep the axle 50 in place. Thus, the present invention does not require a large side force to keep the axle 50 and the wheel 42 in place. The recognition of this fact may be considered an aspect of the present invention for the embodiment as showm. This recognition allows the removable coupling between each end of the axle 50 and the first member 48 and the second member 54 to be optimally designed.
FIG. 3A also illustrates a grind plate 44 (which also may be referred to as a slide plate 44 ) that may be used in conjunction with the heeling apparatus 10 of the present invention. The grind plate 44 provides a smooth or relatively smooth surface to allow a user to “grind” or “slide” on various surfaces such as hand rails, curbs, steps, corners, and the like. The grind plate 44 is preferably somewhat thin and made of a plastic or polymer material. In a preferred embodiment, the grind plate 44 is removably attached to the arch portion 20 of the outsole 30 of the sole 14 . The grind plate 44 may be attached using any known or available fastener, such as, for example, a fastener 46 shown in various locations around the periphery of the grind plate 44 .
FIG. 3B further illustrates an axle 52 in which the wheel 42 A and the wheel 42 B are coupled to either end in the opening 40 A and the opening 40 B, respectively. The axle 52 extends through both the wheels 42 A and 42 B and through a portion of sole 14 , not visible in FIG. 3 B. This serves to support the axle 52 and illustrates the situation where the sole 14 serves as the mounting structure of the wheel assembly. This reduces the overall number of parts. In an alternative embodiment, a metal or some other suitable material may be used within the heel portion 18 of the sole 14 where the axle 52 is positioned to provide additional support and stability. This is an example where the mounting structure is, in effect, integrated into the sole 14 . As can be appreciated by one skilled in the art, the present invention may be implemented in any number of ways.
FIG. 4 is a perspective view of a wheel 60 rotatably mounted on an axle 62 , which also may be referred to as a wheel/axle assembly, for use in a wheel assembly, or in a heeling apparatus, according to one embodiment of the present invention. The wheel 60 and the axle 62 may also be referred to as a wheel/axle assembly 400 . In this embodiment, the axle 62 extends through the wheel 60 and includes two ends that are rounded or bullet shaped. A precision bearing 64 is shown positioned in a recess, which is shown as an annular recess, of the wheel 60 to facilitate the rotation of the wheel 60 around the axle 62 . Preferably a second precision bearing is positioned in a second recess, not shown in FIG. 4, to further facilitate such rotation.
A slip clip, slip ring, or ring clip 66 is shown positioned around, or nearly around, the axle 62 near the precision bearing 64 . This serves to ensure that the precision bearing 64 remains in place in the recess of the wheel 60 . The slip clip or ring clip 66 will preferably be positioned on the axle 62 through a groove, such as a radial groove or radial indentation, in the axle 62 . It should be understood, however, that one of ordinary skill in the art may use any of a variety of other arrangements to ensure that the precision bearing 64 stays in position. In alternative embodiments, the precision bearing 64 may be eliminated or loose bearings may be used.
The wheel 60 rotatably mounted on the axle 62 may, in alternative embodiments, serve as the wheel assembly of the present invention. In such a case, the axle 62 may be mounted to the sole, such as the midsole and heel portion, at its ends while the wheel 60 is rotatably provided in the opening of the sole. In this manner, the need for a mounting structure may be thought of as eliminated or, alternatively, the mounting structure may be thought of as integrated into the sole of the footwear.
FIG. 5 is a perspective view of a mounting structure 70 for use with a wheel rotatably mounted to an axle, such as is illustrated in FIG. 4, to form a wheel assembly. The mounting structure 70 generally includes a heel control plate 72 , a first member 74 , and a second member 76 . In alternative embodiments, a spring, such as a leaf spring, could be provided where the two members contact the heel control plate 72 . This would provide the added benefit of greater cushion and suspension. The two members include an opening, such as the opening 78 of the first member 74 to receive an end of an axle. It should be mentioned that the opening may be provided in virtually any configuration, including extending through the member, or placed at different positions, or even multiple positions for mounting the wheel/axle assembly 400 at a retractable position and an extended position, on the member.
The axle that is to be positioned in the openings of the first member 74 and the second member 76 will preferably be removably coupled. This may be achieved by any number of arrangements and configurations, all of which fall within the scope of the present invention. One such arrangement is the screw/spring/ball bearing arrangement 80 provided in first member 74 . This arrangement provides an adjustable bias or force that can be exerted against the axle when it is inserted into the opening 78 . The screw is accessible and adjustable by the user. The turning of the screw affects the compression of a spring which, in turn, provides a force on a ball bearing that extends out into the opening 78 . When the axle is inserted into the opening 78 , the ball bearing may be displaced an amount and the screw/spring/ball bearing arrangement 80 will provide a side force to allow the axle to be secure, yet removable. A similar arrangement may also be provided in the second member 76 to provide a friction fit or coupling on the other end of the axle 62 .
Although the screw/spring/ball bearing arrangement 80 of FIG. 5 is shown being implemented through a horizontal opening in the first member 74 , it may be implemented in using an opening aligned in virtually in manner in the member. For example, the adjustment of the tension or pressure on the screw/spring/ball arrangement 80 may be achieved through a diagonal opening such that the exposed end of the screw/spring/ball arrangement 80 , normally a screw head end, is provided where the reference line for numeral 74 in FIG. 5 contacts the first member 74 . This provides easier access to adjust the tension and friction fit on the axle 62 when the wheel assembly, such as wheel assembly 100 of FIG. 6, is engaged or positioned within the opening of a sole to form a heeling apparatus. Of course, any of a variety of other arrangements, configurations, and opening alignments may be contemplated and implemented under the present invention.
The mounting structure 70 can be made or constructed of virtually any material, generally depending on the desired mechanical characteristics such as, for example, rigidity and strength. These materials may include, for example, a plastic, a polymer, a metal, an alloy, a wood, a rubber, a composite material, and the like. This may include aluminum, titanium, steel, and a resin. In one embodiment, the mounting structure 70 is made of a metal, such as aluminum, that has been anodized such that the mounting structure 70 presents a black color or hue.
FIG. 6 is a bottom view of a wheel assembly 100 that includes the wheel 60 rotatably mounted to the axle 62 , as shown in FIG. 4, and the mounting structure 70 of FIG. 5 . The first member 74 and the second member 76 each removably couple with the ends of the axle 62 through a bias mechanism implemented using a bias mechanism, such as the screw/spring/ball bearing arrangement 80 . A ball bearing 102 is shown contacting one end of the axle 62 in the opening 78 . Further slip clips or ring clips (which may also be referred to as snap rings or slip rings), such as ring clip 66 , are provided to ensure that the precision bearings positioned in the recesses of the wheel remain in position.
The heel control plate 72 allows the user of the heeling apparatus to gain greater control and to obtain greater performance out of the heeling apparatus.
FIG. 7 is a side view of the wheel assembly 100 positioned above and through the opening to form a heeling apparatus 120 . The heel control plate 72 resides inside the shoe so that the heel of the user may apply pressure to the heel control plate as desired to provide better handling and performance of the heeling apparatus 120 .
FIGS. 8A, 8 B, 8 C, and 8 D are profile views of various wheels 200 that illustrates the surface profile of these wheels that may used in various embodiments of the present invention. In FIG. 8A, a wheel 202 is shown with a flat or square surface or exterior profile 204 . In FIG. 8B, a wheel 206 is shown with an inverted surface profile 208 . In FIG. 8 c , a wheel 210 is shown with round surface profile 212 . Finally, in FIG. 8D, a wheel 214 is shown with a steep surface profile 216 . The present invention may incorporate virtually any available surface profile of a wheel.
FIG. 9 is a perspective view that illustrates a mounting structure 500 of another embodiment for use in a wheel assembly of a heeling apparatus. The mounting structure 500 includes an axle 502 , which may be considered one axle that extends through and is mounted through a member 50 or as an axle 502 that couples with the member 506 along with an axle 504 that couples with the member 506 opposite axle 502 . The mounting structure 500 also includes a heel control plate 508 coupled with the member 506 .
The mounting structure 500 allows for two wheels to be mounted to form a wheel assembly. A wheel may be rotatably mounted on the axle 502 , preferably using a precision bearing, and a wheel may be rotatably mounted on the axle 504 , also preferably through a precision bearing as illustrated previously herein.
The axle 502 and the axle 504 include a threaded portion such that a nut, such as a lock nut 510 may be included to secure a wheel to each axle. In other embodiments, the end of the axles may include internal threads, as opposed to external threads as shown, so that a screw, such as the hex screw as shown in FIG. 10 . It should be understood that virtually any available coupling may be provided between the axle and the member.
FIG. 10 is a perspective view that illustrates a wheel assembly 520 that uses yet another embodiment for use in a heeling apparatus and includes a wheel 522 rotatably mounted to an axle 524 using a precision bearing 526 , and a first member 528 and a second member 530 coupled to each end of the axle 524 through a screw, such as hex screw 532 . The wheel assembly 520 is similar to wheel assembly 100 , which was described above in connection with FIG. 6, except that the wheel/axle assembly cannot be as easily inserted and removed.
FIG. 11 is a side, partial cutaway view that illustrates one embodiment of a heeling apparatus 600 that illustrates a wheel assembly 602 provided in a sole 604 and an opening 606 in the sole 602 that does not extend completely through the sole 602 . As such, the mounting structure 608 may be provided or integrated into the sole 602 and may not be readily or easily removed. A wheel 610 is also shown extending partially below the bottom of the sole 602 , which provides the advantage of stealth heeling.
FIG. 12 is a side view of another embodiment that illustrates a heeling apparatus 620 of the present invention with a removable wheel cover 622 positioned to cover a wheel 624 and an opening 626 in a sole 628 . The removable wheel cover 622 allows for the wheel to be provided in an extended position, i.e., below the bottom surface of the sole 628 , yet not engage a surface to roll. Although the heeling apparatus 620 of the present invention allows a user to walk and run, even with the wheel in an engaged position, the removable wheel cover 622 provides protection from dirt and debris and provides greater stability.
In an alternative embodiment, a wheel stop, not expressly shown in FIG. 12, may be provided, in lieu of or in conjunction with the removable wheel cover 622 , to stop the rotation of the wheel 624 . In one embodiment, the wheel stop is made of virtually any material, such as a sponge or flexible material, that can be wedged between the wheel 624 and the opening 626 to stop or prevent the rotation of the wheel 624 and to stay in place through friction.
In other embodiments of the wheel cover 622 , a wheel cover is provided when the wheel 624 has been removed from the heeling apparatus 620 . In a preferred embodiment, this wheel cover is generally flush with the remainder of the bottom of the sole 608 , and, hence, provides the function of a regular shoe when desired and protects the opening. This wheel cover may couple in any available manner, but preferably will couple to the wheel assembly in the same or similar manner that the wheel/axle assembly couples to the mounting structure. The removable wheel cover could clip or attach to the wheel assembly in many different ways.
FIG. 13 is a bottom view that illustrates another embodiment of a heeling apparatus 700 with a spherical ball 702 serving as a wheel and positioned in a mounting structure 704 in an opening in the heel portion of the sole 706 .
FIG. 14 is a perspective view that illustrates a “heeler” 800 using the present invention to “heel.” Heeling can be achieved using various techniques and, generally, requires a skill set of balance, positioning, flexibility, and coordination.
An illustrative method for using a heeling apparatus on a surface may include running on a surface by using a forefoot portion of a sole of the heeling apparatus to contact the surface, and then rolling on the surface with a wheel of the heeling apparatus extended below the bottom of the sole through an opening in the sole by using a wheel of the heeling apparatus to contact the surface. Before running on a surface, the method may include walking on the surface while wearing the heeling apparatus with a wheel of the heeling apparatus extended below the bottom of a sole portion of the heeling apparatus before running on the surface. Heeling may also be performed on a hill or a surface that includes a decline.
The method of heeling may also include engaging the wheel of the heeling apparatus to extend below the bottom of the sole portion of the heeling apparatus before walking on the surface. The method may also include walking on the surface while wearing the heeling apparatus before engaging the wheel of the heeling apparatus and with the wheel of the heeling apparatus retracted. Other variations on the method may include transitioning from rolling on the surface to either running, walking, or stopping on the surface by running on the surface through using the forefoot portion of the sole of the heeling apparatus to contact the surface just after rolling on the surface.
The preferred position while heeling is illustrated by the heeler 800 in FIG. 14 where one heeling apparatus 802 is placed in front of the other heeling apparatus 804 while rolling on a surface. As can be seen from a back heel portion 806 of the heeling apparatus 804 , sometimes the clearance between the back heel portion 806 and the surface is small. As a result, in a preferred embodiment, the back heel portion 806 is made of a wear resistant material.
The method of heeling may also implement any number of techniques for slowing or stopping. For example, rolling may be slowed by contacting the forefoot portion of the sole of the heeling apparatus to contact the surface to create friction and to remove the wheel from the surface. Another example includes slowing by contacting a heel portion of the sole of the heeling apparatus to contact the surface.
FIG. 15 is a perspective view that illustrates a wheel 902 rotatably mounted to a collapsible axle 904 , which also may be referred to as a wheel/axle assembly 900 , similar to FIG. 4 . The collapsible axle 904 may be implemented in any number of ways, such as an adjustable axle that is spring loaded, similar to what is shown in FIG. 16, or as a screw collapsible axle. This allows the wheel/axle assembly 900 to be more easily removable and/or retractable to a position where the wheel would not engage the ground if the wheel/axle assembly 900 where implemented in a heeling apparatus.
FIG. 16 is a cutaway view that illustrates a collapsible axle 904 of the wheel/axle assembly 900 of FIG. 15 implemented as a spring loaded collapsible axle. As can be seen, the collapsible axle 904 may be adjusted or shortened by inwardly compressing both ends of the collapsible axle 904 to overcome the internal spring force.
FIG. 17 is a perspective view that illustrates another mounting structure 920 for use with the wheel/axle assembly 900 and the collapsible axle 904 , as illustrated in FIG. 15 and FIG. 16, respectively, to form a wheel assembly. The collapsible axle 904 may couple to a first member 922 and a second member 924 at a first position 926 at the first member 922 and the second member 924 so that the wheel is in a retracted position. The collapsible axle 904 may also couple to the first member 922 and the second member 924 at a second position 928 so that the wheel is in an extended position.
FIG. 18 is a side, cutaway view that illustrates a wheel assembly 940 positioned through an opening in a sole 942 that illustrates one embodiment of an axle 944 that couples to a mounting structure 946 to provide a retractable wheel 948 using an assembly that may be referred to as a king pin arrangement or dual king pin arrangement. This allows the retractable wheel 948 to be adjusted up or down, as desired, and from a retractable position to an extended position. A king pin 950 (which may be implemented as a threaded screw or bolt) is shown threadingly engaged in a threaded opening in a member of the mounting structure 946 . As the king pin 950 is screwed further into the opening in the member, the axle 944 is further retracted. A king pin 950 will also be provided at the other member to raise the other side of the axle 944 . In other embodiments, such as the mounting structure 500 in FIG. 9, a single king pin could be provided through the single member to provide retractable wheels through the coupling of the members and the axle.
An example of a king pin type assembly is illustrated in U.S. Pat. No. 4,295,655, which is incorporated herein by reference for all purposes, issued to David L. Landay, et al., was filed on Jul. 18, 1979, was issued Oct. 20, 1981. This patent illustrates a king pin type assembly that could be implemented in an embodiment of the present invention.
FIG. 19 is a bottom view that illustrates the wheel assembly 940 of FIG. 18 and further illustrates the dual king pin arrangement and the king pins 950 through the members of the mounting structure 946 .
FIG. 20 is a side view that illustrates one member of the mounting structure 946 and further illustrates the coupling of the axle 944 to the mounting structure 946 using the dual king pin arrangement similar to FIG. 18 . As discussed above, this allows the axle 944 , and hence the attached wheel, to be transitioned to any of a desired levels, and from a retracted position to an extended position.
It should be understood that the axle may couple to a member of a mounting structure using any available technique and in virtually an unlimited number of ways. For example, an axle may couple to the first member and the second member of a mounting structure to move from a retracted position to an extended position through a spring arrangement. Similarly, an axle may couple to the first member and the second member of a mounting structure to move from a retracted position to an extended position through a hinged arrangement.
Many other examples are possible, for example U.S. Pat. No. 3,983,643, which is incorporated herein by reference for all purposes, issued to Walter Schreyer, et al., was filed on May 23, 1975, was issued Oct. 5, 1976 illustrates a retractable mechanism that may implemented in one embodiment of the present invention. U.S. Pat. No. 5,785,327, which is incorporated herein by reference for all purposes, issued to Raymond J. Gallant, was filed on Jun. 20, 1997, issued on Jul. 28, 1998 illustrates simultaneously retractable wheels.
FIG. 21 is a breakaway and perspective view that illustrates a two piece wheel 970 that includes an inner core 972 , an outer tire 974 , such as a urethane wheel, an axle 976 (which may not be shown to skill), and a bearing 978 that may be used in the present invention. In a preferred embodiment, the bearing 978 is small in comparison to the two piece wheel 970 , for example, the bearing 978 may have an outer diameter that is less than half the outer diameter of the outer tire 974 . This can provide significant advantages, that include a softer ride, better control, and are longer lasting. This is because the outer tire 974 can be larger and thicker. In other embodiments, the bearing 978 is larger and has an outer diameter that is more than half the outer diameter of the outer tire 974 . In a preferred embodiment, the inner core portion of the two piece wheel is made of a harder material that provides rigidity for enhanced bearing support, while the outer tire portion is made of a softer material, such as a soft urethane, for improved performance and a quieter ride. These types of wheels may be referred to as a “dual durometer” type wheel.
Thus, it is apparent that there has been provided, in accordance with the present invention, a heeling apparatus and method that defines a new activity and sport that satisfies one or more of the advantages set forth above. Although the preferred embodiment has been described in detail, it should be understood that various changes, substitutions, and alterations can be made herein without departing from the scope of the present invention, even if all of the advantages identified above are not present. For example, the various embodiments shown in the drawings herein illustrate that the present invention may be implemented and embodied in a variety of different ways that still fall within the scope of the present invention. Also, the techniques, designs, elements, and methods described and illustrated in the preferred embodiment as discrete or separate may be combined or integrated with other techniques, designs, elements, or methods without departing from the scope of the present invention. For example, the wheel assembly may be removable or integrated into the sole of the footwear. Although the present invention has been primarily described with only one wheel positioned in the opening of the heel, the present invention certainly contemplates and covers multiple wheels positioned in the opening of the heel. Other examples of changes, substitutions, and alterations are readily ascertainable by one skilled in the art and could be made without departing from the spirit and scope of the present invention. | 1a
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SUMMARY OF THE INVENTION
According to the present invention there is provided a feeding wagon for cattle comprising a groundwheel supported frame holding a receptacle from which cattle can withdraw crop, and a crop feeding device with which the wagon can be provided, at least during loading of the wagon, this crop feeding device including a pick-up member for picking up crop lying on the ground and an advancing member co-operating with the pick-up member for carrying the crop so picked-up into the receptacle.
For a better understanding of the invention and to show how the same may be carried into effect, reference will now be made, by way of example, to the accompanying drawings, in which:
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic side view of a feeding wagon provided with a crop feeder,
FIG. 2 is an enlarged sectional view of the crop feeder and the front part of the feeding wagon of FIG. 1,
FIG. 3 is a sectional view of the wagon taken on the lines III--III in FIG. 1,
FIG. 4 shows part of a roof of the wagon taken in the direction of the arrow IV in FIG. 3,
FIG. 5 shows a second embodiment of part of the wagon taken on the lines III--III in FIG. 1,
FIG. 6 illustrates a detail of the wagon of FIG. 5 taken in the direction of the arrow VI in FIG. 5,
FIG. 7 is a side view of the feeding wagon of FIG. 1 shown without the crop feeder,
FIG. 8 is a side view of a third embodiment of the wagon, shown provided with a crop feeder, and also with a crop receptacle,
FIG. 9 is a plan view showing the wagon of FIG. 8 and a part of the crop receptacle which has been uncoupled from the wagon and removed therefrom,
FIG. 10 is an enlarged, longitudinal, sectional view of a foremost part of the wagon shown in FIG. 8,
FIG. 11 is a plan view of part of the wagon of FIGS. 8 to 10 taken in the direction of the arrow XI in FIG. 10 with the crop receptacle uncoupled and removed,
FIG. 12 is a side view of a crop receptacle such as can be coupled to the wagon of FIGS. 8 to 11,
FIG. 13 is a front view of the receptacle of FIG. 12, taken in the direction of the arrow XIII in FIG. 12,
FIG. 14 shows on an enlarged scale a foremost part of the wagon of FIGS. 8 to 11 during the operation of coupling the crop receptacle to the wagon,
FIG. 15 shows on an enlarged scale a rearmost part of the wagon of FIGS. 8-11 during the operation of coupling the receptacle to the wagon,
FIG. 16 is a plan view of the wagon taken in the direction of the arrows XVI--XVI in FIG. 15 with the crop receptacle uncoupled,
FIG. 17 is a front view of a further embodiment of crop receptacle,
FIG. 18 is a front view of another embodiment of crop receptacle,
FIG. 19 is a side view of a further embodiment of a wagon with a crop receptacle coupled thereto, and
FIG. 20 is a front view of the crop receptacle shown in FIG. 19.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The crop feeding or forage wagon shown in FIGS. 1 to 4 has a frame 1 that includes two frame beams 2 extending in the direction of length of the feeding wagon on either side thereof and interconnected, inter alia by a frame beam 3. The wagon is supported from a plurality of ground wheels 4. Preferably three such wheels are arranged on each side of the wagon. The feeding wagon furthermore has upright side walls 5, a front wall 6 and a rear wall 7. A floor 8 (shown in FIG. 3) is arranged between the frame beam 2. The sidewalls 5, the front wall 6, the rear wall 7 and the floor 8, together with a roof 9, enclose a crop receptacle 10.
The crop feeder 11 is provided near the front of the frame beam 3, coupled to the wagon by means of coupling means formed by fork-shaped parts 12 on each side of the wagon, between each of which an arm 14 can be coupled with the aid of a locking or coupling pin 13. The arms 14 are connected with an auxiliary frame 16 so as to be pivotable about a horizontal shaft 15 extending transversely of the intended direction of operative travel A of the wagon, the auxiliary frame 16 being preferably formed by hollow beams and having, viewed on plan, an approximately rectangular shape. The frame 16 carries the operative portions of the feeder 11, which include a pick-up member 17 pivoted to the auxiliary frame 16 near the bottom at the front of this frame, and an advancing member 18 located obliquely above the pickup member 17, as shown in FIG. 2. Each coupling pin 13 serves, in addition, as a horizontal, pivotal shaft extending transversely of the direction of travel A between the wagon and the crop feeder 11. Near the front the auxiliary frame 16 is pivotally connected with a drawbar 19, by means of which the wagon can be attached to a tractor, whose power take-off shaft can be linked to an auxiliary shaft 20. The auxiliary shaft 20 drives the pick-up member 17 and the advancing member 18 in known manner through transmission gears of conventional structure.
FIG. 2 shows that on the top of the auxiliary frame 16 a plate 21 is fastened throughout the width of the auxiliary frame in a position inclined forwardly and downwardly away from the rear part of the frame 16, upright rims 22 of which plate are bent over at right angles. Near the rear a substantially horizontal plate 24 joining the plate 21 is adapted to pivot about a horizontal shaft 23 extending transversely of the direction of travel A and near its rear end this plate 24 joins the frame beam 3. Bent-over rims 25 of the plate 24 join the upright rims 22. The upright rims 22 and the bent-over rims 25 are relatively disposed so that, when the rear part of the feeder 11 turns about the shaft 23, the rims 22 and the rims 25 can slide along one another. Near the lower part of the plate 21 bearings are provided to support a horizontal shaft 26 at right angles to the direction of travel A. Two plates 27 near the sides of the wagon are freely rotatable about the shaft 26. The plates 27 extend forwardly away from the shaft 26 and are interconnected by means of a curved plate 28, extending transversely of the direction of travel A. The curved plate 28 has secured to it the ends of a U-shaped beam 29. Bearings secured to the plates 27 hold a shaft 30. The shaft 30 is associated with a roller or drum 31 of the pick-up member 17, to which spring steel tines 32 are secured. The tines 32 are controlled in a known manner (as shown in U.S. Pat. No. 828,552) so that, when turning about the shaft 30 in the direction of the arrow B (FIG. 2), they extend at least substantially radially near the lower part of the path, whereas near the upper part of their path the tines 32 extend tangentially. On either side of the feeder ground wheels 33 are pivotally connected by means of wheel carriers 33A with the auxiliary frame 16, and are coupled via a slotted connecting member with the pick-up member 17 for supporting the pick-up member 17 adapted to turn about the shaft 26. The wheels 33 are preferably used for adapting the pick-up member 17 to unevennesses of the ground.
Above the auxiliary frame 16 plates 34 extend vertically upwards from the plate 22 and are interconnected by a plurality of horizontal beams 35 and 35A, extending at right angles to the direction of travel A. Bearings secured to the plates 24 hold a horizontal shaft 36 at right angles to the direction of movement. Pinions 37 are provided near the ends of the shaft 36 located near the plates 34. The teeth of the pinions 37 are in mesh with the teeth of gear wheels 38 secured to stub shafts 39 extending parallel to the shaft 36 and journalled in bearings fastened to the plates 34.
Bearings, secured to the peripheries of gear wheels 38 forming a driving member, hold a tube 40 of the advancing member 18. The tube 40 extends parallel to the shaft 36 and is provided with a plurality of tines 41 arranged, viewed in the direction of the tube, in a row one behind the other and extending downwardly away from the tube 40. At each end of the tube 40 an arm 42 extends upwardly from the tube, the arms 42 being in line with the tines 41, viewed in the direction of length of the tube. The ends of the arms 42 remote from the tube 40 are pivotally coupled with the ends of coupling rods 44 by means of pins 43 extending parallel to the tube 40. The ends of the coupling rods 44 remote from the arms 42 are pivotally coupled with ears 46 to the frame beams 35A with the aid of pins 45 extending parallel to the pins 43. This advancing member 18 is protected by a screening hood 47, the rear wall of which is inclined rearwardly and downwardly to the rear of the feeder 11. On the bottom the member 18 is screened by a plurality of relatively spaced beams 48, the ends of which are secured to the beams 35. From the front end each beam 48 has a downwardly inclined portion at an angle of about 30° to the horizontal, extending to the rear and terminating near the vertical plane going through the rotary axis of the gear wheels 38 (formed by the stub shafts 39) in an upwardly inclined portion at an angle of about 15° to the horizontal. The beams 48 are spaced apart by a distance such that the tines 41 can pass between the beams 48.
In the paths described by the tines 41 a plurality of cutters may be arranged in a manner not shown for cutting the crop into short lengths. The number of, and the spacing between the cutters is chosen in accordance with the desired length of the cuttings.
By means of a pivotal shaft 49 located beneath the pivotal shaft 15 a hydraulic cylinder 50 of the single action type is pivoted to each arm 14. At the end remote from the pivotal shaft 49 each cylinder 50 is pivoted to a horizontal beam 51 extending transversely of the direction of travel A and secured to the lower side of the auxiliary frame 16 near the front of the plates 21. Near the rear the auxiliary frame 16 is supported from two ground wheels 52 located one on each side. These ground wheels 52 support not only the auxiliary frame 16, but in operation also the front of the frame 1 of the wagon. To this end, by means of the hydraulic cylinders 50 the arms 14 can be turned with respect to the pivotal shaft (formed by the pins 13) as a result of which two supports 53 provided one on each side of the wagon beneath the frame beams at the front of the wagon are lifted from the ground (condition illustrated in FIGS. 1 and 2). The supports 53 viewed from the side, have a trapezoidal shape. If desired, extensible legs may be provided at the front for holding the front of the wagon at the adjusted height above the ground when the crop feeder 11 is uncoupled from the wagon.
The lower part of the wagon comprises a plurality of tubular beams 54 (FIG. 3) curved substantially in the shape of a U, viewed in the direction of travel A. Viewed from the side the beams 54 (FIG. 1) are arranged at equal distances apart of about 50 cms throughout the length of the wagon. The web between the upright limbs of each substantially U-shaped beam 54 is formed by a bottom beam 55 having, viewed in the direction of travel A (FIG. 3), an upwardly extending bend so that the two upwardly converging parts of the beam 55 are at an angle of about 7.5° to the horizontal. The limbs of each substantially U-shaped beam 54 are formed by beams 56 converging in downward direction and being at an angle of about 65° to the horizontal. At about two-thirds of the height of each beam 56 a tubular stiffening beam 57 extends from outside one upright limb to outside the other upright limb. Viewed in the direction of travel A each beam 57 has an approximately U-shaped form, the upright limbs of which at first diverge in downward direction and then, from the level of the tops of the wheels 4, converge to the web, which is secured to the bottoms of the frame beams 2 and runs horizontally between the beams 2. The bottom beams 55 are provided with a steel sheet of about 3 mms in thickness, forming the floor 8. At the corners of the beams 54 plates 58 on each side of the wagon extend away from the frame beam 2 in an upwardly inclined position along the beams 56. Above the wheels 4 they are bent over outwardly and horizontally. The plates 58 extend in the direction of travel A throughout the length of the wagon. The plates 58, each of which forms a feeding gutter or trough, are secured by means of tubes 59 to the inner faces of the outermost portions of the stiffening beams 57. Viewed on plan and transversely of the direction of travel A, the width of each feeding trough corresponds at least substantially with the width of an apertured lower part of the corresponding sidewall 5. Near the top of the beams 56, on the inner sides thereof, on each side of the wagon two horizontal tubular rods 62 and 63 are suspended from chains 60 and 61 respectively so as to extend in the direction of travel A throughout the length of the wagon. Viewed from the side (FIG. 1) the rods 62 and 63 divide the space between the tops of the beams 56 and the tubes 59 into three portions of substantially equal heights. The chains 60 and 61 are secured by means of pins 64 to plates 65, which are secured near the top ends of the beams 56.
In the regions of the feeding troughs formed by the plates 58, the sidewalls 5 have a plurality of openings provided over the whole length of the wagon, their height being about 100 cms, measured in a vertical direction. The beams 56 are disposed between the openings to prevent an excessive outflow of fodder when the cattle are feeding.
The top ends of the beams 56 are provided with horizontal, channel section beams 66, the limbs of which extend upwardly. The beams 66, arranged around the wagon, viewed on plan, stiffen the sidewalls 5, the front wall 6 and the rear wall 7. The beams 66 have secured to them the upper parts of the sidewalls 5 of the crop receptacle 10 these walls being made from profiled steel sheet preferably of about 3 mms in thickness. Viewed in the cross section of FIG. 3, the sidewalls 5 above the beams 66 together with the roof 9 form an integral, uninterrupted plate 67. Profiled reinforcements of the steel plate 67 formed by portions 68 prolonged along the roof are shaped so that the plate 67 and the portions 68 have the shape of a U, viewed in the direction of travel A and in cross section, the ends of the limbs of this U join the beams 66. The profiled portions 68 are proportioned so that the upwardly extending portions 68 along the sidewalls 5, near the top of the wagon, in a horizontal cross-section, have a larger length and width than near the beams 66. The horizontal cross-section is preferably approximately square, the dimensions near the beams 66 being about 6×6 cms and near the top of the wagon about 20×20 cms. In the sectional view of FIG. 3 the outer circumference of each profiled portion 68 has an approximately rectangular shape and near the roof 9 the profiled portion 68 is at a height of about 4 meters about the ground and the width of the U-shaped portion 68 is about 2.10 to 3 ms, preferably about 2.50 ms. The plate 67 enclosing the receptacle 10 has a substantially trapezoidal shape as shown in FIG. 3. The two upwardly converging inner walls of the sidewalls 5 formed by the plate 67 are each at an angle of about 3° to the vertical, longitudinal plane of symmetry of the wagon. Viewed from the side (FIG. 1) the portions 68 are distributed along the sidewalls 5 so that a portion 68 joins every other beam 56. For the purpose of draining rainwater the junction between the plate 67 and the profiled portions 68 with the beam 66 is such that water is conducted by the uninterrupted steel plate 67 towards the gutter formed by the beams 66 (FIG. 4), this gutter having openings near the front or rear of the wagon or both, through which the water can escape. Through openings at equal intervals in the beam 66, water can be conducted away via the beams 56 through openings in the bottom beam 55. Water contained in the wagon can flow away laterally along the slightly inclined bottom plate 8 to be conducted away near the corners of the U-shaped hollow beams 54.
The plate 67 is joined by the front and rear walls 6 and 7 respectively, also made from steel sheet of about 3 mms in thickness. It is advantageous to construct the rearwall 7 so that it can be opened for discharging the crop, if desired, or for carrying out other operations in the receptacle 10. Near the bottom the front wall 6 has a substantially rectangular opening 69, through which the crop is pushed by the advancing member 18 into the receptacle 10. When the crop feeder 11 is uncoupled and removed from the wagon the opening 69 can be closed by means of a rolling screen 70.
FIGS. 5 and 6 show a replacement for the rods 62 and 63 in the form of chain network or screen 71 fastened to the inner side of the lower part of the receptacle 10. The chain network 71 preferably consists of meshes of approximately square shape having dimensions of about 15×15 cms. Viewed in the cross-section of FIG. 5, the chain network is suspended near the top with the aid of tags 72 on the inner sides of the beams 66, the chain network 71, from the beam 66 on one side, being inclined away from the tags 72 along the beam limbs 56 on this side in downwardly direction, then extending along the bottom beams 55 and subsequently being inclined upwardly along the opposite beam limbs 56 to the opposite beam 66. Near the corners of the U-shaped beams 54 the chain network 71 may have further fastening points, if desired.
The crop feeding or forage wagon described above operates as follows.
The wagon can be coupled with the aid of the drawbar 19 and with the crop feeder 11 attached to a tractor or a similar vehicle and can be moved in the direction of the arrow A. The operative parts of the crop feeder 11, formed by the pick-up member 17 and the advancing member 18, can be driven through a driving mechanism not shown in the Figures from the power take-off shaft of the vehicle drawing the wagon. The drum of the pick-up member 17 is rotated in the direction of the arrow B, whereas the free ends of the tines 41 of the advancing member 18 are moved in the direction of the arrow C along a reniform path. This reniform path is essentially such that the crop is inserted approximately in a horizontal direction into the crop receptacle 10.
While the crop is being picked up, the wheels 33 bear on the ground for supporting the pick-up member 17 so that the latter can match unevennesses of the ground. Crop lying on the ground is caught by the tines 32 and pushed upwards through the gap between the parts of the plates 27 located in front of the beams 29. The beams 29 serve as scrapers for the tines 32 for preventing the crop from sticking to the tines. The diameter of the drum 31 is such that the drum carries the crop up to the level of the floor 8 of the wagon. The crop lifted by the tines 32 is taken over by the tines 41 and pushed in an at least substantially horizontal direction rearwardly into the receptacle 10, the tines 41 mowing between the scrapers formed by the beams 48. The positions of the beam 48 and the movement of the tines 41 are such that the angle of engagement between the crop and the sides of the tines 41 is always larger than 90° to minimize jamming of crop between the tines 41 and the beams 48. As already mentioned, if desired with respect to the nature of the crop, cutters may be disposed in the reniform path of the tines in a manner not shown for cutting up the crop.
Owing to the construction described above for the advancing member 18 associated with the crop feeder 11 the crop is inserted in an at least substantially horizontal direction into the crop receptacle of the feeding wagon, and the crop located inside does not slide back into the feeder channel, while the comparatively large quantities of crop simultaneously inserted into the receptacle ensure a satisfactory advancement of the crop into the receptacle.
To couple the crop feeder 11 with the wagon the arms 14 are coupled with the front of the feeding wagon which can then be lifted after the coupling pins 13 have been put in place, by turning the arms 14 about the shaft 15 in the direction of the arrow D, the desired relationship between the feeder and the wagon being thus established. Since the feeder 11 itself is supported from the ground wheels 52 on each side it is advantageous that in operation the feeder device and the wagon can turn relatively to one another about the shaft formed by the coupling pins 13. The rear part of the feeder device, formed by the plate 24 and the rims 25, is capable of turning about the shaft 23 with respect to the remainder of the feeder device, which is desirable with a view to a satisfactory junction between the feeder device and the transverse beam 3 of the wagon.
In operation crop is pushed by the tines 41 through the opening 69 in the front wall 6 of the wagon into the receptacle 10. When the feeder 11 is uncoupled, the opening 69 is closed by the screen 70 so that loaded crop cannot get out of the wagon in an undesirable manner. When the feeder 11 is removed, the wagon is supported at the front by the supports 53, or by the extensible legs if these are provided.
The disposition of the three wheels 4 on each side of the wagon is such that only slight pressure is exerted on the front of the wagon.
Depending upon circumstances the wagon may have fewer or more than the three compartments.
As already mentioned, the cattle feed from openings in the two sidewalls. During the loading operation these openings are closed at least partly by means of the rods 62 and 63. For supplying the load of crop to the cattle it is only necessary to disengage the pins 64 so that the rods 62 and 63 slide down to the floor 8. The rods 62 and 63 are constructed so that, when suspended during the loading operation, the rods offer minimum resistance to the crop, when this is pushed rearwardly, while on the other hand the rods prevent loss of crop from the crop receptacle. The rods 62 and 63 may consist of, for example, five portions, each portion being suspended separately. In this way openings for the cattle can be realized according to need. In the alternative embodiment of FIGS. 5 and 6 in which the rods 62 and 63 are replaced by the chain network 71, this chain network prevents substantially all loss of crop. If desired, the rods 62 and 63 may be arranged on the inner side of the receptacle 10 and the chain network 71 on the outer side of the receptacle.
The trough-shaped feeding gutters 58 beneath the openings in the sidewalls 5, on either side of the wagon, serve for preventing loss of fodder falling from the openings. By constructing the floor plate 8 so that away from the vertical, longitudinal plane of symmetry of the wagon the floor is inclined downwardly, even a small residue of crop in the wagon can be taken by the cattle. Moreover, any liquid can flow away in a lateral direction.
Owing to the completely closed construction of the top parts of the walls 5 and the roof 9 the crop in the loading space 10 is very effectively protected from weather conditions. Rain is conducted away through the gutters 66 and, if desired, connections via the beams 56 may be used for conducting the water away in a downward direction.
The walls of the wagon are preferably provided with a plurality of reinforcements which is of great importance in view of the high pressing force exerted by the advancing member via the crop pushed into the receptacle. It has been found that, when an advancing member is used which pushes the crop in an approximately horizontal direction into the receptacle, no conveying means on the floor are required, since the tines pushing on the crop horizontally can fill the whole receptacle 10 without the need for further means. It is required, however, for the inner walls of the receptacle 10 to be as smooth as possible, while the top has to be completely closed so that a minimum of friction is produced between the walls and the crop. The profiled reinforcements in the sidewalls are proportioned so that they can withstand the laterally working pressing force to the optimum extent. Since the inner walls are slightly inclined in upward direction, the crop located near the top of the receptacle can readily drop down. The base of the receptacle formed by the floor 8 and the substantially U-shaped beams 54 is particularly reinforced near the corners of the U-shape by the stiffening beams 57. These beams have a very advantageous effect with respect to the high pressure and to the high loading capacity of the wagon of about 10,000 kgs. The U-shaped construction of the lower part of the receptacle joins the U-shaped construction of the upper part of the wagon, the two pairs of limbs of the U-shaped structures joining one another near the beams 66. This is also advantageous to absorb the high lateral pressure.
After the wagon is loaded, it can be conveyed towards the cattle feeding site, where the crop feeder 11 is uncoupled and removed and the wagon is left with the cattle. The crop feeder may be utilized for loading a further wagon, while the cattle are feeding on the first load. On the basis of a comsumption of 20 kgs of crop a day for one cow, the wagon, having a capacity of about 10,000 kgs, can feed one hundred cows for a period of five days. The feeding site of the cattle may be an open cow barn or a meadow and, if desired, the wagon may be conveyed to another place without re-coupling the crop feeder 11 (FIG. 7).
Owing to the efficiency of the feeding system described the labor requirements for feeding cattle, which is at present still high, can be reduced considerably. Moreover, the material required in this feeding system is effectively employed. In addition, the quantity of crop lost with this system is at a minimum, since the crop is picked up directly from the field and loaded in the wagon, where it is protected from bad weather, while without intermediate storage the crop is fed directly to the cattle so that crop loss is minimized. Even during feeding the crop is left in the wagon until eaten.
This crop feeding or forage wagon illustrated in FIGS. 8-11 has a frame 101 that includes two frame beams or frame portions 102, located one on each side of the wagon and extending in the direction of length of the wagon, these beams being interconnected near the front by a frame beam or portion 103. The frame portions 102 and 103 are preferably formed by hollow beams. Viewed in plan, the frame 101 has approximately the shape of a U, the portion 103 forming the web between the limbs. Thus the rear part of the frame is quite open. The rear ends of the beams 102 are formed by rearwardly diverging, plate-shaped guiding parts 104 arranged symmetrically to the direction of travel A, each portion comprising an intermediate piece 105 joining the beam 102 at an angle of about 65° and an end piece 106 at an angle of about 15° to the beam 102. The wagon is supported from a plurality of wheels 107. The wagon is preferably provided with a total of eight wheels 107, which are arranged in pairs on an axle 108 so that the wheels 107 are located on either side of the beam 102. In this way four pairs of wheels are provided.
At the corners formed by the beams 102 and 103 guide plates or guide means 109 are provided, their shape being triangular, viewed in plan.
The front of the frame beam 103 is provided with a crop feeder 110 formed by a pick-up member 111 and a conveying member 112. The members 111 and 112 are secured with the aid of two upright plates 113 (FIG. 10) arranged on either side of the crop feeder and extending upwardly away from the beam 103. Near the bottom of the plates 113 a drum is provided with spring steel tines 115, the drum with the tines forming the pick-up member 111. The drum is journalled by means of a shaft 116 extending transversely of the direction of travel A and substantially in a horizontal direction. The tines 115 are disposed in known manner (not shown) so that during rotation about the shaft 117 of the drum 114 in the direction of the arrow B (FIG. 10) they are directed at least substantially radially near the lower part of their path, whereas near the top part of their path the tines 115 are tangentially directed.
Between the side plates 113 a preferably hollow shaft 118 extends parallel to the shaft 116. The shaft 118 has secured to it a plurality of tines 119, arranged viewed in plan in a row side by side and which, viewed from the side, extend downwards away from the shaft 118. A coupling arm 120 is pivoted to the top end of each tine 119. The ends of the arms 120 remote from the tines 119 are pivotally coupled with a hollow beam 121, which covers the whole width of the crop feeder 110. The beam 121 constitutes at the same time a fastening part for a hood 122, which protects the top of the crop feeder.
The crop feeder 110 is driven from a tractor or other prime mover with the aid of an auxiliary shaft 123, which is coupled with a gear box 124, on either side of which an output shaft 125 is driven, the shaft 125 being parallel to the shaft 116. The shaft 125 is provided on either side of the feeder 110 with a rope or belt transmission (not shown) driving the pick-up member 111. The shaft 125 is provided at each of its ends with a gear wheel 126 (FIG. 11), which is drivably in mesh with a gear wheel 127 driving a shaft 128, which is parallel to the shaft 116. Each shaft 128 has a gear wheel 129, which drives the tines 119 in the direction of the arrow C in FIG. 10 by means of a gear wheel 130 co-operating with the gear wheel 129, the gear wheel 130 being secured to a shaft 131, which is also parallel to the shaft 116.
On the bottom the conveying member is protected by a plurality of relatively spaced, tubular guide elements 132, located in between the tines 119. The pick-up member 111 is protected by guide brackets 133, located in between the rows of tines 115. In the space between the element 132 and the bracket 133 the crop is vigorously pushed to the rear in a substantially horizontal direction.
On either side of the crop feeder 110 there is provided an auxiliary frame comprising two beams 134, secured to the front of the beam 103 and extending away from the beam 103 in slightly upward direction. The foremost ends of the beams 134 are interconnected by a hollow tube 135. On the rear of the tube 135, on either side of the crop feeder 110, two supporting members 136 extend rearwardly and upwardly and hold the plates 113 on the sides. The front of the tube 135 is provided with a drawbar 137, which can be attached to the coupling point of the tractor. Near the lateral ends of the tube 135 tags 138 (FIG. 14) are provided, each of which holds a pivotal arm 140 by means of a shaft 139, the arms 140 extending as shown in FIG. 10, upwards and slightly forwards in the direction of travel A. Near the top of each of the arms 140 one end of a hydraulic cylinder 141, actuated from the tractor, is pivotally arranged. Each hydraulic cylinder 141 is pivoted by the end remote from the associated arm 140 to two parallel tags 138A secured to the top of the beams 134. The arms 140 are interconnected above the coupling point of the cylinder 141 by a hollow tube 142 extending parallel to the tube 135.
At a distance from the lateral end of the tube 142 a tag 143 is welded to the top side of the tube 142. Through the tag 143 is passed a pin 144, from which two substantially parallel, strip-shaped arms 145 extend rearwardly and inwardly. Viewed from the side (FIG. 10), the arms 145 are interconnected approximately above the beam 103 by a shaft or pin 146, which is passed through a hole near a corner of a plate 147 of substantially triangular shape, viewed from the side. The plate 147 is pivotally supported at another corner by two tags 147A and a shaft located in between. The two tags 147A are secured to the top of the beam 103. Near the third corner of the plate 147, which forms a swash plate and serves together with the hydraulic cylinder 141 as a coupling means, a slot-like opening 148 extends from the top in downward and rearwardly inclined direction, viewed from the side (FIG. 10).
Plates 149 are secured to the sides of the beam 134 on each side of the wagon. The plates 149 serve as supports for ground wheels 150 on each side of the wagon, these wheels being adjustable in a direction of height with the aid of an adjusting mechanism 151. The pick-up member 111 is supported on either side by supporting wheels 150A.
In approximately the same manner as at the front of the wagon, a hydraulic cylinder 153, actuated from the tractor, is located above the pairs of wheels 107 between tags 152 on each side of the wagon (FIG. 15). The tags 152 are secured to the top of the beam 102 and the hydraulic cylinder 153 is inclined upwardly and forwardly with respect to the direction of travel A away from a pivotal shaft 154 passed through tags 152. The piston rod of the hydraulic cylinder 153 is connected with the top ends of the arms 155, which extend downwardly on either side of the beam 102 and are pivotally connected with the lower side of the beam 102. The connection between the piston rod of the cylinder 153 and the arm 155 is formed by a pivotal shaft 156, which couples arms 157 with the cylinder 153. Viewed in side elevation (FIG. 15) the arms 157 extend approximately in a horizontal direction on either side of the cylinder 153 to the rear as far as, viewed in plan (FIG. 16) beyond the beam 102, viewed in the direction of travel A, where the arms 157 are interconnected by a pivotal shaft 158, which is surrounded by a sleeve 159, which is rigidly secured to a plate 160, which is similar to the plate 147 in FIG. 14. Viewed in side elevation (FIG. 15) the plate 160 has a substantially triangular shape and is secured to ears 161 secured to the rear end of the beam 102.
In normal operation a slot-like opening 162 near one of the corners of the plate 160 serving as a swash plate and forming a coupling means together with the hydraulic cylinder 153, extends, viewed in side elevation (FIG. 8), in the coupled state, from the top in downward direction and to the rear with respect to the direction of travel A.
The wagon comprises furthermore a crop receptacle 163, arranged on a frame 164 (FIG. 12). This frame 164 comprises girders 165 extending in the direction of length of the wagon and transverse girders 166. The width of the transverse girders 166 and hence of the frame 164 approximately corresponds to the smallest distance between the guide plates 109 at the front of the wagon (FIG. 11). The sides of the girders 165 are provided at equal intervals with holders 167 of rectangular shape, viewed on plan, for accommodating tubular supporting elements 168. The elements 168 are preferably mounted by means of pins 169 in the holders 167 so as to be readily detachable. Each element 168 is curved, viewed in the direction of travel A in FIG. 13, so that an approximately omegashape form is obtained. Each element 168, which is preferably made from light-weight tubing, extends initially upwards and slightly outwards and is bent after some distance through an angle of 45° to the horizontal plane to the outer side. Approximately halfway up the height of the receptacle where the receptacle has a width of about 3.5 meters each element 168 is approximately at right angles to the horizontal plane and extends upwardly. At the height of the roof each element 168 is bent downwardly (FIG. 13). The receptacle preferably has seventeen steel structures of this kind.
The floor of the receptacle is preferably formed by a corrugated plate 170, arranged so that the corrugations extend in the direction of length of the receptacle. It is advantageous to cause the corrugated plate to slope slightly down near the outer sides. The sidewalls of the receptacle are formed near the bottom by a plurality of horizontal, tubular bars 171, for example, three covering the whole length of the receptacle. The space between the bars 171 and the corrugated plate floor 170 may be completely open, but in accordance with the nature of the crop to be loaded it is advantageous to provide a slide 172 between the elements 169, for example, a slide of thin sheet material or a synthetic resin, adapted to move in a direction of height to form a free opening. To the substantially perpendicular portions of the elements 168 corrugated plates 173 are secured so that the corrugations extend in the direction of length of the receptacle 163. A water draining gutter 174 is preferably provided between the sidewall formed by the corrugated plates 173 and the bars 171. The roof portion located above the corrugated plates 173 and joining the plates 173 is formed by light-weight, U-shaped sheet material 175 extending away from the plates 173 over a distance along the elements 168 up to a small distance from the highest portion of the roof so that, as shown in FIG. 13, an opening is formed throughout the length of the receptacle between the sheet material 175 and the remainder of the roof. The topmost part of the roof is formed by a slightly V-shaped plate 176, which covers the opening between the sheet material by means outwardly extending parts, viewed on plan.
The front and rear sides of the receptacle are closed by a mesh 177, preferably of comparatively strong material. Near the front of the receptacle an opening is left near the bottom for the advancement of crop into the receptacle.
Near the front of the receptacle 163 two supporting parts 178 are fastened between the elements 168 (FIG. 13). The supporting parts 178 are formed each by two relatively parallel portions 179 extending away from the transverse girder 166 in upright direction and, viewed in the direction of travel A, to the front (FIG. 14). Near the top ends the portions 179 are interconnected by a shaft or pin 180. The shaft 180 is formed so that during the coupling operation it can slide in the slot-like opening 148 of the swash plate 147. In a similar manner supporting parts 181 are provided at a distance in front of the rear end of the receptacle. However, contrary to the parts 178, the supporting parts 181 are located, viewed in side elevation (FIG. 13), at a distance beyond the supporting elements 168 and are secured to an outwardly extending transverse beam 182 (FIG. 15). The supporting parts 181 comprise two upwardly extending, stripshaped portions 183 bent over at right angles and extending away from the beam 182 in upward direction and obliquely to the front with respect to the direction of travel A, substantially similar to the portions 179. Near the top the portions 183 hold a shaft or pin 184 between them, the shape of this shaft being such that during the coupling operation it gets into the slot-like opening 162 of the swash plate 160.
On each side of the swash plates 147 claws 185 are arranged on the beam 103 so as to be pivotable about upright shafts. After the receptacle 163 is coupled, the claws grip around one of the foremost elements 168 with the aid of tensile springs 186.
The wagon shown in FIGS. 8-16 operates as follows.
The wagon can be attached by means of the drawbar 137 to a tractor or a similar vehicle and in operation it can be moved in the direction of travel A. For coupling the receptacle 163 with the frame of the wagon the receptacle 163 is provided both near the crop feeder 110 and near the ground wheels 107 with upwardly extending supporting portions 179 and 181 respectively having a horizontal shaft or pin 184. The shafts 180 and 184 respectively constitute coupling points for the receptacle for attachment to the coupling means on the frame 101. When the wagon has to be coupled with the receptacle 163, first the swash plates 147 and 160 are turned rearwardly with respect to the direction of travel A, with the aid of the hydraulic cylinders 141 and 153 respectively, so that the slot-like openings 148 and 162 respectively occupy a horizontal, rearwardly extending position (see FIGS. 14 and 15). In order to have these movements of the swash plates 147 and 160 performed in synchronism, the cylinders 141 and 153 are preferably hydraulically coupled with one another. After this operation the wagon is maneuvered towards the receptacle 163 standing on the ground. Subsequently the U-shaped frame 101 is driven around the receptacle 163, the guide plates 109 taking care of a correct coupling in the last coupling phase, since the receptacle can slide along the plates 109. During the coupling operation the plate-shaped guide parts formed by the parts 105 and 106 operate as guides for the upright supporting portions 181 so that the receptacle can be accurately coupled also on the rear. After completion of the first phase of the coupling operation the lifting device comprising the hydraulic cylinders 141 and 153 is actuated and owing to the resultant outward movement of the piston rods of the cylinders the swash plates 147 and 160 move in the direction of the arrows E and F respectively. During this movement the receptacle is lifted from the ground by means of the coupling means operating as a lifting device and connected on the frame of the wagon. Finally, also under the action of the springs 186, the claws 185 ensure an immovable coupling in the various directions. The final positions of the slot-like openings 148 and 162 after the coupling operation, these openings being inclined upwardly in the direction of travel A, contributes to a satisfactory fixation also in a direction of height. In this way the receptacle 163 can be readily coupled by only one person from the tractor and deposited on the wagon frame 101.
The location of the rearmost coupling means on the beams 102 between the wheels 107 on either side of said beams 102 can contribute to a very satisfactory absorbtion of forces exerted on the wagon frame so that harmful torsional forces on the frame 101 can be avoided. After coupling the inlet opening in the front wall 177 (FIG. 13) occupies, with respect to the conveying member 112, a position such that the wagon is ready for receiving the crop, which can thus be inserted into the receptacle 163. The operational parts of the crop feeder 110 i.e. the pick-up member 111 and the conveying member 112, can be driven by the power take-off shaft of the vehicle moving the wagon through the auxiliary shaft 123 and the further transmission gear. The drum 114 of the pick-up member 111 rotates in the direction of the arrow B and the tines 119 on the shaft 118 rotate in the direction of the arrow C, the free ends of the tines 119 moving along a reniform path so that the crop is vigorously pushed in a substantially horizontal direction into the receptacle 163. If it is desired with regard to the nature of the crop, knives may be arranged in a manner not shown in the path of the tines for cutting up the crop. In loading, the design of the floor plate 107 contributes to an advantageous displacement of the picked-up crop to the rear.
When loading short-stemmed crop it may be advantageous temporarily to close the openings in the lower side of the sidewall near the crop feeder. This can be done with the aid of the plates 172. The vigorous conveying member 112 pushes the crop up to the rear wall of the receptacle. At the same time the crop is pushed upwardly so that the whole receptacle will be completely filled with crop.
When the receptacle 163 is filled to the desired extent, it can be uncoupled by causing the swash plates 147 and 160 by means of the cylinders 141 and 153 respectively to turn in directions opposite the arrows E and F respectively so that the receptacle is lowered towards the ground. When the receptacle is standing on the ground, it is only necessary to drive the wagon frame 101 forwards for achieving disengagement. After the receptacle is deposited on the ground, a further receptacle may be coupled with the wagon frame 101 in order to continue harvesting of fodder without loose of time.
The filled receptacle 163 is suitable as a storage for preserving the crop for some time and in addition for feeding crop to the cattle. The cattle can feed after any slides 172 have been opened, the fodder being drawn by the cattle through the openings in the lower parts of the sidewalls. In order to minimize losses of fodder, the floor plate 170 may be spherical or wedgeshaped. Humidity from the ground cannot penetrate through the closed floor 170. Since the receptacle 163 has a covering roof, below which a gap is left for ventilation, and since the receptacle 163 has meshes at the front and the rear, a satisfactory circulation of air across the receptacle 163 is ensured, which has a favorable effect on a preservation of the loaded crop for a longer time. Owing to the inclined sidewalls near the bottom of the receptacle the crop cannot become wet near the feeding opening, while the aeration is improved. In this way an effective one-man operational cycle can be performed with minimum loss of fodder, since after the operations on the field the crop is directly fed to the cattle. Moreover, the user can employ the wagon for many further purposes, since other types of receptacle may also be coupled thereto.
Owing to the large dimensions of the receptacle, whose width is about 3.5 meters and whose height is also about 3.5 meters, very large quantities of crop can be loaded; in accordance with the kind of crop and the moisture content 10,000 to 30,000 kgs of crop can be loaded.
In the embodiment shown in FIG. 17 the receptacle has on the lower side, the same construction as in the first embodiment, but the roof is formed by preferably a circular bent-over corrugated plate 187 of, preferably, thin steel sheet or a synthetic resin. The corrugations extend transversely of the direction of length of the receptacle. In this manner a comparatively cheap, but strong receptacle is obstained, which may be very attractive in the event of a need for a plurality of alternating troughs. The corrugations ensure in addition a satisfactory drainage of water.
FIG. 18 shows another embodiment of a receptacle, which may be employed not only for feeding cattle but also for other purposes. Near the floor an outlet member 188 is provided in the form of a worm conveyor, the floor sloping down thereto in an approximately funnel-shaped fashion. The floor 189 is supported from supporting elements 168. The remainder of the walls 190 is self-supporting and completely closed apart from an opening 191 on the top of the receptacle, which can be closed. The receptacle shown in FIG. 18 is an example suitable for many other purposes than feeding cattle, for example, for transporting bulk goods such as cereals. Such receptacles ensure a high efficiency of the wagon system.
FIG. 19 shows an alternative embodiment of the wagon, in which the frame 101 is provided at the front with a mowing device 192, which comprises in this embodiment cutter elements 193 adapted to rotate about upright shafts. Approximately midway the length of the wagon frame a crop feeder 194 is arranged, the construction of which is mainly identical to the crop feeder 110 already described, but herein it is completely arranged beneath the floor of the receptacle 195. The receptacle 195 is largely identical to the receptacle 163 already described, but it is differently coupled with the wagon frame 101. The coupling is performed by means of hydraulic compression cylinders in the shape of hydraulically extensible legs 196. The floor of the receptacle 195 is preferably equipped with bottom flaps 197, adapted to turn about horizontal shafts extending in the direction of length of the receptacle and being located near the sides of the receptacle 195. As is shown in FIG. 20, the bottom flaps 197 can be turned over a controllable distance towards the ground in the direction of the arrow G by means of an adjusting mechanism (not shown).
The receptacle 195 shown in FIG. 19 and 20 permits of mowing and loading crop in a single run. It is furthermore possible, after the mowing device 192 is switched off to employ the receptacle in this embodiment only for loading purposes. It may be very advantageous for the crop feeder 194 to be arranged at a distance from the front of the wagon with a view to the effective possibilities of inserting crop into such a receptacle. Since the recepticle is equipped with extensible legs 196, it can be disposed at a desired height above the ground. It is then advantageous that a certain space is left beneath the floor of the receptacle, so that the cattle can attain the crop beneath the floor or can draw it from the floor after the bottom flaps 197 have been turned open to a suitable extent. If desired, the sidewalls may be completely closed as shown in FIG. 18. It is furthermore possible to provide the receptacle 163, already described, with pivotable sidewalls similar to the bottom flaps 197 of FIG. 19. Other combinations of the embodiments described may be utilized, for example, an outlet member as shown in FIG. 18 may be provided on the floor of the receptacle 163 of FIG. 8.
While various features of the cattle feeding wagons, and parts associated therewith, which have been described, and are illustrated in the drawings, are be set forth in the following claims as inventive features, it is to be noted that the invention is not necessarily limited to these features and that it may encompass all features which have been described both individually and in various combinations. | 1a
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REFERENCE TO PENDING PRIOR PATENT APPLICATION
This patent application claims benefit of now abandoned prior U.S. Provisional Patent Application Ser. No. 60/372,324, filed Apr. 12, 2002 by Eric S. Steenlage et al. for METHOD AND APPARATUS FOR RECONSTRUCTING A LIGAMENT, which patent application is hereby incorporated herein by reference.
FIELD OF THE INVENTION
This invention relates to surgical methods and apparatus in general, and more particularly to surgical methods and apparatus for reconstructing a ligament.
BACKGROUND OF THE INVENTION
Stable healing of a tendon graft to the adjacent bone is generally considered to be the single most important factor in any type of tendon or ligament reconstruction. Successful incorporation of the graft is primarily dependent on two factors. First, the graft must be fixed in such a way as to maximize the contact area between the graft and the bone, thereby providing the greatest amount of surface area for graft incorporation. Second, the graft fixation must be stable, minimizing the amount of motion between graft and bone. This will minimize the amount of weak fibrous tissue that forms at the bone-graft interface and maximize the degree to which a more stable bone-soft tissue interface develops at the point of bone-graft contact.
One of the specific areas in which this problem of bone-to-tendon graft healing has received the greatest amount of attention is in the area of cruciate ligament reconstruction. Anterior cruciate ligament (ACL) reconstruction in particular has been an area of intense interest. Graft fixation techniques for ACL reconstruction have become an area of intense debate, research, and product development. Graft fixation during the ACL reconstruction procedure will be used as an example to demonstrate the properties of the new fixation concept described here. Other applications, such as but not limited to other types of ligament reconstruction, are obviously possible as well.
One of the graft fixation techniques that has become increasingly popular is interference screw fixation. Many recent advances have been made in improving the pullout strength of tendon grafts when using interference screw fixation. Better tunnel location, tunnel compaction, tighter graft/tunnel fit, improved graft preparation/suturing techniques, and the use of longer, biodegradable screws have all contributed to nearly doubling the pullout strengths obtained from the initial interference fixation studies.
One of the fundamental problems associated with interference screw fixation has remained unchanged, however. More specifically, the presence of the interference screw on one side of the graft limits the bone/graft contact to only a portion of the graft's circumferential area. Histology studies have suggested that in the long term, the most stable bony ingrowth of the graft into the surrounding bone occurs primarily at the outer rim of the bone tunnel. With interference screw fixation this ingrowth is possible only on the side of the graft that is in direct contact with bone; the other half of the graft contacts only the screw and hence is not available for bony ingrowth.
Thus, in practice, there is effectively no bony ingrowth where the interference screw intervenes between the tendon graft and the host bone.
The use of bioresorbable screws may provide the opportunity for additional bone ingrowth after the bioresorbable screw has been resorbed. However, the timing, extent and type of ingrowth occurring on the screw side of the tendon, after the bioresorbable screw has been resorbed, has yet to be fully determined.
In addition to the foregoing, spinning of the tendon graft during insertion of the interference screw is a well-documented problem that is difficult to control once it has begun. This “tendon spin” can damage the graft and result in impingement and less-than-ideal graft positioning, possibly affecting the clinical results.
As a result of the foregoing, one of the arguments for extra-cortical or non-aperture types of fixation, such as graft suspension systems like the ENDOBUTTON™ system or cross-pinning, is that there is, theoretically, circumferential bone/tendon graft contact, making full circumferential bony ingrowth at least a theoretical possibility. However, such distal types of fixation are often less stiff and provide less stable fixation of the graft in the bone tunnel. This decreased stability and subsequent increased graft-tunnel motion may inhibit the formation of a stable graft-bone interface, interfering with graft incorporation into the adjacent bone and the creation of a functionally stable ligament reconstruction. In addition, this increased graft motion has been associated with widening of the bone tunnel. This tunnel widening, thought to be due to the so-called “windshield wiper” and “bungee-cord” motion of the graft within the bone tunnel, is indicative of an unstable graft-bone construct that is prone to failure.
Improving the biologic potential of graft fixation by increasing the native bone/tendon graft contact area, while still compressing the graft and closing the bone tunnel using interference fixation, would be a desirable goal. Maintaining adequate fixation strength when using any new technique is obviously critical, and improving fixation strength while also improving the biologic properties of the fixation method would obviously represent a significant improvement in graft fixation.
This application describes a new method and apparatus to achieve these goals.
SUMMARY OF THE INVENTION
The preferred form of the present invention includes numerous novel aspects. Among these are:
(1) creation of an intervening layer of bone between the tendon graft and the compressing interference screw device; (2) allows insertion of the interference screw compression device at an oblique angle, contacting and at least partially penetrating the end of the tendon graft deep in the bone tunnel with the tip of the device—this creates the possibility of tangential interstitial fixation of the graft; and (3) development of a new interference compression device specifically designed to maximize the biomechanical and biological advantages made possible with the two concepts listed above.
A significant aspect of this new graft fixation system is the creation of a layer of native bone between the tendon graft in the bone tunnel and the interference screw used for fixation. The graft used may be a soft tissue tendon or tendon with attached bone block(s), etc. More particularly, with the present invention, using reconstruction of the ACL as an example, the tibial and femoral bone tunnels are first prepared and then the tendon is passed into them in the usual manner. Femoral fixation will be described as an example here. A small cut is made in the bone directly above, and in line with, the femoral bone tunnel so as to create an intervening wedge-shaped layer of bone. This is preferably done with a specifically designed osteotome, with or without a guide system, to ensure maximum control during the creation of the intervening bone layer. The intervening layer of bone can be created in one of two ways.
The bone layer can be created so that it is wedge-shaped, thickest at the outer end of the bone tunnel, and converging toward, and preferably converging with, the bone tunnel at the deep end of the tunnel. An interference screw device is then placed into the osteotomy site, with or without the use of a guidewire. The interference device is advanced so that the underlying layer of bone is compressed into the bone tunnel that contains the tendon graft, thereby achieving interference fixation while surrounding the tendon graft with native bone. The interference device is preferably advanced into the bone tunnel to a depth where the screw tip meets, and preferably passes at least part way through, the end of the tendon graft in the tunnel. This enhances the biomechanical fixation strength of the graft-bone tunnel construct.
Alternatively, the intervening layer of bone can be created with the osteotomy cut being made in a parallel fashion with the underlying bone tunnel, creating a more uniform intervening layer of bone between the graft and fixation device. Thus, in this form of the invention, the interference screw will be advanced substantially parallel to, and will not engage, the graft ligament.
The technique of the present invention may be used alone, as the sole manner of fixing the graft ligament in the bone tunnel, or it may be used in combination with other non-aperture fixation devices such as the ENDOBUTTON™ system or cross-pinning, etc. Such hybrid fixation utilizes the reproducible biomechanical fixation these devices provide while compressing the graft and closing the bone tunnel using this new method.
When used with tendon grafts with attached bone blocks, such as bone-patella tendon-bone (BPTB) grafts, fixation will also be enhanced by “locking” the bone block deep in the bone tunnel, deep to the bone wedge layer that has been compressed into the graft by the interference device. When using either soft tissue grafts or grafts with attached bone blocks, stable fixation at the aperture of the bone tunnel, necessary to minimize the previously described motion of the tendon within the tunnel, is provided.
This new approach also helps solve the problem of providing aperture fixation when using BPTB grafts. More particularly, the tendinous portions of these grafts are usually longer than the normal intra-articular length of the native cruciate ligament. As a result, reconstruction using a BPTB graft usually requires that the bone plug either be fixed deep in the bone tunnel, making aperture fixation impossible, or the bone plug on one end of the tendon must be doubled back on itself prior to graft passage, which presents technical difficulties. The new approach presented here provides fixation of the tendon block deep in the bone tunnel while also providing stable aperture fixation.
Significantly, the foregoing new fixation technique retains the established benefits of the interference fixation techniques currently widely utilized in ligament reconstruction. At the same time, creation of an intervening layer of bone to provide circumferential bone/tendon graft contact significantly enhances the potential for bone ingrowth into the tendon graft, which is important for clinically successful results.
A fixation device specific for this technique may enhance the benefits of the new approach described above. Several different device designs are possible. One such device is essentially a combination of a screw and pin. The screw portion, essentially similar to an interference screw, enables introduction of the implant while providing compression fixation. The modified tip of the device, of which several configurations are possible, is designed to enhance fixation strength by providing a combination of oblique interstitial transfixation and compression of the end of the tendon graft deep in the bone tunnel.
In one form of the invention, there is provided a method for reconstructing a ligament, the method comprising: creating a bone tunnel within a host bone, the bone tunnel having a proximal end and a distal end, and defining a central axis extending from the proximal end to the distal end; creating an intervening layer of bone between the central axis of the bone tunnel and a rigid portion of the host bone, the intervening layer having a first side and a second side in opposition to one another, the first side of the intervening layer facing toward the central axis of the bone tunnel and the second side of the intervening layer facing toward the rigid portion of the host bone; and compressing the intervening layer of bone against a graft ligament positioned within the bone tunnel.
In another form of the invention, there is provided apparatus for reconstructing a ligament, the apparatus comprising: creation means for creating an intervening layer of bone between a central axis of a bone tunnel and a rigid portion of the host bone, the intervening layer of bone having a first side and a second side in opposition to one another, the first side of the intervening layer facing toward the central axis of the bone tunnel and the second side of the intervening layer facing toward the rigid portion of the host bone; and compression means for compressing the intervening layer of bone against a graft ligament positioned within the bone tunnel.
In another form of the invention, there is provided an osteotome for dividing bone adjacent to a bone tunnel, the osteotome comprising: a handle having a proximal end and a distal end, and defining a longitudinal axis extending from the proximal end to the distal end; a blade disposed at the distal end of the handle, the blade having a first side and a second side in opposition to one another, the first side being configured for placement toward the bone tunnel; and at least one of the handle and the blade defining a lumen therethrough, the lumen being substantially parallel to the longitudinal axis of the handle; wherein the osteotome is configured for advancement over a guide device chosen from a group consisting of a guide pin and a guidewire, the guide device extending from bone adjacent to the bone tunnel, the osteotome is advanced into the bone, and the osteotome is withdrawn from the bone so as to create an opening through the bone adjacent to the bone tunnel with an intervening layer of bone therebetween.
In another form of the invention, there is provided an osteotome system for dividing bone adjacent to a bone tunnel, the osteotome system comprising: a guide instrument for placement of a guide device chosen from a group consisting of a guide pin and a guidewire adjacent to the bone tunnel, the guide instrument comprising: a handle having a proximal end and a distal end, and defining a first longitudinal axis extending from the proximal end to the distal end; a foot extending from the distal end of the handle, the foot having a first surface and a second surface in opposition to one another, the first surface configured for placement into the bone tunnel toward a center region thereof, and the second surface configured for placement into the bone tunnel toward a wall thereof; and an aimer extending from a given surface of the handle, the aimer defining a bore at a given height from the second surface of the handle, and the bore configured to align the guide device through the bone adjacent to the bone tunnel toward the center region of the bone tunnel; and an osteotome for dividing bone adjacent to the bone tunnel, the osteotome comprising: a handle having a proximal end and a distal end, and defining a longitudinal axis extending from the proximal end to the distal end; a blade disposed at the distal end of the handle, the blade having a first side and a second side in opposition to one another, the first side being configured for placement toward the bone tunnel; and at least one of the handle and the blade defining a lumen therethrough, the lumen being substantially parallel to the longitudinal axis of the handle; wherein the osteotome is configured for advancement over the guide device, the guide device extending from the bone adjacent to the bone tunnel, the osteotome is advanced into the bone, and the osteotome is withdrawn from the bone so as to create an adjacent to the bone tunnel with an intervening layer of bone therebetween.
In another form of the invention, there is provided a system for reconstructing a ligament, the system comprising: a guide instrument for placement of a guide device chosen from a group consisting of a guide pin and a guidewire adjacent to the bone tunnel, the guide instrument comprising: a handle having a proximal end and a distal end, and defining a first longitudinal axis extending from the proximal end to the distal end; a foot extending from the distal end of the handle, the foot having a first surface and a second surface in opposition to one another, the first surface configured for placement into the bone tunnel toward a center region thereof, and the second surface configured for placement into the bone tunnel toward a wall thereof; and an aimer extending from a given surface of the handle, the aimer defining a bore at a given height from the second surface of the handle, and the bore configured to align the guide device through the bone adjacent to the bone tunnel toward the center region of the bone tunnel; an osteotome for dividing bone adjacent to the bone tunnel, the osteotome comprising: a handle having a proximal end and a distal end, and defining a longitudinal axis extending from the proximal end to the distal end; a blade disposed at the distal end of the handle, the blade having a first side and a second side in opposition to one another, the first side being configured for placement toward the bone tunnel; and at least one of the handle and the blade defining a lumen therethrough, the lumen being substantially parallel to the longitudinal axis of the handle; wherein the osteotome is configured for advancement over the guide device, the guide device extending from the bone adjacent to the bone tunnel, the osteotome is advanced into the bone, and the osteotome is withdrawn from the bone so as to create an opening through the bone adjacent to the bone tunnel with an intervening layer of bone therebetween; and an interference compression device for compressing the intervening layer of bone against a graft ligament positioned within the bone tunnel.
In another form of the invention, there is provided a guide device for making a drill hole that will serve as a guide for a specially designed osteotome with a guide tip at its distal end; the drill hole controls the length and shape of the intervening bone layer that is created by the osteotome when the osteotome has its guide tip advanced down the guide hole in the bone, whereby to control advancement of the osteotome into the bone.
In another form of the invention, there is provided an interference screw comprising: a shaft having a distal end and a proximal end; and at least one helical thread extending between said distal end and said proximal end; said distal end of said shaft being configured for piercing a graft ligament.
In another form of the invention, there is provided a construct for a ligament reconstruction, the construct comprising: a host bone having a bone tunnel formed therein, the bone tunnel having a proximal end and a distal end, and the bone tunnel defining a central axis extending from the proximal end to the distal end; a graft ligament disposed within the bone tunnel; the host bone having an opening formed therein adjacent to the bone tunnel, the opening forming an intervening layer of bone between the central axis of the bone tunnel and a rigid portion of the host bone, the intervening layer having a first side and a second side in opposition to one another, the first side of the intervening layer facing toward the central axis of the bone tunnel and the second side of the intervening layer facing toward the rigid portion of the host bone, and the opening configured to incompletely break away the intervening layer of bone from the rigid portion of the host bone so as to hinge inwardly toward the central axis of the bone tunnel and maintain bone-to-bone opposition between the intervening layer and the rigid portion of the host bone; and an interference compression device positioned between the second side of the intervening layer of bone and the rigid portion of the host bone so as to compress the intervening layer of bone against the graft ligament positioned within the bone tunnel.
In another form of the invention, there is provided an osteotome system for dividing bone adjacent to a bone tunnel, the osteotome system comprising: a handle having a proximal end and a distal end, and defining a longitudinal axis extending from the proximal end to the distal end; a blade disposed at the distal end of the handle, the blade having a first side and a second side in opposition to one another, the first side being configured for placement toward the bone tunnel; and a guide tip extending distally away from the blade; wherein the osteotome is configured for advancement into the bone by advancing the guide tip into a guide hole formed in the bone adjacent to the bone tunnel, with the osteotome being advanced into the bone, and then withdrawn from the bone, so as to create an opening through the bone adjacent to the bone tunnel with an intervening layer of bone therebetween.
BRIEF DESCRIPTION OF THE DRAWINGS
These and other objects and features of the present invention will be more fully disclosed or rendered obvious by the following detailed description of the preferred embodiments of the invention, which is to be considered together with the accompanying drawings wherein like numbers refer to like parts and further wherein:
FIG. 1 is a schematic side view showing a graft ligament in a bone tunnel;
FIG. 2 is a schematic side view of a guide which may be used to establish the path for the osteotome to follow when forming the bone wedge;
FIG. 3A is a sectional view taken along line 3 A— 3 A of FIG. 2 ;
FIG. 3B is a sectional view taken along line 3 B— 3 B of FIG. 2 ;
FIG. 4 is a schematic view of a design for a novel osteotome for use in creating a wedge of bone above the femoral tunnel;
FIG. 5 is a sectional view taken along line 5 — 5 of FIG. 4 ;
FIG. 6 is a schematic view showing a guidewire passed through the host bone and into the graft ligament by use of the guide of FIGS. 2 , 3 A and 3 B;
FIG. 7 is a schematic view showing the bone layer created by the osteotome that follows the angle predetermined in FIG. 6 ;
FIGS. 7A , 7 B, 7 C and 7 D show alternative concepts for creating bone layers with alternative geometries;
FIG. 8 is a schematic view showing an interference screw inserted above the intervening bone wedge, with compression and interference fixation of the tendon graft being established between the posterior bone tunnel wall and the anterior bone wedge;
FIG. 9 is a schematic view showing a novel interference fixation device that can be utilized with the present invention;
FIG. 10 is a schematic view showing the invention being used on both the femoral and tibial sides of an ACL reconstruction;
FIG. 10A is a schematic side view of an alternative novel osteotome design, incorporating many of the features of the osteotome described in FIGS. 4 and 5 , but having a distal guide tip designed to follow a pre-drilled guide hole instead of being cannulated to travel over a guidewire;
FIG. 10B is a schematic side view of the novel osteotome shown in FIG. 10A ;
FIG. 10C is a schematic sectional view taken along line 10 C— 10 C of FIG. 10A ; and
FIGS. 11–25 show further aspects of the present invention in the context of an ACL reconstruction.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
This detailed description will again use the femoral side of an ACL reconstruction as an example of the multiple uses of this new concept; however, as noted above, this application is intended to be merely exemplary and the invention may be used on the tibial side of an ACL reconstruction, or in connection with some other type of ligament reconstruction, etc.
Using this new approach, the initial steps in the ACL reconstruction are unchanged from that usually done when using interference screws for graft fixation. Autografts or allografts, with or without attached bone blocks, can be utilized. Arthroscopic examination of the knee is done in the standard fashion, with debridement of the residual anterior cruciate ligament tissue and preparation of the femoral notch. The tendon graft is harvested, prepared, and measured. The bone tunnels are made in the tibia and femur in the standard fashion, typically using one of the commercially available guidance systems. As always, care should be taken with tunnel and tendon preparation, optimizing tunnel location and size, and utilizing appropriate tendon suturing methods. The graft ligament is then inserted into the bone tunnels. See FIG. 1 , which shows the tendon graft inserted into the bone tunnel formed in the bottom of the femur and extending back into the interior of the knee joint.
The present invention diverges from the standard practice once the tendon has been passed into the bone tunnels.
A significant aspect of the present invention is (i) the creation of a small, preferably wedge-shaped, layer of bone between the tendon and the wall of the host bone, and then (ii) the compression of this layer of bone against the tendon using an interference compression device set outside, and bearing against, the intervening layer of bone. The layer of bone is incompletely broken away from its native position, hinging downwards while maintaining some of the bone-to-bone apposition on its edges. With this new method, nearly the entire tendon graft is compressed by native, cancellous bone. All of the benefits of interference fixation are retained, such as exclusion of synovial fluid from the bone tunnel; at the same time, the area of contact between the graft and the host bone is increased.
As described here, the creation of the intervening bone layer can have a positive impact on the effectiveness of the ligament reconstruction procedure. Therefore, the nature and use of the osteotome used to create the bone layer can obviously have a significant impact on the successful execution of this procedure. To this end, a unique osteotome specific for this system will now be described, although the use of other designs and methods may also be utilized to practice the present invention.
One possible osteotome system comprises a guide 100 ( FIGS. 2 , 3 A and 3 B) and an osteotome 200 ( FIGS. 4 and 5 ). Guide 100 is used to establish the path that is to be followed by osteotome 200 , and osteotome 200 is then used to create the bone layer (preferably wedge-shaped) that is displaced by the interference screw so as to fix the graft ligament to the host bone. The present invention may also be practiced without the guide 100 , or without the osteotome 200 , or without both; however, it is believed that the use of guide 100 and osteotome 200 facilitate practicing of the present invention.
More particularly, and looking now at FIGS. 2 and 3 , guide instrument 100 preferably comprises a handle 105 having a foot 110 and an aimer 115 . Foot 110 has a semicircular cross-section ( FIG. 3A ) so that it will fit between the graft ligament and the wall of the bone tunnel. Aimer 115 includes a bore 120 adapted to receive and guide a guide pin or guidewire 125 , which will itself subsequently guide osteotome 200 . A slot 122 ( FIG. 3B ) connects bore 120 to the top of aimer 115 , so that guidewire 125 can be released from aimer 115 , i.e., when the distal end of the guidewire is deployed in a bone and guide instrument 100 is to be withdrawn proximally. The geometry of guide 100 ensures that the osteotome 200 is driven in line with the tunnel.
Preferably aimer 115 is constructed so that its bore 120 and slot 122 follow an axis that converges with the axis of foot 110 , so that the osteotome following this line converges with the deep end of the tunnel, whereby to create a wedge-shaped layer of bone ( FIGS. 6 and 7 ). The geometry of guide 100 also determines the thickness of the heel of the bone wedge. The exact optimal thickness of this wedge can vary, but is typically between about 3–6 mm (discussed in more detail below).
However, if desired, aimer 115 can be constructed so that its bore 120 and slot 122 follow an axis that is parallel to the axis of foot 110 , so that the osteotome following this line will pass substantially parallel to the bone tunnel, whereby to create a relatively flat layer of bone ( FIGS. 7A and 7B ). The geometry of guide 100 will determine the thickness of the bone layer.
In still another form of the invention, aimer 115 may be constructed so that its bore 120 and slot 122 follow an axis that diverges from the axis of foot 110 , so that the osteotome following this line will move away from the bone tunnel, whereby to create a distally-thickening layer of bone ( FIGS. 7C and 7D ).
Osteotome 200 is shown in FIGS. 4 and 5 . Osteotome 200 generally comprises a handle 205 and a blade 210 . When used with the cannulated system, lumen 215 extends through handle 205 and blade 210 . Lumen 215 is sized to receive guidewire 125 therein, so that osteotome 200 can ride down guidewire 125 and create the desired layer of bone. As noted above, the shape of osteotome 200 and its angle of insertion are important elements of this technique. The osteotome 200 is preferably passed into the knee through the same anterior-medial knee portal normally used for screw insertion. This angle of insertion is preferably approximately 20–50 degrees different than the tunnel angle, depending on the degree of knee flexion. With the osteotome anterior to the tunnel, the converging angles of the osteotome and the bone tunnel create an intervening bone wedge layer terminating about 20–30 mm from the tunnel entrance as the osteotome penetrates into the tunnel itself.
The osteotome shape preferably includes several elements, and the particular instrument described here incorporates these elements. It should include a slim, narrow, pointed tip 220 to help guide the instrument and keep it in line with the tunnel. The osteotome should flare fairly steeply on its inferior surface 225 so as to aid in the initial compression of the bone wedge against the tendon. The overall width 230 ( FIG. 5 ) of the osteotome should be slightly narrower than the bone tunnel diameter, creating a bone wedge just narrow enough to allow it to fit into the bone tunnel, with a slight break-away of each side of the wedge from the adjacent bone. Downwardly directed flanges 235 ( FIG. 5 ) on each side of the osteotome aid in separating the intact wedge from the surrounding bone. The bone layer should be thin enough to allow easy compression into the tunnel but thick enough to help maintain the structural integrity of the bone wedge. The shape of the osteotome, at the level of the outer bone edge, is preferably arcuate, rounded or oval, creating an easy starting point for placement of the fixation device.
During use, the ligament is first placed in the bone tunnel ( FIG. 1 ). If using guide 100 , the guide is inserted into the tunnel so that its foot 110 ( FIGS. 2 and 3A ) extends between the outer surface of the ligament and the deep wall of the bone tunnel. Then the guidewire 125 is run down aimer 115 ( FIGS. 2 and 3B ) and into the bone. The guidewire 125 is preferably advanced until it passes into the end of the tendon graft. Guide 100 is then withdrawn, leaving the guidewire 125 in place ( FIG. 6 ). Then osteotome 200 is advanced over the guidewire, into the bone and then withdrawn. Withdrawal of the osteotome leaves behind a small “tunnel above the tunnel”, with an intervening wedge shaped layer of bone ( FIG. 7 ). The bone wedge is depressed inferiorly, into the bone tunnel, with slight micro-fracturing of the bone layer edges, permitting displacement of the wedge. The interference fixation device (e.g., a traditional interference screw or a specially designed interference fixation device 300 such as shown in FIG. 8 ) is then advanced above the wedge of bone, with or without use of a guidewire, and through the osteotomy site, and preferably directly into the end portion of the tendon-graft substance. See FIG. 8 .
One of the currently commercially available interference screws may be used to provide fixation. Alternatively, a wedge-shaped element, or a frusto-conical pin, or some other form of object, preferably with ribs or ridges so as to retard withdrawal, may be used to force the formed layer of bone away from the host bone and thereby effect fixation. However, creation of a new screw shape and configuration specific for this technique represents a new device that should help improve tendon-graft fixation strength. Optimal screw length can be estimated by the use of measurement markings etched directly on the osteotome or by use of a depth gauge, if desired. Lengthening the tip of the screw and making the tip relatively “sharper” than the currently blunt-tipped screws creates a pin-like configuration that allows the tip of the screw to penetrate the tendon substance at the osteotomy/bone tunnel interface, providing some degree of tendon transfixation and thereby improving pullout strength. Altering the pitch and lead of the screw may also be beneficial, as the screw will be primarily interfacing with bone, as opposed to half bone, half tendon as is normally the situation. Also, a screw that has a degree of taper may also work better; the increased diameter at the butt end of the screw may increase compression of the bone wedge into the tendon ( FIG. 8 ).
Thus, for example, in FIG. 9 there is shown a novel interference screw 300 which comprises one preferred form of interference fixation device. Screw 300 generally comprises a body 305 including screw threads 310 . A cutting flute 315 may also be provided. An elongated leading tip 320 is disposed at the distal end of body 305 . Tip 320 is preferably sufficiently sharp to be able to transfix a ligament by passing at least partially therethrough. Screw 300 also includes a non-circular (e.g., hexagonal) recess 325 at its proximal end for receiving a driver (not shown) whereby the interference screw may be turned. If desired, screw 300 may be cannulated with a lumen 330 so that it may be deployed over a guidewire or the like.
As noted above, the foregoing description of the femoral side of an ACL reconstruction is intended to be merely one example of the multiple uses of the present invention. Thus, for example, the invention may also be used on the tibial side of an ACL reconstruction (see, for example, FIG. 10 , which shows the invention being used on both the femoral and tibial sides of an ACL reconstruction). Or the invention may be used in other types of ligament reconstruction.
It is also possible to form the desired layer of bone with a non-cannulated osteotome. More particularly, guide 100 can be used to form a guide hole into the bone with its guide pin or guidewire 125 , whereupon the guide 100 and guide pin or guidewire 125 are removed, leaving a guide hole in the bone. Then an osteotome 200 A ( FIGS. 10A–10C ) is used to form the desired layer of bone. Osteotome 200 A is preferably substantially identical to the osteotome 200 described above, except that its lumen 215 is replaced by a guide tip 215 A. During formation of the desired bone layer, guide tip 215 A is advanced into the guide hole in the bone, whereby to regulate the path and/or depth of penetration of the osteotome.
FIGS. 11–25 show further aspects of the present invention in the context of an ACL reconstruction.
If desired, the techniques of the present invention may be used alone, as the sole manner of fixing the graft ligament in the bone tunnel. Alternatively, the present invention may be used in addition to another type of fixation system, e.g., an ENDOBUTTON™ system or cross-pinning, etc.
There are several significant advantages to using this fixation system over the conventional systems currently in use. First, the tendon is still held in place by tight interference compression, but it is now surrounded by native bone. Compression on each side of the graft by cancellous bone significantly enhances circumferential bone ingrowth potential. The bone wedge has not been displaced significantly, thus allowing rapid bony healing circumferentially around the tendon graft. With the deep end of the screw at least partially imbedded into the deep portion of the tendon, any traction on the graft will likely have a “deadmanlike” pull on the screw tip, wedging the butt end of the screw into the overlying bone as tension on the graft pulls on the screw tip, thereby enhancing fixation. Also, any fixation benefits derived from the presence of a bone block or the use of fixation-augmentation devices attached to the end of the tendon, such as the ENDO-PEARL™ or similar devices, would be enhanced. The displacement of the graft attached to any of these devices or bone blocks would be inhibited by the presence of the bone wedge between the device or bone block and the tunnel outlet. Also, exclusion of synovial fluid from the bone tunnel, an ingrowth-enhancing advantage of interference fixation, is maintained.
A key but often under-appreciated element of the high pullout values in some of the more recent interference fixation studies is that the high values are usually very technique dependent. An interference screw that diverges during insertion can negate the benefits of even the best tunnel and graft preparation. The precise positioning of the screw in the bone tunnel is crucial. However, this is not always easy to control. Also, spinning of the tendon graft during insertion of the screw is a well-documented problem that is difficult to control once it has begun. This “tendon spin” can damage the graft and result in impingement and less than ideal graft positioning, possibly affecting the clinical results. One of the obvious immediate benefits of this new fixation approach is that tendon spin is completely eliminated. The fixation screw device turns against bone on all sides, preventing any occurrence of tendon spinning during insertion of the device. Screw location and placement is more controllable with the new system described here, making the results more predictable. | 1a
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CROSS-REFERENCE TO RELATED APPLICATION
[0001] This non-provisional patent application claims benefit of provisional patent application U.S. Serial No. 60/212,224 filed Jun. 15, 2000, now abandoned.
FEDERAL FUNDING LEGEND
[0002] This invention was produced in part using funds obtained through a grant from the National Institutes of Health. Consequently, the federal government has certain rights in this invention.
BACKGROUND OF THE INVENTION
[0003] 1. Field of the Invention
[0004] The present invention relates generally to the field of cellular injury. More specifically, the present invention relates to the use of ascorbic acid and its salts in promoting recovery of cellular functions following cellular injury.
[0005] 2. Description of the Related Art
[0006] Acute renal failure (ARF) is a condition of reduced renal function caused by an acute insult including ischemia and nephrotoxic compounds. Acute renal failure caused by toxicant-induced injury is often associated with injury and death of renal epithelial cells (Anderson and Schrier, 1997; Goldstein and Schnellmann, 1995). However, acute renal failure can also occur in the absence of visible tubular damage (Toback, 1992; Goldstein and Schnellmann, 1995). Numerous toxicants can cause renal dysfunction through their ability to induce sublethal injury to renal cells that results in decreased normal cellular functions without producing cell death and loss.
[0007] Renal proximal tubular cells (RPTC) play a major role in the reabsorption of ions, water, glucose, and solutes from the glomerular filtrate. Renal proximal tubular cells are the primary target of many toxicants due to their active transport functions and selective accumulation of xenobiotics. The most common alterations in renal proximal tubular cells caused by injury are: 1) loss and/or internalization of the brush border membrane microvilli, 2) mitochondrial dysfunction followed by ATP depletion and reduced metabolic functions, 3) decreased Na + -K + -ATPase activity, 4) loss of polarity of the plasma membrane, 5) altered ion homeostasis, and 6) altered transepithelial transport of ions and solutes followed by an impairment of renal proximal tubular cells reabsorptive functions (Venkatachalam et al., 1981; Molitoris et al., 1989; Meister et al., 1989; Molitoris, 1991; Mohrmann et al., 1993; Monteil et al., 1993; Kribben et al., 1994; Alejandro et al., 1995; Molck and Friis, 1997; Weinberg et al., 1997).
[0008] The Na + -K + -ATPase is responsible for the transmembrane movement of Na + and K + and mediates Na + reabsorption by renal proximal tubular cells. The Na + -K + -ATPase is localized on the basolateral membrane where it forms a metabolically stable, detergent-insoluble complex with cytoskeletal proteins such as actin, fodrin, and ankyrin (Molitoris, 1991). Following ischemic injury, Na + -K + -ATPase polarity is lost due to redistribution of this protein, ankyrin and fodrin from the basolateral to the apical membrane (Spiegel et al., 1989; Molitoris, 1991). Other forms of cell injury that lead to the depletion of intracellular ATP also are accompanied by the dissociation of the Na + -K + -ATPase from the cytoskeleton and loss of the Na + -K + -ATPase function, resulting in decreased renal Na + reabsorption (Molitoris, 1991). Injured renal proximal tubular cells are unable to restore Na + reabsorption until the re-establishment of Na + -K + -ATPase localization on the basolateral membrane has occurred (Molitoris, 1991).
[0009] Halogenated hydrocarbons represent a large group of chemicals that produce toxicity after their biotransformation to nephrotoxic cysteine S-conjugates (Elfarra et al., 1986; Dekant et al., 1994). Dichlorovinyl-L-cysteine (DCVC) is a model halocarbon nephrotoxicant that is selective for renal proximal tubular cells and produces renal proximal tubular cell necrosis and acute renal failure (Stevens et al., 1986; Van der Water et al., 1994). In renal proximal tubular cells, dichlorovinyl-L-cysteine is transformed to a thiol-containing reactive metabolite that produces nephrotoxicity through covalent binding to target cellular molecules and inhibition of renal proximal tubular cell functions (Stevens et al., 1986; Chen et al., 1994, Groves et al., 1993). Furthermore, oxidative stress also was implicated in the mechanism of dichlorovinyl-L-cysteine-induced injury in renal proximal tubular cell (Groves et al., 1991). Acute exposure of renal proximal tubular cells to dichlorovinyl-L-cysteine results in the loss of Ca 2+ homeostasis, mitochondrial dysfunction and ATP depletion, lipid peroxidation, DNA damage, loss of brush border enzymes, decreased Na + -K + -ATPase activity and active Na + transport, and inhibition of renal proximal tubular cell transport functions (Lash and Anders, 1987; Groves et al., 1991; Groves et al., 1993; Chen et al., 1994; Lash, 1994; Van der Water et al., 1994; Nowak et al., 1999).
[0010] Renal proximal tubular cell have the capacity for restoring their structure and functions after nonlethal injury induced by toxicants and ischemia/reperfusion injury. The return of renal proximal tubular cell physiological functions is critical for the restoration of normal renal function (Toback, 1992; Toback et. al., 1993). Using an in vitro model of primary cultures of rabbit renal proximal tubular cells grown in improved culture conditions, it has been shown that renal proximal tubular cells proliferate and recover physiological functions following sublethal injury induced by the oxidant t-butylhydroperoxide (Nowak et al., 1998). In contrast, dichlorovinyl-L-cysteine-induced sublethal injury decreases renal proximal tubular cell mitochondrial function, Na + -K + -ATPase activity, active Na + transport, and Na + -dependent glucose uptake but is not followed by the repair of these functions (Nowak et al., 1999). The mechanisms responsible for the inability of renal proximal tubular cell to repair their functions following dichlorovinyl-L-cysteine exposure are not known.
[0011] Thus, the prior art is deficient in an effective mean of restoring the function of renal proximal tubular cells after exposure to halocarbon nephrotoxicant. The present invention fulfills this long-standing need and desire in the art.
SUMMARY OF THE INVENTION
[0012] It has been shown previously that L-ascorbic acid phosphate (AscP) promoted the growth, mitochondrial and transport functions in primary cultures of renal proximal tubular cells (RPTC) (Nowak and Schnellmann, 1996). Furthermore, L-ascorbic acid phosphate stimulated regeneration of the renal proximal tubular cells monolayer following oxidant-induced injury by stimulation of proliferation and migration/spreading (Nowak and Schnellmann, 1997). However, it is not known whether L-ascorbic acid phosphate promotes recovery of renal proximal tubular cells functions following injury induced by halocarbon nephrotoxicant such as dichlorovinyl-L-cysteine.
[0013] The present study was designed to address this issue, and results from the present invention indicate that: 1) proliferation, mitochondrial function, Na + -K + -ATPase protein level and activity, and active Na + -transport do not recover in dichlorovinyl-L-cysteine-injured renal proximal tubular cells cultured in the presence of physiological concentrations of L-ascorbic acid phosphate; 2) pharmacological concentrations of L-ascorbic acid phosphate promote proliferation and repair of mitochondrial function, recovery of Na + -K + -ATPase protein level and activity, and return of active Na + transport in dichlorovinyl-L-cysteine-injured renal proximal tubular cells; and 3) stimulation of proliferation and recovery of mitochondrial function and active Na + transport in renal proximal tubular cells by pharmacological concentrations of L-ascorbic acid phosphate is not due to protective effects of L-ascorbic acid phosphate against dichlorovinyl-L-cysteine-induced cell death and/or decreases in mitochondrial function, Na + -K + -ATPase activity, and active Na + transport. These data also suggest that the beneficial effects of pharmacological concentrations of ascorbic acid in the kidney are not limited to antioxidant action of this molecule and that ascorbic acid may be an important tool in promoting recovery of renal functions following toxicant-induced injury.
[0014] It is an object of the present invention to use ascorbic acid and its salts to promote cell repair and regeneration.
[0015] In one embodiment of the present invention, there is provided a method of recovering cellular functions in cells following injury by contacting the cells with pharmacological concentrations of ascorbic acid or its salts. Preferably, L-ascorbic acid phosphate is used to promote proliferation and repair of mitochondrial function, recovery of Na + -K + -ATPase protein level and activity, and return of active Na + transport in halogenated hydrocarbons-injured renal proximal tubular cells.
[0016] In another embodiment of the present invention, there is provided a pharmaceutical composition, comprising ascorbic acid or its salts and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition is useful for ophthalmic applications or topical applications.
[0017] In yet another embodiment of the present invention, there is provided a method of recovering cellular functions following injury in an individual using a pharmaceutical composition of ascorbic acid. Preferably, such injury are halogenated hydrocarbon-induced nephrotoxicity, ischemia- and drug-induced acute renal failure, glomerulonephritis, acute injury to the eye, eye diseases associated with the over production of collagen (conjunctivitis, diabetes mellitus), eye disease associated with the under production of collagen (alkali burns, rheumatoid arthritis), and skin abrasions, cuts, and burns. More preferably, such treatment is used to promote proliferation and repair of mitochondrial function, recovery of Na + -K + -ATPase protein level and activity, and return of active Na + transport.
[0018] In yet another embodiment of the present invention, there is provided a product for delivery of a therapeutically effective amount of ascorbic acid comprising: (A) a strip comprising: (i) a flexible substrate sheet; and (ii) a therapeutically effective amount of ascorbic acid deposited onto said substrate sheet.
[0019] Other and further aspects, features, and advantages of the present invention will be apparent from the following description of the presently preferred embodiments of the invention. These embodiments are given for the purpose of disclosure.
BRIEF DESCRIPTION OF THE DRAWINGS
[0020] So that the matter in which the above-recited features, advantages and objects of the invention, as well as others which will become clear, are attained and can be understood in detail, more particular descriptions of the invention briefly summarized above may be had by reference to certain embodiments thereof which are illustrated in the appended drawings. These drawings form a part of the specification. It is to be noted, however, that the appended drawings illustrate preferred embodiments of the invention and therefore are not to be considered limiting in their scope.
[0021] [0021]FIG. 1 shows the effects of 0.05 and 0.5 mM L-ascorbic acid phosphate on recovery of renal proximal tubular cells monolayer DNA content following dichlorovinyl-L-cysteine (0.2 mM) exposure. Renal proximal tubular cells were cultured in the presence of 0.05 and 0.5 mM L-ascorbic acid phosphate prior to and following dichlorovinyl-L-cysteine exposure. Data are means ±SE; n=3 separate experiments. Values with different letters on a given day are significantly different (P<0.05) from each other.
[0022] [0022]FIG. 2 shows the effects of 0.05 and 0.5 mM L-ascorbic acid phosphate on recovery of renal proximal tubular cells basal oxygen consumption (QO 2 ) following dichlorovinyl-L-cysteine (0.2 mM) exposure. Renal proximal tubular cells were cultured in the presence of 0.05 and 0.5 mM L-ascorbic acid phosphate prior to and following dichlorovinyl-L-cysteine exposure. Data are means ±SE; n=6 separate experiments. Values with different letters on a given day are significantly different (P<0.05) from each other.
[0023] [0023]FIG. 3 shows the effects of 0.05 and 0.5 mM L-ascorbic acid phosphate on recovery of renal proximal tubular cells ouabain-sensitive oxygen consumption (QO 2 ) following dichlorovinyl-L-cysteine (0.2 mM) exposure. Renal proximal tubular cells were cultured in the presence of 0.05 and 0.5 mM L-ascorbic acid phosphate prior to and following dichlorovinyl-L-cysteine exposure. Data are means ±SE; n=5 separate experiments. Values with different letters on a given day are significantly different (P<0.05) from each other.
[0024] [0024]FIG. 4 shows the effects of 0.05 and 0.5 mM L-ascorbic acid phosphate on recovery of renal proximal tubular cells Na + -K + -ATPase activity following dichlorovinyl-L-cysteine (0.2 mM) exposure. Renal proximal tubular cells were cultured in the presence of 0.05 and 0.5 mM L-ascorbic acid phosphate prior to and following dichlorovinyl-L-cysteine exposure. Data are means ±SE; n=4 separate experiments. Values with different letters on a given day are significantly different (P<0.05) from each other.
[0025] [0025]FIG. 5 shows the confocal laser scanning images of α1 subunit of Na + -K + -ATPase on the apical (A, C, and E) and basolateral (B, D, and F) domain of control (A and B) and sublethally-injured renal proximal tubular cells on day 1 (C and D) and day 4 (E and F) following dichlorovinyl-L-cysteine (0.2 mM) exposure. Renal proximal tubular cells were cultured in the presence of 0.05 mM AscP prior to and following dichlorovinyl-L-cysteine exposure (magnification 800×).
[0026] [0026]FIG. 6 shows the confocal laser scanning images of α1 subunit of Na + -K + -ATPase on the apical (A, C, and E) and basolateral (B, D, and F) domain of control (A and B) and sublethally-injured renal proximal tubular cells on day 1 (C and D) and day 4 (E and F) following dichlorovinyl-L-cysteine (0.2 mM) exposure. Renal proximal tubular cells were cultured in the presence of 0.5 mM AscP prior to and following dichlorovinyl-L-cysteine exposure (magnification 800×).
DETAILED DESCRIPTION OF THE INVENTION
[0027] It has been shown that renal proximal tubular cells recover cellular functions following sublethal injury induced by the oxidant t-butylhydroperoxide but not by the nephrotoxic cysteine conjugate dichlorovinyl-L-cysteine. The present study investigated whether L-ascorbic acid phosphate promotes recovery of renal proximal tubular cells functions following dichlorovinyl-L-cysteine-induced injury. Dichlorovinyl-L-cysteine exposure (0.2 mM; 100 min) resulted in 60% renal proximal tubular cells death and loss from the monolayer at 24 hr independent of physiological (0.05 mM) or pharmacological (0.5 mM) AscP concentrations. Likewise, the dichlorovinyl-L-cysteine-induced decrease in mitochondrial function (54%), active Na + transport (66%), and Na + -K + -ATPase activity (77%) was independent of the AscP concentration. Analysis of Na + -K + -ATPase protein expression and distribution in the plasma membrane using immunocytochemistry and confocal laser scanning microscopy revealed the loss of Na + -K + -ATPase protein from the basolateral membrane of renal proximal tubular cells treated with dichlorovinyl-L-cysteine. DCVC-injured renal proximal tubular cells cultured in the presence of 0.05 mM AscP did not proliferate nor recover their physiological functions over time. In contrast, renal proximal tubular cells cultured in the presence of 0.5 mM AscP proliferated, recovered all examined physiological functions and the basolateral membrane expression of Na + -K + -ATPase by day 4 following dichlorovinyl-L-cysteine injury. These results demonstrate that pharmacological concentrations of AscP do not prevent toxicant-induced cell injury and death but promote complete recovery of mitochondrial function, active Na + -transport, and proliferation following toxicant-induced injury. These data also suggest that the recovery of renal proximal tubular cells functions following toxicant exposure produced by AscP is not due to an antioxidant effect.
[0028] It is an object of the present invention to use ascorbic acid and its salts to promote cell repair and regeneration. It is specifically contemplated that pharmaceutical compositions may be prepared using a pharmacological concentration of ascorbic acid or its salts disclosed in the present invention. It is not intended that the present invention be limited by the particular nature of the therapeutic preparation, so long as the preparation comprises ascorbic acid or its salts. These therapeutic preparations can be administered to mammals for veterinary use, such as with domestic animals, and clinical use in humans in a manner similar to other therapeutic agents. In general, the dosage required for therapeutic efficacy will vary according to the type of use and mode of administration, as well as the particularized requirements of individual hosts. A person having ordinary skill in this art would readily be able to determine, without undue experimentation, the appropriate dosages and routes of administration of ascorbic acid of the present invention.
[0029] Ascorbic acid, also known by its common name of Vitamin C, is a very unstable substance. Although readily soluble in water, rapid oxidation occurs in aqueous media. Solubility of ascorbic acid has been reported to be relatively poor in nonaqueous media, thereby preventing an anhydrous system from achieving a significant level of active concentration. Derivatives have been produced with greater stability than the parent component. See U.S. Pat. No. 5,137,723 (Yamamoto et al.) and U.S. Pat. No. 5,078,989 (Ando et al.) A two-pack approach has been developed where Vitamin C powder and other ingredients are separately packaged in different containers with mixing just prior to use. See U.S. Pat. No. 4,818,521 (Tamabuchi). Water compatible alcohols such as propylene glycol, polypropylene glycol and glycerol have been used as co-carriers alongside water to improve stability. See U.S. Pat. No. 4,983,382 (Wilmott and Znaiden).
[0030] In one embodiment of the present invention, there is provided a method of recovering cellular functions in cells following injury by contacting the cells with pharmacological concentrations of ascorbic acid or its salts. Preferably, L-ascorbic acid phosphate is used to promote proliferation and repair of mitochondrial function, recovery of Na + -K + -ATPase protein level and activity, and return of active Na + transport in halogenated hydrocarbons-injured renal proximal tubular cells.
[0031] In another embodiment of the present invention, there is provided a pharmaceutical composition, comprising ascorbic acid or its salts and a pharmaceutically acceptable carrier. Such compositions are typically prepared as liquid solutions or suspensions, or in solid forms. The compositions are also prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid prior to injection may also be prepared. When used in vivo for therapy, the ascorbic acid of the present invention is administered to the patient or an animal in therapeutically effective amounts, i.e., amounts that enhance cell repair and recovery of cell functions after injury. It will normally be administered parenterally, preferably intravenously, but other routes of administration will be used as appropriate. The dose and dosage regimen will depend upon the nature of the injury and diseases. The schedule will be continued to optimize effectiveness while balanced against negative effects of treatment. See Remington's Pharmaceutical Science, 17th Ed. (1990) Mark Publishing Co., Easton, Penn.; and Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed (1990) Pergamon Press; which are incorporated herein by reference.
[0032] In another embodiment, the present invention contemplates an ophthalmic composition of ascorbic acid or its salts in the form of aqueous eye drops, liposomes, microspheres, proteins, collagen, or soft contact lenses.
[0033] In still yet another embodiment, the present invention contemplates topical administration of ascorbic acid or its salts using solid supports (such as dressings and other matrices) and medicinal formulations (such as creams, lotions, ointments and in some cases, suppositories). In one embodiment, the solid support comprises a dressing. In still another embodiment, the solid support comprises a band-aid. The term “solid support” refers broadly to any support, including, but not limited to, microcarrier beads, gels, Band-Aids.™ and dressings. The term “dressing” refers broadly to any material applied to a wound for protection, absorbance, drainage, etc. Thus, adsorbent and absorbent materials are specifically contemplated as a solid support. Numerous types of dressings are commercially available, including films (e.g., polyurethane films), hydrocolloids (hydrophilic colloidal particles bound to polyurethane foam), hydrogels (cross-linked polymers containing about at least 60% water), foams (hydrophilic or hydrophobic), calcium alginates (nonwoven composites of fibers from calcium alginate), and cellophane (cellulose with a plasticizer) [Kannon and Garrett, Dermatol. Surg. 21:583-590 (1995); Davies, Burns 10:94 (1983)]. The present invention specifically contemplates the use of dressings impregnated with ascorbic acid of the present invention. The term “Band-Aid.” is meant to indicate a relatively small adhesive strip comprising an adsorbent pad (such as a gauze pad) for covering minor wounds.
[0034] In yet another embodiment of the present invention, there is provided a method of recovering cellular functions following injury in an individual using one of the above pharmaceutical compositions of ascorbic acid or its salts. Preferably, such injury are halogenated hydrocarbon-induced nephrotoxicity, ischemia- and drug-induced acute renal failure, glomerulonephritis, acute injury to the eye, eye diseases associated with the over production of collagen (conjunctivitis, diabetes mellitus), eye disease associated with the under production of collagen (alkali burns, rheumatoid arthritis), and skin abrasions, cuts, and burns. More preferably, such treatment is used to promote proliferation and repair of mitochondrial function, recovery of Na + -K + -ATPase protein level and activity, and return of active Na + transport.
[0035] The following examples are given for the purpose of illustrating various embodiments of the invention and are not meant to limit the present invention in any fashion.
EXAMPLE 1
[0036] Reagents
[0037] Female New Zealand White rabbits (1.5-2.0 kg) were purchased from Myrtle's Rabbitry (Thompson Station, Tenn.). S-(1,2dichlorovinyl)-L-cysteine (DCV) was a generous gift from Dr. T. W. Petry (Pharmacia Upjohn, Kalamazoo, Mich.) and was synthesized according to the method of Moore and Green (1988). Sodium dodecyl sulfate (SDS) was obtained from Bio-Rad (Hercules, Calif.). L-Ascorbic acid-2-phosphate magnesium salt and cell culture media were obtained from Wako BioProducts (Richmond, Va.) and Life Technologies (Grand Island, N.Y.), respectively. Anti-rabbit Na + /K + -ATPase subunit α1 monoclonal antibody was supplied by Upstate Biotechnology (Lake Placid, N.Y.). FITC-conjugated goat anti-mouse IgG was purchased from Chemicon (Temecula, Calif.). The sources of the other reagents have been described previously (Nowak and Schnellmann, 1996; Nowak et al., 1998; Nowak et al., 1999).
EXAMPLE 2
[0038] Isolation of Proximal Tubules and Culture Conditions
[0039] Rabbit renal proximal tubules were isolated by iron oxide perfusion method and grown in 35 mm culture dishes in improved conditions as described previously (Nowak and Schnellmann, 1996). The purity of the renal proximal tubular S 1 and S 2 segments isolated by this method is approximately 96%. The culture medium was a 50:50 mixture of Dulbecco's modified Eagle's essential medium (DMEM) and Ham's F-12 nutrient mix without phenol red, pyruvate, and glucose, supplemented with 15 mM NaHCO 3 , 15 mM N-2hydroxyethylpiperazine-N′-2-ethanesulfonic acid, and 6 mM lactate (pH7.4, 295 mosmol/kg). Human transferrin (5 μg/ml), selenium (5 ng/ml), hydrocortisone (50 nM), bovine insulin (10 nM), and L-ascorbic acid-2-phosphate (0.05 mM or 0.5 mM) were added to the medium immediately before daily media change (2 ml/ dish).
EXAMPLE 3
[0040] Toxicant Treatment of Renal Proximal Tubular Cells Monolayer
[0041] Renal proximal tubular cells monolayers reached confluence within 5 days and were treated with dichlorovinyl-L-cysteine (0.2 mM, 100 min) on day 6 of culture. Following dichlorovinyl-L-cysteine exposure, the remaining monolayer was washed with fresh medium and cultured for 4 days. Samples of renal proximal tubular cells were taken at various time points after dichlorovinyl-L-cysteine exposure for measurements of cellular functions. Prior to measurement of any functions, renal proximal tubular cells were washed with ice cold phosphate buffered saline (pH 7.4) or 37° C. culture media (for measurement of oxygen consumption, QO 2 ) to remove non-viable cells.
EXAMPLE 4
[0042] Oxygen Consumption
[0043] Washed renal proximal tubular cells monolayers were gently detached from the dishes with a rubber policeman, suspended in 37° C. culture medium and transferred to the oxygen consumption (QO 2 ) measurement chamber. QO 2 was measured polarographically using Clark type electrode as described previously (Nowak and Schnellmann, 1996; Nowak et al., 1998; Nowak et al., 1999). Ouabain-insensitive QO 2 was measured in the presence of 0.1 mM ouabain and was calculated as a difference between basal and ouabain-insensitive QO 2 .
EXAMPLE 5
[0044] Measurement of Na + -K + -ATPase Activity
[0045] Na + -K + -ATPase activity was determined in cellular lysates by measuring the difference between total ATPase activity and ouabain-insensitive ATPase activity using the method of Schwartz and Evan (1984). Cellular lysates were prepared as described by Forbush (1983). Briefly, 0.1-0.5 mg of renal proximal tubular cells protein was added to 0.1 ml of 25 mM imidazole buffer (pH 7.0) containing 0.065% SDS and 1% bovine serum albumin (BSA). Following incubation for 10 min at 22° C., 0.6 ml of 0.3% BSA in 25 mM imidazole buffer was added to lower the SDS concentration and 0.05 ml aliquots used for measurement of Na + -K + -ATPase activity.
EXAMPLE 6
[0046] Assessment of Renal Proximal Tubular Cells Proliferation
[0047] Monolayer DNA content was used as a marker of renal proximal tubular cells proliferation. Monolayers were solubilized in 0.05 M Tris-HCl (pH 7.4) containing 0.15 M NaCl and 0.05% Triton X-100 and DNA determined in cell lysates by the method of Labarca and Paigen (1980) as described previously (Nowak and Schnellmann, 1996). Protein was measured by the method of Lowry et al. (1951).
EXAMPLE 7
[0048] Immunocytochemical Localization of Na + -K + -ATPase
[0049] At various time points following dichlorovinyl-L-cysteine exposure, control and DCVC-treated renal proximal tubular cells monolayers were washed 3 times with ice-cold PBS and fixed in 3.7% formaldehyde. Following permeabilization with 100% methanol for 10 min at −20° C., renal proximal tubular cells monolayers were washed with PBS containing 0.1% BSA and 0.3% Triton X-100 (PBS/0.1% BSA/0.3% Triton X-100) for 15 min at room temperature. Blocking of non-specific binding was performed for 30 min in PBS containing 8% BSA. Following washing with PBS/0.1% BSA/0.3% Triton X-100 for 15 min, renal proximal tubular cells were incubated overnight at 4° C. with the anti-α1 Na + -K + -ATPase monoclonal antibody (Upstate Biotechnology, Lake Placid, NY) (5 μg/ml) diluted in PBS containing 1% BSA. Monolayers were washed with PBS/0.1% BSA/0.3% Triton X-100 for 30 min and incubated for 3 hr at room temperature with goat anti-mouse IgG fluorescein-conjugated secondary antibody (Chemicon, Temecula, Calif.) diluted in PBS (10 μg/ml). Following washing with PBS/0.1% BSA/0.3% Triton X-100 for 30 min, cells were mounted in mounting media (0.1M Tris-HCl, pH 8.5 containing 0.25% 1,4-diazabicyclooctane, 5% n-propyl gallate, 10% polyvinyl alcohol, and 25% glycerol) and examined using a Zeiss 1 0 confocal laser scanning microscope at a magnification of 800×. Fluorescent images were generated using an argon laser set at 488 nm wavelength and a 520 nm pass barrier filter. Following the establishment of the coordinates of the apical and basal surfaces in renal proximal tubular cells monolayers, 10 optical Z-plane sections were obtained from the basal to apical domain with the step-shift of focal plane of 1 μm. Digital fluorescent images collected from the focal planes were assigned their location relative to the basal or apical surfaces and captured.
EXAMPLE 8
[0050] Statistical Analysis
[0051] Data are presented as means ±SE and were analyzed for significance using two-way ANOVA. Multiple means were compared using Student-Newman-Keuls test. Statements of significance were based on P<0.05. Renal proximal tubules isolated from an individual rabbit represented a separate experiment (n=1) consisting of data obtained from 3 culture dishes.
EXAMPLE 9
[0052] Proliferation of Renal Proximal Tubular Cells
[0053] Monolayer DNA contents in control renal proximal tubular cells (RPTC) grown in the presence of 0.05 and 0.5 mM L-ascorbic acid phosphate were equivalent (FIG. 1). Exposure of confluent renal proximal tubular cells to dichlorovinyl-L-cysteine resulted in 61% loss of monolayer DNA at 24 hr following the treatment, regardless of the concentration of L-ascorbic acid phosphate (0.05 mM and 0.5 mM) in the medium during the culture period and the toxicant exposure (FIG. 1). Monolayer DNA contents in dichlorovinyl-L-cysteine-injured renal proximal tubular cells grown in the presence of a physiological concentration (0.05 mM) of AscP did not increase during the recovery period (FIG. 1). In contrast, monolayer DNA contents in dichlorovinyl-L-cysteine-injured renal proximal tubular cells grown in the presence of a pharmacological concentration (0.5 mM) of L-ascorbic acid phosphate increased by 1.6- and 2.3-fold on days 2 and 4, respectively, and was 81% of controls on day 4 (FIG. 1). These data show that dichlorovinyl-L-cysteine-induced cell death and loss are equivalent in renal proximal tubular cells grown in the presence of physiological and pharmacological concentrations of L-ascorbic acid phosphate, but the higher concentration of L-ascorbic acid phosphate promotes renal proximal tubular cells proliferation and regeneration.
EXAMPLE 10
[0054] Mitochondrial Function of Renal Proximal Tubular Cells
[0055] Basal QO 2 was used as a marker of mitochondrial function in renal proximal tubular cells. In control renal proximal tubular cells, basal QO 2 was equivalent in cells grown in the presence of 0.05 and 0.5 mM AscP (FIG. 2). In sublethally injured renal proximal tubular cells grown in the presence of 0.05 mM L-ascorbic acid phosphate, dichlorovinyl-L-cysteine exposure decreased basal QO 2 by 59% at 24 hr following injury. No significant changes in basal QO 2 occurred in these renal proximal tubular cells during the 4 day recovery period (FIG. 2). Likewise, dichlorovinyl-L-cysteine produced a 62% decrease in basal QO 2 in renal proximal tubular cells grown in the presence of 0.5 mM L-ascorbic acid phosphate. However, in contrast to renal proximal tubular cells grown in the presence of a physiological concentration of L-ascorbic acid phosphate, basal QO 2 in renal proximal tubular cells cultured in the presence of a pharmacological concentration of L-ascorbic acid phosphate completely recovered on day 4 following dichlorovinyl-L-cysteine exposure (FIG. 2).
[0056] At 24 hr following dichlorovinyl-L-cysteine treatment, ouabain-insensitive QO 2 decreased 32% (9.7±1.6 vs. 6.6±2.6 nmol O 2 /min/mg protein in control and dichlorovinyl-L-cysteine-treated renal proximal tubular cells, respectively) in the presence of 0.05 mM L-ascorbic acid phosphate and by 50% (12.9±1.5 vs. 6.5±1.0 nmol O 2 /min/mg protein in control and dichlorovinyl-L-cysteine-treated renal proximal tubular cells, respectively) in the presence of 0.5 mM AscP. Ouabain-insensitive QO 2 remained decreased (45%) through day 4 in dichlorovinyl-L-cysteine-injured renal proximal tubular cells grown in the presence of 0.05 mM AscP but fully recovered in injured renal proximal tubular cells cultured in the presence of 0.5 mM L-ascorbic acid phosphate (data not shown). These data show that dichlorovinyl-L-cysteine-induced decreases in the mitochondrial function are equivalent in renal proximal tubular cells grown in the presence of physiological and pharmacological concentrations of L-ascorbic acid phosphate, but a pharmacological concentration of L-ascorbic acid phosphate promotes recovery of this function following sublethal injury.
EXAMPLE 11
[0057] Basolateral Membrane Function of Renal Proximal Tubular Cells
[0058] Active Na + transport was used as a marker of basolateral membrane function in renal proximal tubular cells. Active Na + transport in renal proximal tubular cells was assessed by measurements of ouabain-sensitive QO 2 and Na + -K + -ATPase activity. Ouabain-sensitive QO 2 was equivalent in control renal proximal tubular cells grown in the presence of 0.05 and 0.5 mM L-ascorbic acid phosphate (FIG. 3). At 24 hr following dichlorovinyl-L-cysteine exposure, ouabain-sensitive QO 2 decreased approximately 66% and was not statistically different in renal proximal tubular cells grown in the presence of 0.05 and 0.5 mM L-ascorbic acid phosphate (FIG. 3). Na + -K + -ATPase activity at 24 hr following dichlorovinyl-L-cysteine treatment was reduced by approximately 77% in cells grown in the presence of 0.05 and 0.5 mM L-ascorbic acid phosphate (FIG. 4). Neither ouabain-sensitive QO 2 nor Na + -K + -ATPase activity recovered following dichlorovinyl-L-cysteine injury in renal proximal tubular cells grown in the presence of a physiological concentration of L-ascorbic acid phosphate (FIGS. 3 and 4). However, ouabain-sensitive QO 2 and Na + -K + -ATPase activity recovered following dichlorovinyl-L-cysteine injury in renal proximal tubular cells grown in the presence of 0.5 mM AscP (FIG. 3 and 4). These data show that dichlorovinyl-L-cysteine-induced decreases in active Na + transport and Na + -K + -ATPase activity are equivalent in renal proximal tubular cells grown in the presence of physiological and pharmacological concentrations of L-ascorbic acid phosphate but a pharmacological concentration of L-ascorbic acid phosphate stimulates repair of these functions following sublethal injury.
EXAMPLE 12
[0059] Subcellular Localization of Na + - K + -ATPase
[0060] To examine Na + -K + -ATPase distribution on the plasma membrane of control renal proximal tubular cells, optical Z-plane sections were produced from basal to apical domains and images collected from various focal planes. FIGS. 5 and 6 show sections through apical (A) and basal (B) domains of control renal proximal tubular cells grown in the presence of 0.05 (FIG. 5) and 0.5 mM (FIG. 6) L-ascorbic acid phosphate. While the Na + -K + -ATPase protein is abundant in the basolateral domain of renal proximal tubular cells, it is almost absent from the apical domain (FIG. 5A and B). These results demonstrate the polarized distribution of Na + -K + -ATPase on the plasma membrane of confluent renal proximal tubular cell cultures, similar to that found in renal proximal tubular cells in vivo. The data also show that there is no difference in the basolateral Na + -K + -ATPase protein levels and distribution between renal proximal tubular cells grown in the presence of a physiological (FIG. 5A and B) and a pharmacological (FIG. 6A and B) concentration of L-ascorbic acid phosphate.
[0061] DCVC-induced injury was associated with the loss of the Na + -K + -ATPase protein from the basolateral domain of renal proximal tubular cells independent of the L-ascorbic acid phosphate concentration in the medium (FIG. 5D and 6D). No recovery of the Na + -K + -ATPase protein occurred in DCVC-injured renal proximal tubular cells grown in the presence of 0.05 mM L-ascorbic acid phosphate (FIG. 5E and F). In contrast, the Na + -K + -ATPase protein levels of renal proximal tubular cells grown in the presence of 0.5 mM L-ascorbic acid phosphate completely recovered during the 4 day regeneration period following dichlorovinyl-L-cysteine injury. Furthermore, the Na + -K + -ATPase protein was localized to the basolateral domain in a manner similar to that of controls (FIG. 6E and F).
[0062] These data demonstrate that dichlorovinyl-L-cysteine exposure in renal proximal tubular cells induces a loss of the Na + -K + -ATPase protein from the plasma membrane. The results also show that DCVC-induced loss of Na + -K + -ATPase from the plasma membrane is equivalent in renal proximal tubular cells grown in the presence of a physiological and pharmacological concentration of L-ascorbic acid phosphate, but a pharmacological concentration of L-ascorbic acid phosphate promotes the restoration of protein levels and polarized distribution of the Na + -K + -ATPase on the plasma membrane. These observations are consistent with: 1) the lack of recovery of the Na + K + -ATPase activity and active Na + transport in DCVC-injured renal proximal tubular cells cultured in the presence of physiological concentrations of L-ascorbic acid phosphate and 2) promotion of recovery of these renal proximal tubular cells functions by pharmacological concentrations of L-ascorbic acid phosphate (FIGS. 3 and 4).
[0063] Discussion
[0064] Renal dysfunction following toxicant-induced injury may result from cellular injury and decreases in physiological cell functions and also by the inhibition of cellular recovery by certain nephrotoxicants. Recently, it has been demonstrated that renal proximal tubular cells in primary culture undergo complete morphological regeneration of the monolayer following sublethal injury induced by an oxidant (tert-butyl hydroperoxide, TBHP) and that this process is due to cellular repair, proliferation and migration/spreading (Nowak and Schnellmann, 1997; Nowak et al., 1998). The decreases in mitochondrial function, intracellular ATP content, Na + -K + -ATPase activity, active Na + transport, and Na + -coupled glucose uptake in sublethally-injured renal proximal tubular cells after TBHP exposure are followed by complete recovery of these functions, with cellular proliferation and monolayer regeneration preceding the return of mitochondrial and transport functions (Nowak et al., 1998). This recovery is not dependent on exogenous mitogens or factors stimulating cellular repair. Thus, renal proximal tubular cells in primary culture have the autocrine mechanisms necessary for complete morphological and functional repair following sublethal injury induced by an oxidant.
[0065] In contrast, dichlorovinyl-L-cysteine exposure that results in a similar degree of cell death and loss (30%) from the monolayer and sublethal injury to the remaining cells, is not followed by monolayer regeneration nor recovery of mitochondrial and transport function (Nowak et al., 1999). The inhibition of renal proximal tubular cells regeneration after dichlorovinyl-L-cysteine-induced injury can be overcome by daily epidermal growth factor (EGF, 10 ng/ml) treatments which suggest, that EGF activates mechanisms of cellular repair that had been inhibited by dichlorovinyl-L-cysteine (Nowak et al., 1999).
[0066] Previously, it was demonstrated that ascorbic acid phosphate increases proliferation and mitochondrial and transport functions in renal proximal tubular cells, and promotes morphological regeneration of renal proximal tubular cells following TBHP exposure by stimulation of proliferation and migration/spreading (Nowak and Schnellmann, 1996; Nowak and Schnellmann, 1997). The present study tested the hypothesis that pharmacological concentrations of L-ascorbic acid phosphate promote recovery of renal proximal tubular cells functions following dichlorovinyl-L-cysteine-induced injury. Renal proximal tubular cells were grown in the presence of physiological (0.05 mM) and pharmacological (0.5 mM) concentrations of L-ascorbic acid phosphate and exposed to 0.2 mM dichlorovinyl-L-cysteine to produce cell injury. The results demonstrate that dichlorovinyl-L-cysteine produced a similar degree of cell death and decreases in renal proximal tubular cells functions at both concentrations of L-ascorbic acid phosphate and suggested that pharmacological concentrations of L-ascorbic acid phosphate had no protective effect against dichlorovinyl-L-cysteine-induced injury in renal proximal tubular cells.
[0067] In the presence of a physiological concentration of L-ascorbic acid phosphate, the decrease in cell number due to dichlorovinyl-L-cysteine-induced cell death was not followed by proliferation and restoration of the monolayer. These data suggest that dichlorovinyl-L-cysteine exposure inhibits renal proximal tubular cells proliferation. In contrast, proliferation occurred following dichlorovinyl-L-cysteine exposure in renal proximal tubular cells grown in the presence of pharmacological concentrations of L-ascorbic acid phosphate. Previous results suggested that the lack of proliferation following dichlorovinyl-L-cysteine exposure in renal proximal tubular cells grown in the presence of physiological concentrations of L-ascorbic acid phosphate is due to the lack of mitogenic signals in dichlorovinyl-L-cysteine-injured renal proximal tubular cells and that EGF stimulates renal proximal tubular cells proliferation and regeneration following dichlorovinyl-L-cysteine-induced injury (Nowak et al., 1999). The present data show that sublethally-injured renal proximal tubular cells grown in the presence of pharmacological concentrations of L-ascorbic acid phosphate maintain the ability to proliferate and restore the monolayer following dichlorovinyl-L-cysteine-induced injury.
[0068] Mitochondrial function, active Na + transport and Na + -K + -ATPase, and Na + -dependent glucose uptake are major targets of dichlorovinyl-L-cysteine in renal proximal tubular cells (Lash and Anders, 1987; Groves et al., 1993; Van de Water et al., 1994, Stevens et al., 1986, Vamvakas et al., 1996, Nowak et al., 1999). In the present model, the decrease in mitochondrial function is observed immediately after dichlorovinyl-L-cysteine removal from the monolayers and prior to any evidence of renal proximal tubular cells injury or death (Nowak et al., 1999). Mitochondrial function in renal proximal tubular cells grown in the presence of physiological concentrations of L-ascorbic acid phosphate did not recover following dichlorovinyl-L-cysteine exposure; in contrast to the complete recovery of this function after oxidant-induced injury (Nowak et al., 1998). However, basal QO 2 recovered on day 2 following dichlorovinyl-L-cysteine exposure in renal proximal tubular cells grown in the presence of pharmacological concentrations of L-ascorbic acid phosphate, demonstrating that that L-ascorbic acid phosphate stimulates the repair of mitochondrial function in renal proximal tubular cells following toxicant injury. Promotion of the recovery of mitochondrial function by pharmacological concentrations of L-ascorbic acid phosphate was not due to protection against dichlorovinyl-L-cysteine toxicity since the decreases in mitochondrial function at 24 hr following dichlorovinyl-L-cysteine exposure were equivalent in the presence of physiological and pharmacological concentrations of L-ascorbic acid phosphate. Therefore, it is concluded that the recovery of mitochondrial function in dichlorovinyl-L-cysteine-injured renal proximal tubular cells grown in the presence of pharmacological concentrations of L-ascorbic acid phosphate is not due to the antioxidant effect of L-ascorbic acid phosphate.
[0069] The present results show that active Na + transport is a target of dichlorovinyl-L-cysteine in renal proximal tubular cells and that this function does not recover in renal proximal tubular cells grown in the presence of physiological concentrations of L-ascorbic acid phosphate (FIG. 3). In contrast, pharmacological concentrations of L-ascorbic acid phosphate stimulate recovery of active Na + transport in renal proximal tubular cells following dichlorovinyl-L-cysteine-induced injury. The return of active Na + transport to control levels occurred on day 4 after dichlorovinyl-L-cysteine exposure and followed the recovery of mitochondrial function. The decrease in active Na + transport is the result of the inhibition of Na + K + -ATPase activity and loss of Na + -K + -ATPase protein in dichlorovinyl-L-cysteine-injured renal proximal tubular cells (Nowak et al., 1999). The mechanism of dichlorovinyl-L-cysteine-induced decrease in Na + -K + -ATPase activity and protein is not clear. Previously, it was shown that dichlorovinyl-L-cysteine causes depolymerization of F-actin and disorganization of cellular cytoskeleton (Van der Water et al., 1994). These alterations are usually associated with loss of cell polarity (Molitoris et al., 1989). Because Na + -K + -ATPase is localized to basolateral membrane and associated with the cytoskeleton through F-actin, depolymerization of actin contributes to the loss of Na + -K + -ATPase protein from basolateral membrane of injured cells. Independently, the loss of mitochondrial function and ATP depletion may also contribute to the decrease in Na + -K + -ATPase activity.
[0070] Na + -K + -ATPase loss after dichlorovinyl-L-cysteine exposure is not followed by the recovery of Na + -K + -ATPase protein nor its basolateral localization in sublethally-injured renal proximal tubular cells cultured in the presence of physiological concentrations of L-ascorbic acid phosphate. This fact may be due to a deficiency in both F-actin polymerization and repair of actin cytoskeleton, and/or decreased synthesis of new Na + -K + -ATPase protein. The lack of recovery of mitochondrial function and ATP levels may further arrest the recovery of Na + -K + -ATPase activity. In contrast, in renal proximal tubular cells cultured in the presence of pharmacological concentrations of L-ascorbic acid phosphate, protein levels of Na + -K + -ATPase completely recovered following dichlorovinyl-L-cysteine-induced injury. Furthermore, Na + -K + -ATPase protein in regenerating renal proximal tubular cells was localized mainly to basolateral membrane which indicated the recovery of renal proximal tubular cells plasma membrane polarity. Recovery of Na + -K + -ATPase protein levels was associated with the return of Na + -K + -ATPase enzymatic activity and recovery of active Na + transport. In addition, L-ascorbic acid phosphate did not protect against the loss of Na + -K + -ATPase protein and activity following dichlorovinyl-L-cysteine exposure (FIGS. 4 and 5). Therefore, one can conclude that pharmacological concentrations of L-ascorbic acid phosphate promote recovery of Na + -K + -ATPase protein and activity through the mechanisms other than the antioxidant effect of this molecule.
[0071] The precise mechanism by which the injured epithelium regenerates through proliferation and recovers normal cellular architecture is not known. Ascorbic acid is a well known stimulator of collagen production and deposition into the basement membrane, and previous reports suggested that L-ascorbic acid phosphate may promote cell proliferation and increase cell density through increased collagen deposition (Peterkofsky, 1991; Murad et al., 1983). The composition of the basement membrane may play an essential role in the recovery process of renal proximal tubular cells by providing extracellular signals for proliferative responses and a structural framework for regaining cellular polarity. However, contribution of other potential mechanisms, unrelated to collagen deposition, to the recovery processes in renal proximal tubular cells is possible.
[0072] In conclusion, the present results show that: 1) proliferation, mitochondrial function, Na + -K + -ATPase protein level and activity, and active Na + -transport do not recover in dichlorovinyl-L-cysteine-injured renal proximal tubular cells cultured in the presence of physiological concentrations of L-ascorbic acid phosphate, 2) pharmacological concentrations of L-ascorbic acid phosphate promote proliferation and repair of mitochondrial function, recovery of Na + -K + -ATPase protein level and activity, and return of active Na + transport in dichlorovinyl-L-cysteine-injured RPTC, and 3) stimulation of proliferation and recovery of mitochondrial function and active Na + transport in renal proximal tubular cells by pharmacological concentrations of L-ascorbic acid phosphate is not due to protective effects of L-ascorbic acid phosphate against DCVC-induced cell death and/or decreases in mitochondrial function, Na + -K + -ATPase activity, and active Na + transport. These data also suggest that the beneficial effects of pharmacological concentrations of ascorbic acid in the kidney are not limited to antioxidant action of this molecule and that ascorbic acid may be an important tool in promoting recovery of renal functions following toxicant-induced injury.
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[0114] Any patents or publications mentioned in this specification are indicative of the levels of those skilled in the art to which the invention pertains. Further, these patents and publications are incorporated by reference herein to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.
[0115] One skilled in the art will appreciate readily that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those objects, ends and advantages inherent herein. The present examples, along with the methods, procedures, treatments, molecules, and specific compounds described herein are presently representative of preferred embodiments, are exemplary, and are not intended a s limitations on the scope of the invention. Changes therein and other uses will occur to those skilled in the art which are encompassed within the spirit of the invention as defined by the scope of the claims. | 1a
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This application claims benefit of priority to U.S. Provisional Patent Application Ser. No. 60/695,446, filed Jul. 1, 2005, the contents of which are hereby incorporated by reference.
FIELD OF THE INVENTION
The present invention relates to novel methods of treatment using hyaluronic acid. More particularly, the invention relates to methods of correcting tissue prolapse and/or tissue atrophy (or loss) by administering injections into the deep part of the skin (i.e., deep fat or just above the bone) using large injections of hyaluronic acid which has been formulated for injection into the superficial part of the skin.
BACKGROUND OF THE INVENTION
Hyaluronic acid, which is also referred to as hyaluronan or “HA,” is a naturally occurring, water soluble polysaccharide that is a major component of the extracellular matrix and is widely distributed in animal tissues. Naturally-occurring HA generally has a molecular weight range of between about 6×10 4 to about 8×10 6 Daltons. It has excellent biocompatibility and does not produce a foreign body or allergic reaction when implanted into a subject.
Methods of preparing commercially available hyaluronan are known. Further, many forms of HA have been employed, for example as surgical aids to prevent post operative adhesions of tissues, as adjuncts to synovial fluid in joints, as fluid replacement and/or surgical aids in ophthalmic surgery, as a scaffold for tissue engineering in vitro or guided tissue regeneration or augmentation in vivo, and the like.
Hyaluronic acid (HA) gel products have been injected into joints for arthritis and superficially into the skin to treat wrinkles. In the skin they are typically injected as tiny drops or feathered into the skin as fine lines in the layer called the dermis. The skin is divided into the epidermis the most outer layer and then the dermis and then the fat and lastly the muscle and or bone. If one injects into the fat using the above techniques with the available commercial products, it is expected that the material will disappear quickly because the body breaks down the material with a naturally occurring enzyme called hyaluronidase. HA that is deposited in the form of relatively small microdroplets or feathered lines can be readily broken down by hyaluronidase.
Previous attempts to inject a small amount of hyaluronic acid material along the ridge of the bone have been made, but they generally use a small amount of hyaluronic acid material to try to soften the appearance of grooves, such as those that commonly occur under the eyes.
Recently, in 2006, a deep form of HA treatment using a larger molecule of HA was approved in 2006 for injection into deep tissues using a large bore needle. However, this technique requires a surgical incision to permit entry of the needle. The longevity of this treatment is presently believed to be about 1 year.
Accordingly, none of the above-mentioned techniques provides long-term methods for minimizing the appearance of deep wrinkles or folds in the skin by administering bolus injections of hyaluronic acid. There is a need in the art for long-term, non-surgical methods that are useful for reducing or eliminating undesirable folds or wrinkles of the skin.
SUMMARY OF THE INVENTION
In the technique of the present invention, a relatively large amount of hyaluronic acid, for example an entire syringe, is emptied into one area without moving the needle, thereby creating a deep nodule or bolus of the hyaluronic acid material that does not break down readily. Without being limited by any particular mechanism of action, it is theorized that when this technique is employed, the breakdown of the HA is prevented because of limited access by the hyaluronidase, or because of the creation of an amorphous avascular mass which is walled off and therefore inaccessible to enzymes. This deep nodule or bolus of HA lifts up the skin.
The methods of the invention are useful for correcting tissue prolapse and/or tissue atrophy (or loss), particularly in the area of the upper middle face and cheek. The methods of the invention involve administering injections into the deep part of the skin (i.e., deep fat or just above the bone) using large injections of hyaluronic acid which has been formulated for injection into the superficial part of the skin. By defining certain important injection sites, the present inventor has been able to develop a technique which allows the cheek to be sculpted and permits the groove under the eye to be lifted, giving a more youthful appearance.
Embodiments of this invention include raising the cheek and lifting the groove under the eye to a higher location typically seen in a younger face. A unique feature of the present invention technique is the creation of the bolus, that is, creating a nodule in the deep tissue that can obliterate the groove and also raise the cheeks, while providing better durability and a long-lasting effect.
In a first embodiment of the invention, the bolus technique is used to form a nodule of hyaluronic acid in an imperfection in the skin of a patient. The imperfection may be a wrinkle, fold, scar, or sunken area.
In another embodiment of this invention, an injection can be made the same way into the tissue to create the effect of an implant. Preferred locations for such implants include the chin and the cheek. Creating such a nodule in the deeper tissue may also have applications in other areas of the body.
In a further embodiment of this invention, the bolus technique is utilized to repair what is referred to as malar bags or festoons, which are sacks of loose skin seen under the eyes, by filling the area under the bag with a nodule.
Other features and advantages of the present invention will become apparent to those skilled in the art upon examination of the following or upon learning by practice of the invention.
DETAILED DESCRIPTION OF THE DRAWINGS
FIG. 1 is a photograph showing a side view of a prominent malar bag under a patient's left eye.
FIG. 2 is a photograph showing a front view of the prominent malar bag under the patient's left eye.
FIG. 3 is a photograph showing a showing a side view of the patient's left eye after being treated in accordance with the methods of the present invention.
FIG. 4 is a photograph showing a front view of the patient's left eye after being treated in accordance with the methods of the present invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The term “hyaluronic acid” (HA) as used in the present application refers to hyaluronic acid or salts of hyaluronic acid, such as the sodium, potassium, magnesium and calcium salts, among others. The term “hyaluronic acid” is also intended to include not only elemental hyaluronic acid, but hyaluronic acid with other trace of elements or in various compositions with other elements, as long as the chemical and physical properties of hyaluronic acid remain unchanged. In addition, the term “hyaluronic acid” as used in the present application is intended to include natural formulas, synthetic formulas or combination of these natural and synthetic formulas.
Embodiments of this invention are directed to a technique where a relatively large amount of hyaluronic acid, for example an entire syringe, is emptied into one area creating a deep nodule of the hyaluronic acid material in the deep tissue that does not break down readily, perhaps by limiting access to the hyaluronidase. The deep nodule or bolus lifts up the skin.
The methods of the invention may be beneficially used to correct tissue prolapse and/or tissue atrophy (or loss) in any area, and are particularly useful when applied in the area of the upper middle face and cheek. The methods of the invention involve administering injections into the deep part of the skin (i.e., deep fat or just above the bone) using large injections of a hyaluronic acid composition that has been formulated for injection into the superficial part of the skin. By defining certain important injection sites, the present inventor has been able to develop a technique which allows the cheek to be sculpted and also raises the groove under the eye giving a more youthful appearance.
Embodiments of this invention include raising the cheek and lifting the groove under the eye to a higher location, as is typically seen in a younger face. One unique feature of the Tri-Site Bolus™ technique of the present invention is the creation of the bolus, that is, creating a small nodule in the deep tissue that can obliterate the groove and also raise the cheeks and also have a longer durability. The nodule can be, for example, approximately the size of a grape. However, modification of the shape and size of the nodule to suit the particular application is envisioned in accordance with the present invention.
In another embodiment of this invention, an injection can be made the same way into the chin to create the effect of a chin implant. Such implants can also be created in other locations where a raised contour is desired, such as the cheekbones.
Creating the non-visible nodule in the deeper tissue may have applications for other areas. For example, the nodule may be formed in the fatty tissue of the cheek, in order to counter the hollow-cheeked appearance that commonly occurs as a result of aging.
In another embodiment of this invention, the same bolus technique is utilized to repair what is referred to as malar bags, which are sacks of loose skin seen under the eyes. Typically, surgery cutting out the excess skin was the only option. FIGS. 1-4 are photos that show the correction of a prominent malar bag under the left eye of a patient using the methods of the present invention. Thus, the bolus technique can be effectively utilized for correction of malar bags using injections of hyaluronic acid.
The injections used in the methods of the present invention can be made, for example, at a depth of 0.3-1.5 cm below the surface of the skin. However, one of skill in the art will appreciate that the depth at with the injection is made will vary depending on the specific injection site. Further, the injections can be administered without requiring large bore needles or surgical incisions, as the methods of the present invention utilize small bore needles. Preferably, the hyaluronic acid bolus is injected into the skin using a needle having a gauge of from 24 (0.559 mm) to 30 (0.305 mm), where the bolus is more preferably injected using a needle having a gauge of from 26 (0.457 mm) to 28 (0.356 mm), and is most preferably injected using a 27 gauge needle (0.406 mm).
A hyaluronic acid product having a thickness of 30 viscosity is presently preferred. Examples of products that can be used include Juvederm® (a highly-crosslinked hyaluronic acid product sold by Allergan, Inc.) and RESTYLANE® Perlane® (a non-animal stabilized hyaluronic acid product used to fill deep folds, sold by Q-Med AB). For example, the product Juvederme® 30 can be effectively used in the embodiments of this invention. However, use of any medically-acceptable hyaluronic acid product is envisioned in accordance with the present invention.
In some embodiments of this invention, about 1.5 to 6, preferably about 3 to 4, full syringes (for example 0.7 cc or 0.8 cc syringes) can be injected on each side of the subject's face to fill wrinkles or folds in the skin. It is preferred that at least 1 cc, more preferably at least 2 cc, even more preferably about 2 to 3 cc, are injected on each side. One of skill in the art will appreciate that the amount of hyaluronic acid to be injected will also vary depending on the specific injection site.
Although the methods of the present invention primarily address the use of hyaluronic acid, use of other injectables is also envisioned. Additional uses for the methods of the present invention, beyond use in the cheeks, under the eyes, and in the chin, are also envisioned. For example, and without Limitation, the methods of the present invention may also be useful for filling scars or other surface deformities in the skin.
It will, of course, be appreciated that the above description has been given by way of example only and that modifications in detail may be made within the scope of the present invention.
The invention is capable of modification, alteration, and equivalents in form and function, as will occur to those ordinarily skilled in the pertinent arts having the benefit of this disclosure.
While the present invention has been described for what are presently considered the preferred embodiments, the invention is not so limited. To the contrary, the invention is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the detailed description provided above. | 1a
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FIELD OF THE INVENTION
The present invention relates to a vacuum cleaner.
BACKGROUND OF THE INVENTION
The conventional vacuum cleaner has a simple function of sucking the dust adhered on a floor or carpet by utilizing the strong sucking power of a sucking motor. However, for some articles such as carpet which is impossible to wash at home, the conventional vacuum cleaner can not perform an effective cleaning.
In an attempt to give a solution to the above described problem, a vacuum cleaner (as shown in FIG. 4) has previously been developed, and this vacuum cleaner is constituted such that: a water reservoir C is disposed between a dust collecting section A and a driving section B; an extended tube E is connected to the leading end of a hose D (connected to the dust collecting section A); and a plurality of head sections F such as a dust sucking port, a water sucking port and the like are provided on the leading end of the extended tube E, thereby making it possible to use them selectively depending on the requirement.
Meanwhile, Japanese Utility Model Publication No. Sho-57-189546 proposes a shampoo type cleaner, as shown in FIG. 5, constituted such that: a cleaning brush G and a water blocking brush G' are installed at the lower end of a head section F; a washing water supplying tube H and a detergent supplying tube H' are formed on the top of the cleaning brush G in order to supply water and detergent; and a sucking mouth I is formed along the sides of the tubes H,H'.
However, the above described cleaning apparatuses have disadvantages such that the user has to take the trouble of replacing the head sections, and that the water drops remaining on the floor have to be removed by the user after the completion of the cleaning.
SUMMARY OF THE INVENTION
The present invention is intended to overcome the above described disadvantages of the conventional techniques.
Therefore it is the object of the present invention to provide a vacuum cleaner having the function of a wet wiring rag in which wet cleaning and the supply of washing fluid is possible and in which dirt and dirty water as well as dust and floating materials can be sucked up.
In achieving the above object, the vacuum cleaner of the present invention having the function of a wet wiping rag and including a dust collecting section, a driving section and a water reservoir, further includes: a head body having a tube inserting portion connected to the dust collecting section, and also having a washing water connecting portion extended from a side of the head body to enable the supply of water from the water reservoir to be possible; a rag detachably clad on the circumference of a roller freely rotatably installed in such a manner as to extend between the opposite sides of the head body; wheels having respectively a floor contact portion and closely contacted to gears provided to the opposite ends of the roller; a cover having dirty water collecting holes near the rags, and also having a washing water reservoir fixedly installed on the bottom of the head body and with a discharge hole formed below the washing water connecting portion; a frontal brush and blade installed respectively on the bottom of the frontal and rear portion of the head body; and a rear brush installed on the bottom of the cover.
Further, the frontal brush is provided with a plurality of slots on the bottom thereof.
Further, the rear brush is formed in an arcuate shape.
BRIEF DESCRIPTION OF THE DRAWINGS
The above object and other advantages of the present invention will become more apparent by describing in detail the preferred embodiment of the present invention with reference to the attached drawings in which:
FIG. 1 is a side sectional view showing the critical portion of the vacuum cleaner having the function of a wet wiping rag according to the present invention;
FIG. 2 illustrates the brush portion of the present invention in which: FIG. 2a is a perspective view of the frontal brush; and FIG. 2b is a perspective view of the rear brush;
FIG. 3 is a perspective view showing the operational relation between the roller and the wheels;
FIG. 4 is a perspective view of the whole body of a conventional vacuum cleaner; and
FIG. 5 is a side sectional view showing the head portion of another conventional vacuum cleaner.
DESCRIPTION OF THE PREFERRED EMBODIMENT
FIG. 1 is a side sectional view of the critical portion of the vacuum cleaner having the function of a wet wiping rag according to the present invention. In the drawing, reference numeral 1 indicates a head body, and this head body 1 includes: a tube inserting portion 2 extended from the top toward the rear in an inclined form; a washing water connecting portion 3 for supplying the washing water and projected from a side thereof; a brush securing slot 4a and a blade securing slot 4b provided on the bottoms of the frontal and rear portions thereof; and an opening formed on the bottom thereof.
A roller 6 is installed in such a manner that it should extend between the opposite sides of the head body 1, and the roller 6 is attached with a rag 5 in a detachable manner, while gears 6a are formed on the opposite ends of the roller 6. At the opposite sides of each of the gears 6a, there are installed wheels 8 on which contacting portions 7 (made of a soft material in order to prevent slipping) are attached and which are closely contacted with the gears 6a to be revolved together. The rag 5 is made of a non-woven fibre and is detachable.
A cover 9 is installed by being inserted in the bottom of the head body, and this cover 9 is provided with a washing water reservoir 10 at a position opposite to that of the washing water connecting portion 3, while a supply hole 11 is formed on the bottom thereof in order to supply washing water W to the rag 5. Further, an auxiliary dirty water collecting hole 12 is formed in the cover 9 near the rag 5 in order to suck up the dirty water from the rag 5, and brush securing slots 4a,4c are formed on the bottom of the head body and the cover 9, respectively. The cover 9 and body 1 together form a housing.
The cover 9 which is installed on the bottom of the head body 1 includes a dust sucking hole 13 through which dusts and dirty materials are sucked in.
A frontal brush 15a and a rear brush 15c are fixedly installed into the brush securing slots 4a,4c, respectively.
As shown in FIG. 2a, the frontal brush 15a is provided with a plurality of slots on the bottom thereof in order to facilitate the absorption of dusts and other dirty materials.
As shown in FIG. 2b, the rear brush 15c is formed in an arcuate shape, so that it should be easy to collect dusts and other dirty materials.
A blade 15b is securely fitted into the blade securing slot 4b, in such a manner that the blade should be able to collect water from the rear portion of the rag 5, so that the water should be re-absorbed during a reverse advancement.
In the drawings, reference numeral 17 indicates a handle in the form of an extended tube connected to the outside of the tube inserting portion 2 and connected to the dust collecting section, 18 indicates a washing water tube fitted into the washing water connecting portion 3 in order to supply water from the washing water reservoir, 19,19' indicate securing protuberanes for installing the cover 9.
The vacuum cleaner having the function of a wet wiping rag according to the present invention as described above can be let to perform cleaning operations by positioning the head body 1 to a place to be cleaned, and by advancing it back and forth, with the extended tube 17 grasped with hands.
Under this condition, if a sucking force is caused to act on the sucking hole 13 by the function of the driven motor, the dusts and other dirty materials which are detached from the floor by the frontal and rear brushes are sucked into the sucking hole 13. At the same time, the gears 6a which are closely contacted with the floor contacting portions 7 are revolved in accordance with the revolutions of the wheels 8, and therefore, the rag 5 which is attached on the roller 6 as shown in FIG. 3 cleans the floor like a wet wiping rag in a frictional relation with the floor.
Under this condition, the washing water which is filled through the washing water tube 18 into the washing water reservoir 10 is supplied through the discharge hole 11 to the circumferential surface of the roller 6 in a certain amount, so that the floor should be cleaned like with a wet rag. Thus, when the wheels 8 are revolved forwardly or rearwardly, the frontal brush 15a collects dusts and other dirty materials from the frontal area to send them through the slots 16 (formed on the bottom thereof) to the dust sucking hole 13. Meanwhile, the rear brush 15c which is formed in an arcuate shape further facilitates the collection of the dust and other dirty materials to send them to the sucking hole 13. Meanwhile, the blade 15b scrapes the dusts and other dirty materials which are not detached by the brushes, so that the detached dusts and other dirty materials as well as dirty water should be absorbed into the rag 5 during the rearward advancement, thereby making it possible to remove all the water remaining on the floor.
Meanwhile, the dirty materials and dirty water which are absorbed into the rag 5 are collected into the dirty water collecting hole 12 which is formed on the cover 9, and therefore, the rag 5 can be maintained always in a clean state, thereby making the cleaning more efficient.
The roller 6 revolves in a direction opposite to that of the wheels 8 because of the existence of the gears 6a, and therefore, during a forward advancement, the friction between the rag 5 and the floor is further increased, thereby increasing the cleaning efficiency further.
According to the vacuum cleaner of the present invention having the function of a wet wiping rag, dusts and other dirty materials are sucked into a sucking hole, and at the same time, a revolving rag produces frictions with the floor in order to absorb dirty materials and dirty water, with the result that the cleaning work becomes easy and convenient, that the cleaning time is shortened, and that a thorough cleaning becomes possible by sucking the dusts and other dirty materials detached from the floor by the blade. | 1a
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[0001] This application is a continuation of U.S. patent application Ser. No. 13/806,834, filed Mar. 18, 2013, which is a 371 nationalization of Application No. PCT/IS2011/050010 filed Jun. 24, 2011, which claims the benefit of priority of U.S. Provisional Application No. 61/358,472 filed Jun. 25, 2010, the entirety of which are incorporated herein by reference.
FIELD OF THE DISCLOSURE
[0002] The present disclosure is within the field of medical devices, in particular biometric devices for measuring biosignals, and relates particularly to electrodes for such devices and in particular electrode belts and connectors for such belts.
BACKGROUND
[0003] Electrode belts are known, both for direct contact galvanic electrodes for measure cardiography signals and inductive belts used in respiratory inductive plethysmography. Prior art belts have various types of connectors, for transmitting the received signal to the respective device. There remains a need for improved belt connectors that are reliable and easy to use and maintain.
SUMMARY
[0004] The disclosure provides a belt connector for electrically connecting an electrode belt to a biometric device to be carried on a human or animal body. The belt connector is preferably made from one single piece which can be economically manufactured in order to function as a single-use consumable, to be used with a matching biometric device. The belt connector comprises a molded plastic frame having a front side and a rear side, the frame having a receiving hole, having radial flexibility to function as a female snap button fastener for receiving and fastening on the front side of the frame a male snap protrusion. The belt connector further comprises fastening means for fastening to the frame a belt end of the electrode belt, and a member adjacent to the snap fastener receiving hole to engage an electrode wire end electrically connected to the belt such that the wire end is in electrical contact with the hole, either by extending into the hole or coming in electrical contact e.g. through a bridging conductor, with a conducting male snap fastener inserted in the receiving hole.
[0005] The belt connector and belt should be configured such that a person wearing the belt under operation is insulated from current running through the belt, in order to meet existing standards for medical devices. The belt connector of the present disclosure is configured accordingly, and in a preferred embodiment, the belt connector comprises a shield member which is arranged on the rear side of the frame to electrically shield the wire end from the rear side exterior of the belt connector.
[0006] The belt connector preferably comprises a cover enclosing the connector and wire end. The cover may suitably include a pre-perforated hole overlapping the hole of the frame, or in other embodiments is made from such material that can readily be perforated by pressing the connector onto a male fastener which fits the receiving hole of the frame.
[0007] The belt end is fixedly engaged with the connector and the electrode wire connected to the connector such that the electrode wire is in electrical contact with the female snap fastener hole and thereby comes in electrical contact with a conducting male snap fastener inserted in the hole.
[0008] Preferably the belt end is engaged with the connector in a fashion allowing adjustment of the length of the belt.
BRIEF DESCRIPTION OF THE FIGURES
[0009] FIGS. 1A , 1 B, 1 C, and 1 D illustrate a belt connector according to a first embodiment.
[0010] FIG. 1A shows a prospective top view according to the first embodiment.
[0011] FIG. 1B shows a prospective bottom view according to the first embodiment.
[0012] FIG. 1C shows a top plan view according to the first embodiment.
[0013] FIG. 1D shows a bottom plan view according to the first embodiment.
[0014] FIGS. 2A , 2 B, and 2 C illustrate a belt connector and connected belt according to a second embodiment.
[0015] FIG. 2A shows a prospective top view according to the second embodiment.
[0016] FIG. 2B shows a prospective bottom view according to the second embodiment.
[0017] FIG. 2C shows a prospective top view according to the second embodiment.
DETAILED DESCRIPTION
[0018] The disclosed belt connector is suitable for various types of electrode belts, such as for cardiographic measurements, both in clinical settings or for training purposes, but also for belts such as RIP (respiratory inductive plethysmography) belts.
[0019] As mentioned above, the belt connector is intended for electrically connecting an electrode belt to a biometric device, the term biometric device in this context includes any devices for receiving electrical biosignals as well as extension cables, intermediate devices, connecting boxes, etc. or other means for receiving and transmitting the biosignals.
[0020] The belt connector is preferably made from any of various suitable non-conducting plastic materials, such as but not limited to ABS (acrylonitrile butadiene styrene), PC/ABS, polyethylene, e.g. low density polyethylene (LDPE) or high density polyethylene (HDPE), or derivatives such as polyethylene terephthalate (PET) or polyfluoroethylene (PTFE), or more preferably polypropylene, polyvinyl chloride, or polyamide (nylon). In other embodiments the connector is made from paper based material or other material from natural fibers.
[0021] The electrode belt is generally a flexible belt such as commonly used in respiratory inductance plethysmography (RIP) devices today. Such electrode belt is preferably a flexible textile belt where an electrode wire is interwoven in the belt or can be laminated between two layers, typically in a zig-zag fashion to allow longitudinal elasticity.
[0022] The molded frame of the connector has a front side and a rear side, which are defined as follows: the front side of the frame faces the biometric device which is fastened onto the connector for operation and the rear side faces away from the device. In the presently preferred embodiment the rear side of the connector faces the body of the patient when mounted, i.e. the belt connector comes between the patient and the biometric device. However, the biometric device can also be configured such that the device faces the patient and the belt connectors lie on top of the device, i.e. connect to the device on the face of the device facing away from the patient, thus in such embodiment the front side of the connectors face the patient and the rear side face away from the patient.
[0023] The frame has a receiving hole with radial flexibility to function as a female snap button fastener for receiving and fastening on the front side of the frame a male snap protrusion. A mating biometric device will thus have a corresponding mating male snap fastener which can be fastened securely onto the belt connector. The hole can preferably be shaped circular or semi-circular but may in other embodiments have any other suitable shape, such as a general elongated shape shaped by two parallel members, suitably including guiding members to ensure proper positioning of the mating male snap member, a square opening, or the like.
[0024] The radial flexibility of the hole can in one embodiment be achieved by one or more slot extending from the hole. The embodiment shown if FIGS. 1 and 2 shows two slots extending across from each other in the belt direction. The one or more slot are preferably formed by at least one elongated member having flexibility transverse to its longitudinal axis (e.g. by being sufficiently thin), thus imparting flexibility to the width of the hole. Preferably the hole is between two elongated members where one or both have sufficient and suitable flexibility to provide a snap fastener hole with suitable fastening strength.
[0025] As mentioned, the belt connector comprises a member adjacent to the snap fastener receiving hole to engage an electrode wire coming from the belt end. This wire must come in electrical contact with the receiving hole, either by extending into the hole or coming in electrical contact with the hole e.g. through a bridging conductor. In one embodiment, the wire end is crimped onto the member such the crimping tubing fixes the wire and conducts and connects electrically the wire to the receiving hole, such that thus the wire and the belt is in electrical contact with a conducting male snap fastener inserted in the receiving hole.
[0026] The slot mentioned above can also function to provide an additional opening for a mating male projection on the biometric device. By this arrangement it is assured that the device cannot be incorrectly fastened, and the device will not fit any generic non-proprietary belts having connectors with female fasteners but without the correctly shaped and placed extended hole.
[0027] The connector frame has in another embodiment a separate further hole, not joined to the main fastener and electrical connection hole, where the further hole can mate with a corresponding male projection on the biometric device. Alternatively, the biometric device can have a female hole for mating with a corresponding male projection on the belt connector.
[0028] The connector frame further comprises fastening means for fastening to the frame a belt end of an electrode belt. The fastening means can in one embodiment comprise a slot with a row of teeth, pins or hooks, transverse to the belt direction, to engage a belt end. The slot preferably allows to insert through it a loop of the belt such that the belt length is adjusted and fixed, but preferably so that a user can later re-adjust the length.
[0029] In another embodiment, the fastening means comprise a ridge member, which can be a flat or sharp elongated ridge or ridge or row comprising pins or hooks, which ridge lies transverse to the belt direction and to which a belt end can be fastened onto with heat melting or gluing. Alternatively, the ridge member can have pins hooks that grab onto the belt fabric without need of heating.
[0030] Preferably, the frame has also an adjustment slot for user adjustment of the belt, which can configured with either of the two described fastening means, the adjustment slot having a row of teeth, pins or hooks transverse to the belt direction, through which adjustment slot a loop of the belt can be inserted, which hooks onto the teeth/pins when pulled on, such that the length of the belt can be readily adjusted but also secured in the desired adjusted length.
[0031] The connector will preferably include a cover substantially or essentially fully enclosing the frame, which cover either includes a pre-made hole overlapping the receiving hole of the frame, or can be readily perforated by pressing the connector onto a male fastener which fits the receiving hole of the frame. A suitable cover can be arranged by a suitably sized paper, plastic or fabric sticker (foldable sheet with glue on one side) which sticker is folded over the frame after the belt end has been fastened and the wire end electrically connected to the receiving hole, or the cover can be from but not limited to a paper envelope, a plastic envelope and a textile envelope, which envelope is suitably fastened by gluing, sewing or the like.
[0032] In the embodiments where the biometric device has a further male projecting member which fits within the slot of the frame or within a separate mating hole, the cover is suitably arranged with corresponding openings for such hole or slot for receiving such mating male member, and the cover may also have a suitable hole allowing the protrusion of a male protruding member being a part of the frame which fits in a mating receiving hole or slot on the mating biometric device.
[0033] In a preferred embodiment, the connector comprises a shield member which is arranged on the rear side of the frame to electrically shield the wire from the rear side exterior of the belt connector. The shield member is in one embodiment a sheet member extending from the frame, which sheet member is configured to be folded over onto the rear side of the frame to cover the hole and engaged wire. Such shield member molded in one piece with the frame with enough 30 strength but suitably flexible to allow folding at least once without braking allows the use of a cover enclosing the frame, which cover need not be electrically insulating, as the shield insulates the only part of the connector which could conduct electrical current of the connector, except through the hole.
[0034] In another aspect, the present disclosure sets forth a process for making an electrode belt with biometric belt connectors, comprising:
placing an end of a flexible electrode belt with an incorporated wire onto a belt connector as defined above, in the suitable direction in which it is to be fastened onto the connector, such that a portion of the belt end extends beyond the ridge member or row of pins, pressing a heat element ultrasonic hot body or other means of heat transfer onto the belt and ridge member, and through the action of the heat, shearing an end piece of the belt but leaving intact the incorporated wire, thus revealing an end of the wire, through the action of heat from the heat element, fastening by heat melting the belt to the ridge, and fastening the wire end to a member adjacent to the hole of the connector frame, such that the end is in electrical contact with the hole and comes in electrical contact with a conducting male snap fastener inserted in the hole.
[0039] The process further preferably comprises enclosing the connector frame with the fastened belt end and connected wire with a cover such as suitably a cover as described above.
[0040] FIGS. 1A , 1 B, 1 C, and 1 D illustrate a belt connector according to a first embodiment. FIG. 1A shows a prospective top view according to the first embodiment.
[0041] FIG. 1B shows a prospective bottom view according to the first embodiment. FIG. 1C shows a top plan view according to the first embodiment. FIG. 1D shows a bottom plan view according to the first embodiment.
[0042] FIGS. 2A , 2 B, and 2 C illustrate a belt connector and connected belt according to a second embodiment.
[0043] FIG. 2A shows a prospective top view according to the second embodiment.
[0044] FIG. 2B shows a prospective bottom view according to the second embodiment.
[0045] FIG. 2C shows a prospective top view according to the second embodiment.
[0046] As seen in the first and second embodiments of FIGS. 1A , 1 B, 1 C, and 1 D and FIGS. 2A , 2 B, and 2 C, respectively, a biometric belt connector ( 1 ) is electrically connected to an electrode belt ( 2 ). The connector ( 1 ) may comprise a molded plastic frame ( 3 ) having a front side ( 4 ) and a rear side ( 5 ), a shaped circular or semi-circular hole ( 6 ) with radial flexibility to function as a female snap button fastener, fastening means ( 7 ) which comprise a ridge member ( 12 ). According to the first embodiment, the ridge member ( 12 ) may include a series of buts which are provided transverse to the belt direction and to which the belt end can be fastened onto with heat melting or gluing. The frame ( 3 ) may include two members ( 8 , 13 ) adjacent to the hole ( 6 ), the two members ( 8 , 13 ) forming a slot ( 11 ) extending from the hole and a second slot ( 15 ) across from the first slot ( 11 ).
[0047] The elongated members and slots provide the hole with sufficient flexibility (i.e. elasticity in the width of the hole) to function as a female snap fastener. The member ( 13 ) also functions to engage an electrode wire end ( 9 ) from the belt end electrically connecting the belt with the hole and which comes in electrical contact with a conducting male snap fastener inserted in the hole. The connector further comprises a belt slot ( 14 ) with teeth members or pins ( 17 ), through which slot a loop of the belt ( 2 ) can be inserted such that it is held by the teeth/pins when pulled back, to adjust the length of the belt.
[0048] The connector further comprises a shield member ( 10 ) which may be molded in one piece with the frame ( 3 ) and joined to the frame with foldable hinges ( 16 ) such that the shield member can be folded over to cover the rear side of the hole and wire end. | 1a
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BACKGROUND OF THE INVENTION
The following publications disclose azapentalenes and thiapentalenes of a variety of structures: (1) D. H. Reid et al, JCS 775 (1975); (2) R. M. Christie et al, JCS 848 (1977); (3) C. Th. Pedersen, JCS 994 (1977); (4) D. H. Reid et al, JCS 2097 (1975); (5) R. H. Reid et al, JCS 854 (1977) and (6) G. L'Abbe et al, Angew. Chem. Int. Ed. Engl. 16 (1977) No. 6.
DESCRIPTION OF THE INVENTION
The oxadithiadiazapentalene compounds of the invention are represented by the formula (I) ##STR3## wherein X is chloro, bromo or iodo and R is alkyl of 1 to 6 carbon atoms; haloalkyl of 1 to 6 carbon atoms and of 1 to 3 of the same or different halogen selected from fluoro, chloro, bromo or iodo; halovinyl of 1 to 3 of the same or different halogens selected from fluoro, chloro, bromo or iodo; cycloalkyl of 3 to 6 carbon atoms; thiocyanatoalkyl of 1 to 3 carbon atoms; phenyl or phenoxy substituted with up to 3 (0 to 3), preferably up to 2 (0 to 2), of the same or different substituents selected from hydroxy, fluoro, chloro, bromo, iodo, trifluoromethyl, trichloromethyl, tribromomethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkoxycarbonylalkoxy of 3 to 6 carbon atoms, nitro, cyano, thiocyanato or isothiocyanato; phenoxymethyl or phenylthiomethyl wherein the phenyl ring is substituted with up to 3 ( 0 to 3), preferably up to 2 (0 to 2), of the same or different substituents selected from fluoro, chloro, bromo, iodo or alkyl of 1 to 4 carbon atoms; benzyloxymethyl or benzylthiomethyl wherein the benzyl ring is substituted with up to 2 of the same or different substituents selected from fluoro, chloro, bromo, iodo or alkyl of 1 to 4 carbon atoms; furyl; or thienyl.
Representative alkyl R groups include methyl, ethyl, isopropyl, t-butyl, and hexyl. Representative haloalkyl R groups include fluoromethyl, dichloromethyl, tribromomethyl, 1-chloroethyl, 2-iodoethyl, pentachloroethyl, 3-bromopropyl, 2-iodo-4-fluorobutyl and 2,4-dichlorohexyl. Representative halovinyl R groups include 2-chlorovinyl, 1,2-dibromovinyl and trifluorovinyl. Representative cycloalkyl R groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Representative thiocyanatoalkyl R groups are thiocyanatomethyl and 3-thiocyanatopropyl. Representative substituted-phenyl and phenoxy R groups include 4-hydroxy-2-methylphenyl, 2,4-difluorophenyl, 4-bromophenyl, 2,4,6-trichlorophenyl, 4-trifluoromethylphenyl, 3,5-dimethylphenyl, 3-methoxyphenoxy, 3-(methoxycarbonylmethoxy)phenoxy, 2,4-dinitrophenoxy, 4-cyanophenyl and 4-isothiocyanatophenyl. Representative substituted phenoxymethyl and phenylthiomethyl R groups include 4-chlorophenoxymethyl, 2,4-dibromophenoxymethyl, 4-methylphenoxymethyl, 3,4-dimethylphenylthiomethyl and 2-methyl-4-iodophenylthiomethyl. Representative substituted benzyloxymethyl and benzylthiomethyl R groups include 3,5-difluorobenzyloxymethyl, 3-bromobenzyloxymethyl, 4-iodobenzyloxymethyl, 2,4-dichlorobenzylthiomethyl and 3,5-dimethylbenzylthiomethyl.
A preferred class of oxadithiadiazapentalene compounds is that wherein X is chloro, bromo or iodo and R is phenyl substituted with up to 2 (0 to 2) of the same or different substituents selected from hydroxy, fluoro, chloro, bromo, nitro, iodo, alkyl of 1 to 4 carbon atoms, trifluoromethyl or trichloromethyl.
Another preferred class of oxadithiadiazapentalene compounds is that wherein X is chloro, bromo or iodo and R is phenoxymethyl, phenylthiomethyl, benzyloxymethyl or benzylthiomethyl wherein the aromatic ring is substituted with up to 2 (0 to 2) of the same or different substituents selected from fluoro, chloro, bromo, iodo or alkyl of 1 to 4 carbon atoms. In this class, R preferably is phenoxymethyl substituted with up to 2 of the same or different substituents selected from fluoro, chloro, bromo, iodo or alkyl of 1 to 4 carbon atoms.
The most preferred class of oxadithiadiazapentalene compounds is that wherein X is chloro, bromo or iodo, preferably chloro, and R is haloalkyl of 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms, and of 1 to 3 of the same or different halogens selected from fluoro, chloro or bromo or iodo. The most preferred compounds of this class are those wherein R is monohalomethyl wherein the halo is chloro, bromo or iodo.
Representative compounds of the invention include:
2-methyl-3-oxa-3aλ 4 ,4-dithia-6-chloro-1,5-diazapentalene
2-(2-chloroethyl)-3-oxa-3aλ 4 ,4-dithia-6-chloro-1,5-diazapentalene
2-tribromovinyl-3-oxa-3aλ 4 ,4-dithia-6chloro-1,5-diazapentalene
2-(2-thiocyanatoethyl)-3-oxa-3aλ 4 ,4-dithia-6-chloro-1,5-diazapentalene
2-(2-hydroxy-4-bromophenyl)-3-oxa-3aλ 4 ,4-dithia-6-chloro-1,5-diazapentalene
2-(4-trichloromethylphenyl)-3-oxa-3aλ 4 ,4-dithia-6-chloro-1,5-diazapentalene
2-(4-cyanophenyl)-3-oxa-3aλ 4 ,4-dithia-6-chloro-1,5-diazapentalene
2-(3-iodophenoxy)-3-oxa-3aλ 4 ,4-dithia-6-chloro-1,5-diazapentalene
2-cyclopropyl-3-oxa-3aλ 4 ,4-dithia-6-iodo-1,5-diazapentalene
2-(2,4-dinitrophenyl)-3-oxa-3aλ 4 ,4-dithia-6-bromo-1,5-diazapentalene
2-(4-methoxyphenyl)-3-oxa-3aλ 4 ,4-dithia-6-chloro-1,5-diazapentalene
2-(phenoxymethyl)-3-oxa-3aλ 4 ,4-dithia-6-bromo-1,5-diazapentalene
2-(3-iodophenylthiomethyl)-3-oxa-3aλ 4 ,4-dithia-6-chloro-1,5-diazapentalene
2-(4-methylbenzylthiomethyl)-3-oxa-3aλ 4 ,4-dithia-6-chloro-1,5-diazapentalene
2-(4-chlorobenzylmethyl)-3-oxa-3aλ 4 ,4-dithia-6-chloro-1,5-diazapentalene
2-(3-furyl)-3-oxa-3aλ 4 ,4dithia-6-bromo-1,5-diazapentalene
2-(2-thienyl)-3-oxa-3aλ 4 ,4-dithia-6-bromo-1,5-diazapentalene
The oxadithiadiazapentalene compounds are produced by reacting a sulfur halide e.g., a sulfur dihalide such as sulfur dichloride or a sulfur monohalide such as sulfur monochloride, and an N-cyanomethyl carboxamide represented by the formula (II): ##STR4## wherein R has the same significance as previously defined. The N-cyanomethyl carboxamide (II) is generally prepared by reacting an acid chloride RCOCl wherein R is as defined above and a cyanomethylamine by conventional procedures.
The precise mechanism and the reaction intermediates involved in the reaction of the sulfur halide and the carboxamide (II) are not known with certainty. However, it is known that the stoichiometry of the reaction is at least about two mols of sulfur halide per mol of carboxamide. Therefore, suitable molar ratios of carboxamide to sulfur halide are about 1:2 to 1:8, although molar ratios of about 1:2 to 1:5 are preferred. The preferred sulfur halide reactant is a sulfur dihalide, especially sulfur dichloride.
Preferably, reaction (I) is conducted in the presence of catalytic amount of a guaternary ammonium salt. Generally, amounts of quaternary ammonium salt per mol of sulfur halide vary from about 0.01 to 0.3, although amounts from 0.05 to 0.2 mols per mol of sulfur halide are preferred. Suitable quaternary ammonium salts are tetralkylammonium halides wherein the alkyl has 1 to 6 carbon atoms and the halide is fluoro, chloro, bromo or iodo, e.g., tetramethylammonium chloride or tetrabutylammonium bromide. When a quaternary salt is employed as a catalyst, the anion is preferably the same halide as the halide of the sulfur halide reactant.
In general, the reaction is accomplished by reacting the carboxamide (II), the sulfur halide and the quaternary salt catalyst in an inert liquid organic diluent. Suitable inert diluents include alkanes and haloalkanes, such as hexane, isooctane, or dichloromethane; aromatic compounds, such as benzene, toluene, chlorobenzene; oxygenated hydrocarbon such as acyclic alkyl ethers, such as dimethoxyethane and dibutyl ether; and cyclic ethers such as dioxane, tetrahydrofuran and tetrahydropyran. Generally, the amount of diluent employed ranges from 1 to 50 mols per mol of sulfur halide.
The reaction is suitably conducted at a temperature of 0° C. to the boiling point of the diluent, although temperatures between 0° C. and 100° C. are preferred. Generally, the reactants are contacted at ambient temperature or lower, e.g., about 0° C. to 25° C., and the reaction is completed at elevated temperatures, e.g., about 25° to 100° C. The reaction is conducted at or above atmosphere pressure. The reaction time will, of course, vary depending on the reaction temperature and the particular reactants employed. Generally, however, the reaction time varies from 1/2 hour to 24 hours. The progress of the reaction can sometimes be determined by the evolution of hydrogen halide gas from the reaction mixture and the completion of the reaction can sometimes be determined by the cessation of gas evolution. The oxadithiadiazapentalene product is isolated from the reaction mixture by conventional procedures, e.g., extraction, chromatography, crystallization, etc.
Compounds of the invention having a substituted methyl group at the two position of the ring can be also prepared by reacting a oxadithiadiazapentalene of the formula ##STR5## wherein Y is chloro, bromo or iodo, with the appropriate nucleophilic reactant. For example, the compound wherein R is iodomethyl can be prepared by reacting the corresponding chloromethyl compound with sodium iodide; the compound wherein R is thiocyanatomethyl can be prepared from a compound of formula (III) and ammonium thiocyanate; and compounds wherein R is phenoxymethyl, phenylthiomethyl, benzyloxymethyl or benzylthiomethyl can be prepared by reacting an appropriate oxide or mercaptide salt (e.g., sodium phenoxide or benzyl mercaptide) with a compound of formula (III).
The compounds of formula (I) wherein R is iodomethyl or thiocyanatomethyl are preferably prepared from a compound of formula (III).
EXAMPLE 1
Preparation of 2-(3,4-dichlorophenyl-3-oxa-3aλ 4 ,4-dithia-6-chloro-1,5-diazapentalene
A solution of 24 g (0.23 mol) triethylamine in 50 ml dichloromethane was added dropwise over about 40 minutes to a stirred mixture of 10.7 g (0.1 mol) aminoacetonitrile hydrochloride and 20.9 (0.1 mol) 3,4-dichlorobenzoyl chloride. The reaction mixture become warm and the hydrochloride almost completely dissolved. The reaction mixture was washed with water, thereby causing the separation of a solid. The solid was filtered, washed with water and dried to give 9.3 g of a white solid. A 1.0 g sample of the solid was recrystallized from 50 ml benzene to give 0.7 g of N-cyanomethyl-3,4-dichlorobenzamide, m.p. 144°-145° C. Elemental analysis for C 9 H 6 Cl 2 N 2 O showed: %Cl, calc. 30.9, found 31.1.
A solution of 5.4 g (0.023 mol) N-cyanomethyl-3,4-dichlorobenzamide, 10 g (0.09 mol) sulfur dichloride, 1 g tetrabutylammonium chloride and 300 ml dichloromethane was stirred at about 25° C. Gases were evolved during the reaction. After stirring for 75 minutes, thin-layer chromatography did not show any of the unreacted benzamide. The reaction mixture was evaporated under reduced pressure to give a red solid. The solid was chromatographed on silica gel (benzene eluant) to give 4.3 g of a yellow solid, melting point 144°-160° C. Two recrystallizations from hexane/benzene raised the melting point to 170°-172° C. The infrared spectrum of the product showed strong adsorption at 6.2 micron. Elemental analysis for the product is tabulated in Table I, as Compound No. 1.
EXAMPLE 2
Preparation of 2-chloromethyl-3-oxa-3aλ 4 ,4-dithia-6chloro-1,5-diazapentalene
A 153-g (1.4 mol) sample of sulfur dichloride was added slowly over a two-hour period to a mixture of 65.8 g (0.49 mol) N-cyanomethyl-alpha-chloroacetamide and 2 g tetrabutylammonium chloride in 500 ml dichloromethane. The reaction mixture was stirred at about 250° C. for 4 hours and filtered to give 76 g of a yellow solid. The solid was refluxed in toluene until solution occurred and stripped to give 50.7 g of product, m.p. 120°-122° C. The infrared spectrum of the product showed strong adsorption at 6.3 micron. Elemental analysis for a recrystallized sample melting at 122°-124° C. is tabulated in Table I, as Compound No. 5.
EXAMPLE 3
Preparation of 2-iodomethyl-3-oxa-3aλ 4 ,4-dithia-6-chloro-1,5-diazapentalene
A mixture of 7 g (0.033 mol) 2-chloromethyl-3-oxa-3aλ 4 ,4-dithia-6-chloro-1,5-diazapentalene and 10.0 g (0.066 mol) sodium iodide in 100 ml acetone was stirred for 1 hour at about 25° C. The reaction mixture was filtered to remove solids formed during the reaction. The filtrate was evaporated under reduced pressures and the residue was crystallized from benzene/hexane to give 5.5 g of the product as an orange solid, m.p. 107°-108° C. Elemental analysis for the product is tabulated in Table I as Compound No. 9.
EXAMPLE 4
Preparation of 2-(2-furyl)-3-oxa-3aλ 4 ,4-dithia-6-chloro-1,5-diazapentalene
A 20.2-g (0.2 mol) sample of triethylamine was added dropwise over 20 minutes to a stirred and cooled (ice bath) mixture of 9.3 g (0.1 mol) aminoacetonitrile hydrochloride in 150 ml chloroform. A solution of 13.2 g (0.1 mol) 2-furoyl chloride in 25 ml dichloromethane was then added dropwise over 20 minutes. The ice bath was removed and the reaction mixture stirred for 25 minutes. The reaction mixture was then washed with water, dried over magnesium sulfate and evaporated to give 7.4 g of crude N-cyanomethyl-2-furamide, as a beige solid, m.p. 85°-93° C. Recrystallization from benzene gave the furamide as a white solid, m.p. 101°-102° C. Elemental analysis for C 7 H 6 N 2 O showed: %C, calc. 56.0, found 56.0; %H, calc. 4.06, found 4.11; %N, calc. 18.7, found 19.1.
A solution of 17 g (0.15 mol) sulfur dichloride in 25 ml dichloromethane was added dropwise over 20 minutes to a solution of 6.3 g (0.4 mol) N-cyanomethyl-2-furamide and 0.5 g tetrabutylammonium chloride in 100 ml dichloromethane. Gases were evolved from the resulting cherry-red reaction mixture. The reaction mixture was then stirred for 2 hours at about 25° C., during which time solids separated. The solids were filtered and heated under reflux in 25 ml toluene until gas evolution ceased. On cooling, 3.5 g of 6-chloro-2-(2-furyl), as a yellow solid melting at 126°-133° C., was obtained. The infrared spectrum of the product showed strong adsorption at 6.2 micron. Elemental analysis for the product is tabulated in Table I, as Compound No. 8.
EXAMPLE 5
Preparation of 2-(4-chlorophenylthio-methyl)-3-oxa-3aλ 4 ,4-dithia-6-chloro-1,5-diazapentalene
A solution of 0.1 mol sodium p-chlorophenylmercaptide was prepared by reacting at about 0° C., 14.5 g (0.1 mol) p-chlorophenylmercaptan and 2.4 g (0.1 mol) sodium hydride in 150 ml dimethylformamide. To the solution cooled to 0° C. was then added in small portions 13.2 g (0.1 mol) N-cyanomethyl-alpha-chloroacetamide. The reaction was stirred for 1 hour at 25° C. and poured into 500 ml ice water. The reaction mixture was then filtered to give a solid. The solid was dissolved in dichloromethane and the resulting solution was dried over magnesium sulfate and evaporated to give 18.7 g of N-cyanomethyl-alpha-(p-chlorophenylthio)acetamide, as a white solid which melted at 89°-91° C. after recrystallization from hexane/benzene.
A mixture of 8.0 g (0.033 mol) of N-cyanomethyl-alpha-(p-chlorophenylthio) acetamide, 0.5 g tetrabutylammonium chloride and 14 g (0.135 mol) sulfur dichloride in 150 ml dichloromethane was stirred at about 25° C. for 1 hour. Gases were evolved and solids formed. The solids were filtered and heated in 75 ml toluene until gas evolution ceased and a homogeneous solution was obtained. The solution was evaporated under reduced pressure to give 3.5 g of 2-(4-chlorophenylthiomethyl)-3-oxa-3aλ 4 ,4-dithia-6-chloro-1,5-diazapentalene as a yellow solid. Recrystallization from hexane gave the product a bright yellow solid metling at 97°-100° C. Elemental analysis for the product is tabulated in Table I, as Compound No. 10.
EXAMPLE 6
Preparation of 2-thiocyanatomethyl-3-oxa-3aλ 4 ,4-dithia-6-chloro-1,5-diazapentalene
5.0 g (0.023 mol) 2-chloromethyl-3-oxa-3aλ 4 ,4-dithia-6-chloro-1,5-diazapentalene and 2.0 g (0.026 mol) ammonium thiocyanate were stirred with 75 ml acetone to give a clear solution. In a few minutes, salt begin to separate. Stirring was continued for 24 hours. The salt was filtered. The acetone was removed at reduced pressure to leave solids. The solids were taken up in benzene and applied to a column of 75 g silica gel. Elution gave 3.4 g yellow solid melting at 103°-110° C. Crystallization from benzene-hexane gave bright-yellow solid melting at 109°-110° C. Elemental analysis is tabulated in Table I, as Compound No. 20.
EXAMPLE 7
Preparation of 2-cyclopropyl-3-oxa-3aλ 4 ,4-dithia-6-chloro-1,5-diazapentalene
A slurry of 20 g (0.19 mol) cyclopropanecarboxylic acid chloride, 18.5 g (0.2 mol) aminoacetonitrile hydrochloride and 5 drops concentrated sulfuric acid in 300 ml chloroform was stirred and heated at reflux for 24 hours. The reaction was filtered and then evaporated under reduced pressure to give an oil (13.1 g), which solidified on treatment with a little hexane. Recrystallization of the solid from benzene gave N-cyanomethylcyclopropanecarboxamide as a white solid melting at 91°-92° C. Elemental analysis for C 6 H 8 N 2 O showed: %C, calc. 58.1, found 57.9; %H, calc. 6.5, found 6.5; %N, calc. 22.5, found 22.5.
A solution of 33 g (0.32 mol) sulfur dichloride in 25 ml dichloromethane was added dropwise to a solution of 10 g (0.08 mol) N-cyanomethylcyclopropanecarboxamide and 0.5 g tetrabutylammonium chloride in 150 ml dichloromethane. Solids began to separate during the additon. The reaction was exothermic and was maintained at about 25° C. by cooling with an ice bath. After completion of the addition and stirring for about 1.5 hours, the reaction mixture was filtered to isolate the precipitated solids. The solids were stirred with 75 ml toluene and heated at reflux until gas evolution ceased and a homogeneous solution was obtained. The toluene was evaporated under reduced pressure to leave a solid. The solid was recrystallized from hexane/benzene to give 5.5 g of 2-cyclopropyl-3-oxa-3aλ 4 , 4-dithia-6-chloro-1,5-diazapentalene as a yellow solid melting at 94°-95° C. Elemental analysis for the product is tabulated in Table I as Compound No. 21.
EXAMPLE 8
Preparation of 2-trichlorovinyl-3-oxa-3aλ 4 , 4-dithia-6-chloro-1,5-diazapentalene
A slurry of 38.8 g (0.2 mol) trichloroacrylyl chloride and 18.5 g (0.2 mol) aminoacetonitrile hydrochloride in 150 ml chloroform was stirred and heated under reflux for 30 hours, while gases evolved and most of the hydrochloride salt dissolved. The reaction mixture was filtered while hot and the solvent evaporated under reduced pressure to give 36.1 g of N-cyanomethyl trichloroacrylamide, as an off-white solid melting at 56°-59° C. Recrystallization from benzene-hexane gave a white solid melting at 58°-60° C. Elemental analysis for C 5 H 3 Cl 3 N 2 O showed: %Cl, calc. 49.8, found 50.0.
A solution of 19.2 g (0.16 mol) sulfur dichloride in 25 ml dichloromethane was added dropwise over 20 minutes at about 25° C. to a stirred solution of 10 g (0.04 mol) N-cyanomethyl trichloroacrylamide and 0.5 g tetrabutylammonium chloride in 100 ml dichloromethane. Gases were evolved during the addition. After completion of the addition and stirring for 3.5 hours, the reaction mixture was evaporated under reduced pressure to give an oil. The oil was crystallized from hexane to give 2-trichlorovinyl-3-oxa-3aλ 4 , 4-dithia-6-chloro-1,5-diazapentalene as a yellow solid. Elemental analysis for the product is tabulated in Table I as compound No. 23.
EXAMPLE 9
Preparation of 2[3,5-dinitro-4-(2,4-dichlorophenoxy)phenyl]-3-oxa-3aλ 4 , 4-dithia-6-chloro-1,5-diazapentalene
A mixture of 7 g (0.017 mol) N-cyanomethyl-3,5-dinitro-4-(2,4-dichlorophenoxy) benzamide, 9.2 g (0.068 mol) sulfur monochloride, 0.5 g tetrabutylammonium chloride and 150 ml dichloromethane were stirred at about 25° C. After about 2 hours, gases began to evolve. After stirring a total of 20 hours, the solids (5.7 g) were separated from the reaction mixture and heated under reflux in toluene for 15 minutes. The toluene solution was treated with charcoal and filtered. The filtrate was diluted with hexane to precipitate 3.0 g of the product as an orange solid, m.p. 212°-216° C. Recrystallization from benzene-hexane gave the product as a yellow solid, m.p. 216°-218° C. Elemental analysis for C 15 H 5 Cl 3 N 4 O 5 S 2 showed: %S, calc. 13.0, found 13.8; %Cl. calc. 21.6, found 19.7.
Other compounds of the invention were prepared by procedures similar to those of Examples 1-9. These compounds are reported in Table I. The structures of the compounds reported in Table I were verified by infrared spectroscopy and/or nuclear magnetic resonance analysis. The structure of Compound No. 26 was also verified by X-ray crystallographic analysis. All thiadiazinethione compounds of the invention showed a strong absorption based at about 6.1 to 6.4 microns.
FUNGICIDAL UTILITY
The compounds of the invention are useful for controlling fungi, particularly plant fungal infections caused by Botrytis cinerea, leaf blights caused by organisms such as Pythrium ultimum, Helminthosporum sativum, Fusarium moniliforme, Rhizoctonia solani, Monolinia fructicola and Uromyces phaseoli typica. However, some fungicidal compounds of the invention may be more fungicidally active than others against particular fungi.
When used as fungicides, the compounds of the invention are applied in fungicidally effective amounts to fungi and/or their habitats, such as vegetative hosts and non-vegetative hosts, e.g., animal products. The amount used will, of course, depend on several factors such as the host, the type of fungus and the particular compound of the invention. As with most pesticidal compounds, the fungicides of the invention are not usually applied full strength, but are generally incorporated with conventional biologically inert extenders or carriers normally employed for facilitating dispersion of active fungicidal compounds, recognizing that the formulation and mode of application may affect the activity of the fungicide. Thus, the fungicides of the invention may be formulated and applied as granules, as powdery dusts, as wettable powders, as emulsifiable concentrates, as solutions, or as any of several other known types of formulations, depending on the desired mode of application.
Wettable powders are in the form of finely divided particles which disperse readily in water or other dispersant. These compositions normally contain from about 5-80% fungicide, and the rest inert material, which includes dispersing agents, emulsifying agents and wetting agents. The powder may be applied to the soil as a dry dust, or preferably as a suspension in water. Typical carriers include fuller's earth, kaolin clays, silicas, and other highly absorbent, readily wettable, inorganic diluents. Typical wetting, dispersing or emulsifying agents include, for example: the aryl and alkylaryl sulfonates and their sodium salts; alkylamide sulfonates, including fatty methyl taurides; alkylaryl polyether alcohols, sulfated higher alcohols, and polyvinyl alcohols; polyethylene oxides, sulfonated animal and vegetable oils; sulfonated petroleum oils, fatty acid esters of polyhydric alcohols and the ethylene oxide addition products of such esters; and the addition products of long-chain mercaptans and ethylene oxide. Many other types of useful surface-active agents are available in commerce. The surface-active agent, when used, normally comprises from 1% to 15% by weight of the fungicidal composition.
Dusts are freely flowing admixtures of the active fungicide with finely divided solids such as talc, natural clays, kieselguhr, pyrophyllite, chalk, diatomaceous earths, calcium phosphates, calcium and magnesium carbonates, sulfur, lime, flours, and other organic and inorganic solids which act as dispersants and carriers for the toxicant. These finely divided solids have an average particle size of less than about 50 microns. A typical dust formulation useful herein contains 75% silica and 25% of the toxicant. Useful liquid concentrates include the emulsifiable concentrates which are homogeneous liquid or paste compositions which are readily dispersed in water or other dispersant, and may consist entirely of the fungicide with a liquid or solid emulsifying agent, or may also contain a liquid carrier such as xylene, heavy aromatic naphthas, isophorone, and other nonvolatile organic solvents. For application, these concentrates are dispersed in water or other liquid carrier, and are normally applied as a spray ot the area to be treated.
Other useful formulations for fungicidal applications include simple solutions of the active fungicide in a dispersant in which it is completely soluble at the desired concentration, such as acetone, alkylated naphthalenes, xylene, or other organic solvents. Granular formulations, wherein the fungicide is carried on relatively coarse particles, are of particular utility for aerial distribution or for penetration of cover-crop canopy. Pressurized sprays, typically aerosols wherein the active ingredient is dispersed in finely divided form as a result of vaporization of a low-boiling dispersant solvent carrier, such as the Freons, may also be used. All of those techniques for formulating and applying fungicides are well known in the art.
The percentages by weight of the fungicide may vary according to the manner in which the composition is to be applied and the particular type of formulation, but in general comprise 0.5% to 95% of the toxicant by weight of the fungicidal composition.
The fungicidal compositions may be formulated and applied with other active ingredients, including other fungicides, insecticides, nematocides, bactericides, plant growth regulators, fertilizers, etc.
EXAMPLE A
Tomato Late Blight
Compounds of the invention were tested for the control of the Tomato Late Blight organism Phytophthora infestans conidia. Five- to six-week-old tomato (variety Bonny Best) seedlings were used. The tomato plants were sprayed with a 250 ppm solution of the test compound in acetone, water and a small amount of a non-ionic emulsifier. The sprayed plants were then inoculated one day later with the organism, placed in an environmental chamber and incubated at 66°-68° F. and 100% relative humidity for at least 16 hours. Following the incubation, the plants were allowed to dry and then were maintained at 60-80% relative humidity for approximately 7 days. The percent disease control provided by a given test compound was based on the percent disease reduction relative to untreated check plants. The compounds giving effective control at the test concentration are tabulated in Table II.
EXAMPLE B
Tomato Early Blight
Compounds of the invention were tested for the control of the Tomato Early Blight organism, Alternaria solani conidia. Tomato (variety Bonny Best) seedlings of 6 to 7 weeks old were used. The tomato plans were sprayed with a 250 ppm solution of the test compound in an acetone-and-water solution containing a small amount of an non-ionic emulsifier. The sprayed plants were inoculated one day later with the organism, dried and maintained at 60-80% relative humidity for about 12 days. Percent disease control was based on the percent disease development on untreated check plants. The compounds giving effective control at the test concentration are tabulated in Table III.
EXAMPLE C
Celery Late Blight
Compounds of the invention were tested for the control of Celery Late Blight using celery (Utah) plants 11 weeks old. The Celery Late Blight organism was Septoria apii. The celery plants were sprayed with solutions of the candidate toxicant mixed with acetone, water and a nonionic emulsifier. The plants were then inoculated with the organism and placed in an environmental chamber and incubated at 66°-68° F. in 100% relative humidity for an extended period of time (approximately 48 hours). Following the incubation, the plants were allowed to dry and then were maintained at a 60-80% relative humidity for approximately 14 days. The percent disease control provided by a given candidate toxicant is based on the percent disease reduction relative to untreated check plants. The compounds giving effective control at the test concentrations are reported in Table IV.
EXAMPLE D
Botrytis cinerea control
Compounds of the invention were tested for Botrytis cinerea control using detached, well-developed primary leaves of a 4-6 week old horsebean plant. The leaves were dipped into a 40 ppm solution of the test compound in acetone and water containing a small amount of a nonionic emulsifier, then taken out and placed in a petri plate lined with two pieces of filter paper. The leaves were allowed to dry while the filter paper was kept moist by adding water as required. The treated leaves were then inoculated with the spores of Botrytis cinerea fungus grown on potato. The plate was covered after inoculation and kept at 23.5° C. The filter-paper lining of the plate was kept saturated with water throughout the test. The rate of disease incidence was determined in 3 to 5 days, when the disease symptoms were fully evident on non-treated check leaves. The percentage disease control provided by the test compound was calculated as the percentage disease reduction based on the non-treated check leaves. The effectiveness of the compounds tested for fungicidal activity is reported in Table V in terms of micrograms/cm 2 for 99% control of the fungus.
EXAMPLE E
Powdery Mildew
The powdery mildew test was made using bean seedlings (var. Bountiful) with well-developed primary leaves. The pathogen was Erysiphe polygoni. The bean seedlings were sprayed with a 250 ppm solution of the test compound in an acetone-water mixture containing a nonionic emulsifier. The treated plants were inoculated one day after spray application of the test compound with the pathogen. The plants were then maintained in a greenhouse at 60-80% relative humidity and at a temperature of 68°-70° F. The rate of infection on the leaves was made after about 10 days. The percent disease control provided by a given test compound was based on the disease reduction relative to untreated check plants. The compounds of the invention giving effective control at the test concentrations are reported in Table VI.
EXAMPLE F
Mycelia Inhibition
The compounds of the present invention were evaluated for fungicidal effectiveness by means of a mycelial inhibition test. This test is designed to measure the fungitoxic activity of fungicidal chemicals in terms of their degree of inhibition of mycelium growth. Each compound to be tested was dissolved in acetone to 500 ppm concentration. Paper strips were innoculated with the particular mycelium growth by covering the paper with a potato dextrose broth culture of mycelial suspension. The inoculated papers were then placed on potato dextrose agar plates and sprayed by means of a micro-sprayer with the fungicidal solution. The treated paper strips were incubated at 25° C. and data are taken after 24 hours. Fungicidal activities are measured by a zone of inhibited mycelial growth from the center of the paper strip. The effectiveness of the compounds tested for fungicidal activity is reported in Table VII in terms of micrograms/cm 2 for 99% control of the fungus.
HERBICIDAL UTILITY
The compounds of the present invention wherein R is aryloxymethyl are also herbicidal in both pre- and post-emergent applications. For pre-emergent control of undesirable vegetation, the herbicidal compounds will be applied in herbicidally effective amounts to the locus or growth medium of the vegetation, e.g., soil infested with seeds and/or seedlings of such vegetation. Such application will inhibit the growth of or kill the seeds, germinating seeds and seedlings. For post-emergent applications, the herbicidal compounds will be applied directly to the foilage and other plant parts. Generally, the herbicidal compounds of the invention are most effective against broadleaved weeds.
The compounds of the present invention can be used alone as herbicides. However, it is generally desirable to apply the compounds in herbicidal compositions comprising one or more of the herbicidal compounds intimately admixed with a biologically inert carrier. The carrier may be a liquid diluent or a solid, e.g., in the form of dust powder or granules. In the herbicidal composition, the active herbicidal compounds can be from about 0.01 to 95% by weight of the entire composition.
Suitable liquid diluent carriers include water and organic solvents, e.g., hydrocarbons such as benzene, toluene, kerosene, diesel oil, fuel oil, and petroleum naphtha. Suitable solid carriers are natural clays such as kaolinite, atalpulgite and montmorillonite. In addition, talcs, pyrophillite, diatomaceous silica, synthetic fine silicas, calcium alumino-silicate and tricalcium phosphate are suitable carriers. Organic materials such as walnut-shell flour, cottonseed hulls, wheat flour, wood flour or redwood-bark flour may also be used as solid carriers.
The herbicidal composition will also usually contain a minor amount of a surface-active agent. Such surface agents are those commonly known as wetting agents, dispersing agents and emulsifying agents, and can be anionic, cationic or nonionic in character. The herbicidal compositions may also contain other pesticides, adjuvants, stabilizers, conditioners, fillers, and the like.
The amount of herbicidal compound or composition administered will vary with the particular plant part or plant growth medium which is to be contacted, the general location of application--i.e., sheltered areas such as greenhouses, as compared to exposed areas such as fields--as well as the desired type of control. Generally, for both pre- and post-emergent control, the herbicidal compounds of the invention are applied at rates of 0.2 to 60 kg/ha, and the preferred rate is in the range 0.5 to 40 kg/ha.
Pre-emergent herbicidal tests on representative compounds of the invention were made using the following method:
Pre-Emergent Test
An acetone solution of the test compound was prepared by mixing 750 mg of the compound, 220 mg of a nonionic surfactant and 25 ml of acetone. This solution was added to approximately 125 ml of water containing 156 mg of surfactant.
Seeds of the test vegetation were planted in a pot of soil and the test solution was sprayed uniformly onto the soil surface at a dose of 33 micrograms/cm 2 . The pot was watered and placed in a greenhouse. The pot was watered intermittently and was observed for seedling emergence, health of emerging seedlings, etc., for a 3-week period. At the end of this period, the herbicidal effectiveness of the compound was rated based on the physiological observations. A 0-to-100 scale was used, 0 representing no phytotoxicity, 100 representing complete kill. The results of these tests appear in Table VIII.
TABLE I__________________________________________________________________________ ##STR6##Compound Melting Sulfur ChlorineNo. R Point, °C. Calc. Found Calc. Found__________________________________________________________________________1 3,4-(Cl).sub.2 -φ 170-172 19.7 20.3 32.7 31.12 2-F-φ 177-178 23.3 23.5 12.9 13.83 4-Cl-φ 156-157 22.0 22.8 24.3 21.94 3-CF.sub.3 -φ 160-161 19.8 20.0 10.9 11.25 ClCH.sub.2 122-124 28.0 27.2 31.0 30.56 φ 158-160 25.0 23.4 13.8 14.47 4-NO.sub.2 -φ 166-167 21.2 19.5 11.7 10.88 2-furyl 126-133 26.0 26.1 14.4 13.99 ICH.sub.2 107-108 20.0 21.2 11.0 10.910 4-Cl-φ-SCH.sub. 2 97-100 28.5 28.6 21.0 21.611 4-Cl-φ-CH.sub. 2 SCH.sub.2 110-111 27.4 27.8 20.2 19.712 2-thienyl 131-134 36.6 36.7 13.5 15.113 2-OH-φ 150-165 23.5 22.6 13.0 12.114 Cl.sub.3 C 99-100 21.5 22.0 47.5 46.515 2,6-(Cl).sub.2 -φ 188-190 19.4 20.0 32.2 32.616 3,5-(Cl).sub.2 -φ 186-187 19.4 20.1 32.2 31.317 2-NO.sub.2 -5-Cl-φ 167 19.0 18.1 21.1 20.518 CH.sub.2 CH(Cl).sub.2 -φ 90-91 23.1 25.9 38.3 37.519 2-CH.sub.3 -4-Cl-φ-O CH.sub.2 131-133 19.1 19.2 21.2 21.220 NCSCH.sub.2 -φ 109-110 38.2 38.9 14.1 13.921 Cyclopropyl 94-95 29.0 29.6 16.1 16.222 3-SCN-φ 168-169 30.7 30.0 11.3 9.823 Cl.sub.2 CCCl 108-109 20.7 20.9 45.7 44.224 CH.sub.3 CHI 78-79 19.1 20.0 10.6 11.325 4-Cl-φ-O CH.sub.2 181-182 20.0 19.2 22.1 20.826 CH.sub.3 CHCl 61-64 26.4 26.4 29.2 29.227 2,5-Cl.sub.2φOCH.sub.2 164-165 18.0 18,0 30.0 28.228 2-I-φ 176 16.8 16.6 9.3 10.329 2,4-Cl.sub.2φOCH.sub.2 150-151 18.0 18.0 30.0 28.130 CH.sub.3 CO.sub.2 CH(CH.sub.3)Oφ 118-122 17.9 16.1 9.9 10.1__________________________________________________________________________ φ = phenyl phenyl
Table II______________________________________Compound Tomato Late BlightNo. % Control______________________________________1 602 933 984 355 816 937 909 6210 8111 9312 8913 2717 8018 8921 9723 9824 2328 7529 88______________________________________
TABLE III______________________________________Compound Tomato Early blightNo. % Control______________________________________1 395 736 757 238 569 8112 6813 5114 2121 2324 7125 8829 69______________________________________
TABLE IV______________________________________Compound Celery Late BlightNo. % Control______________________________________3 684 239 7119 92______________________________________
Table V______________________________________CompoundNo. Botrytis Cinerea______________________________________2 1.63 1.18 0.159 0.3712 1.415 1.618 0.8220 0.88______________________________________
TABLE VI______________________________________Compound Powdery MildewNo. % Control______________________________________2 353 764 806 10012 5416 2319 5722 3523 9525 2928 6929 37______________________________________
TABLE VII______________________________________Compound Pythium Rhizoctonia Aspergillus FusariumNo. ultimum solani niger moniliforme______________________________________4 >1.7 0.65 >1.7 >1.75 0.12 0.38 1.1 >1.78 0.29 0.34 0.49 0.959 0.12 0.6 0.52 0.8210 >1.7 1.2 0.52 >1.711 >1.7 0.5 0.46 >1.712 >1.7 0.5 1.2 >1.713 >1.7 0.5 0.98 >1.720 -- 0.33 0.6 >1.7______________________________________
TABLE VIII______________________________________Com-pound Herbicidal Effectiveness - Pre/PostNo. O W C M P L______________________________________19 35/10 75/40 85/0 100/100 100/100 100/9525 0/0 20/0 70/0 95/85 90/85 90/8527 0/0 55/0 55/90 87/80 80/75 82/9029 0/20 95/20 97/20 100/100 100/100 100/97______________________________________ L = Lambsquarter (Chenopodium album) M = Mustard (Brassica arvensis) P = Pigweed (Amaranthus retroflexus) C = Crabgrass (Digitaria sanguinalis) W = Watergrass (Echinochloa crusgalli) O = Wild Oats (Avena fatua) | 1a
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FIELD AND BACKGROUND OF THE INVENTION
The invention relates to a pull-out mechanism for use on each side of a drawer or the like and including a support rail which is to be secured to a furniture cabinet, a pull-out rail which is to be secured to the drawer and a central rail arranged between the support and pull-out rails, the weight of the drawer being transmitted between the rails by rollers or the like. Respective deflection rollers are arranged at front and rear ends of the central rail. A control cable is secured to the support rail and to the pull-out rail and is guided over the deflection rollers.
Various pull-out mechanisms for drawers are known, wherein a drawer can be pulled entirely out of a furniture cabinet and is still held by the rails of the pull-out mechanism. In the case of some pull-out mechanisms, a device is provided which is intended to ensure that the rails run differentially with respect to one another. Such device can, for example, include a toothed wheel which is mounted on the central rail and meshes with toothed racks on the pull-out rail and the support rail. A simplified construction would be the arrangement of a frictional wheel on the central rail.
A particularly precise guidance of the central rail is achieved using a control cable which is secured to the support rail and the pull-out rail and which runs on both sides of the central rail and is guided at front and rear ends over belt guides of the central rail. A pull-out mechanism of this type is described in DE-A1-29 04 116. A similar pull-out mechanism in which a control cable is guided over rollers is known from U.S. Pat. No. 4,025,138.
SUMMARY OF THE INVENTION
It is an object of the invention to provide a pull-out mechanism having a control cable-type control in which a pull-out rail easily can be removed from a central rail.
It is a further object of the invention to provide that the control cable can be tensioned.
These objects according to the invention are achieved in that a cable has two free ends connected to respective coupling parts. One coupling part is a receiving part and the other is an inserting part. Both parts have profiles in the shape of toothed racks, by way of which the inserting part can be coupled into the coupling part over a capture region corresponding to the length of the toothed racks. One of the coupling parts can be coupled to the support rail or pull-out rail.
So that the closed drawer is always pulled entirely into the furniture cabinet, in one embodiment of the invention a retraction means, arranged on the support rail or on the pull-out rail, includes a spring-loaded entrainer which can travel along a liner guidance path longitudinally of the rails and can be locked at the two ends of the guidance path. The central rail has a peg or the like on which the entrainer acts in the rear retraction region, thus pulling the central rail into a fully inserted position thereof.
So that the front panel is always pushed snugly against the side walls of the furniture cabinet, the pull-out rail has to be positioned precisely in relation to the control cable. In one embodiment of the invention, this is achieved by provision of two further coupling parts which can be coupled to one another by way of profiles in the shape of toothed racks. One such part is an inserting part and is secured to a control part, e.g. the cable. The other such part is a receiving part and is secured to the pull-out rail or the support rail, preferably the pull-out rail. Such receiving part has a trough-shaped recess into which the inserting part can be pushed. As a result, the drawer can be placed onto the control cable and coupled using the pull-out rail, whereupon the drawer can be pulled as far as a stop relative to the control cable.
BRIEF DESCRIPTION OF THE DRAWINGS
An embodiment of the invention will be described in detail below with reference to the accompanying drawings, wherein:
FIG. 1 is a perspective exploded view of parts of a pull-out mechanism and a drawer frame;
FIG. 2 is a vertical section through one side of the drawer;
FIG. 3 is a perspective view of a central rail;
FIG. 4 is a vertical section through a rear portion of the drawer frame and the pull-out mechanism;
FIG. 5 is a perspective view of a pull-out rail with an adapter;
FIG. 6 is a perspective exploded view of rear running rollers and a rear adapter;
FIG. 7 is a perspective view of a control cable and two couplings;
FIG. 8 is an enlarged perspective view of the cable coupling;
FIG. 9 is an enlarged perspective view of the coupling which connects the control cable to the pull-out rail, such coupling being shown from the front;
FIG. 10 is a view similar to FIG. 9, and illustrating that coupling of the coupling part of the pull-out rail is from above;
FIG. 11 is a perspective exploded view of means for securing a front panel;
FIG. 12 is a view similar to FIG. 11, but of a further embodiment of a front panel securing means; and
FIGS. 13 to 15 are side views of the securing means according to FIG. 12.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
A drawer is formed by two metal drawer side frames 28, a front panel 39, a drawer bottom plate 38 and the rear wall 27.
Within the drawer frame 28 there are three adapters 16, 17, 18 which are secured to a pull-out rail 15, for example welded thereto. A support rail 2 is secured to a cabinet side wall 36 in conventional manner by way of a securing web 40. The drawer bottom plate 38 lies on a horizontal web 41 of a pull-out rail 15. In the horizontal web 41 are tabs 42 which can be pushed from the horizontal web 41 and have barbed configurations so that they can be pushed into a groove or the like in the drawer bottom plate 38 and thus anchor the drawer bottom plate 38 on the pull-out rail 15. A central rail 5 is positioned between the pull-out rail 15 and the support rail 2. The central rail 5 has a lower profile or portion 5' in which there is a carriage 3 (FIG. 1) to which rollers are mounted. Thus, the central rail 5 is guided relative to the support rail 2 by way of the rollers mounted in the carriage 3. Furthermore, the central rail 5 is provided with an upper, partially U-shaped profile or portion 5". Rollers 22, 23 are mounted on rear adapter 18 of the pull-out rail 15 and run on webs 43, 44 of center rail 5 (FIG. 4). Web 45 of pull-out rail 15 runs on a roller 6 (FIG. 1) which is mounted on the lower profile 5' of the central rail 5.
The central rail 5 has thereon front and rear cable rollers 9, and a control cable 10 is mounted to run on cable rollers 9. The control cable 10 which is formed for example from a wire or synthetic cable, has a catch-type cable coupling device 3 (FIG. 1) including two coupling parts or portions 12, 13 which are connected to ends of the control cable 10 (FIGS. 7, 8). In this case the coupling part 12 is constructed as a female part or a housing having two interior retaining members or profiles 46 in the shape of racks formed by teeth 50. Side walls are provided with apertures 47 which provide the housing of the coupling part 12 with a certain elasticity. The coupling part 13 has a web or projection 48 which is provided with retaining members or profiles 49 in the shape of racks formed by teeth 51 of a shape complementary to the profiles 46 of the coupling part 12. The web 48 can be pushed into the housing of the coupling part 12 far enough for the control cable 10 to be tensioned. The teeth 50, 51 of the profiles 46, 49 are in the shape of barbs inclined to face towards one another in order to facilitate pushing the web 48 of the coupling part 13 into the housing of the coupling part 12. At its end facing the coupling part 13, the coupling part 12 is provided with a U-shaped recess 51. The coupling part 13 has a lateral hook 53, by means of which it can be inserted into an opening 14 (FIG. 1) in the support rail 2. Thus, the coupling part 13 can be anchored to the support rail 2 by way of the hook 53. On both sides of the hook 53 are guide pegs 54 that also project into the opening 14 and improve the sealing of the hook 53 in the opening 14.
In order to connect the control cable 10 to the pull-out rail 15, a further coupling is provided. Such coupling includes an outer coupling part 19 and an inner coupling part 11. The outer coupling part 19 is secured to the pull-out rail 15 by means of screws or rivets 20 (FIG. 1) which project through securing holes. Outer coupling part 19 surrounds the inner coupling part 11. The inner coupling part 11 is torpedo-shaped and can be pushed into a trough-shaped recess 55 in the outer coupling part 19. A slot-type aperture 120 having opposite ends which widen into circles is provided in outer coupling part 19. This increases the elasticity of the coupling part 19, which is made from synthetic material. On interior walls of the trough-shaped recess 55 are two retaining members or profiles in the shape of racks formed by teeth which are complementary to a retaining member or profile 56 in the shape of a rack formed by teeth 57 of the inner coupling part 11. The teeth 57 of the profile 56 are constructed to be annular. The cross-section of the teeth 57 are barbed or inclined in the shapes of isosceles triangles. Outer edges of the teeth 57 can be rounded. The coupling part 11 is, as can be seen from FIGS. 9, 10, constructed to be approximately cylindrical or torpedo-shaped and has at opposite ends thereof frustoconical end portions 58.
In order to connect the coupling parts 11, 19 to one another, as shown in FIG. 9 the coupling part 19 can be pushed onto the coupling part 1 from the front or axially, or as shown in FIG. 10 it can be pushed onto the coupling part 11 from above. In order to position the coupling part 19 in relation to the coupling part 1 precisely enough for the front panel 39 to be pushed snugly against side walls 36 of the furniture cabinet by a retraction means 1, the drawer can be pulled forwardly with the pull-out rail 15 and the coupling part 19 relative to the coupling part 11 until engagement between the two coupling parts 11, 19 prevents further relative movement. On taking the drawer out of the furniture cabinet, the drawer is lifted up and the coupling part 19 is lifted upwardly away from the coupling part 11. Retraction means i includes a spring-loaded retainer and is mounted on either the support rail 2 or the pull-out rail 15. Central rail 5 has a peg or similar member 121 against which the retainer acts. The retainer is movable longitudinally of the rails and can be locked at two ends of the path of such movement. The entrainer is operable to pull central rail 5 into a fully inserted position thereof.
At the front end of the lower profile 5' of the central rail 5, running roller 6 is mounted on tabs 59 by means of a rivet 7. The running web 45 of the pull-out rail 15 runs on the running roller 6. Adapters 16, 17, 18 are secured to the pull-out rail 15. Rollers 22, 23 are mounted on the rearmost adapter 18 by means of rivets 21. Rollers 22, 23 are guided in the upper profile 5" of the central rail 5 and are located in the interior of the adapter 18 one behind the other. Front roller 22 is narrower than the rear roller 23 and, when the drawer is moved, is support against the web 43 of the central rail 5. The web 44 of the profile 5" of the central rail 5 is constructed to be U-shaped, with a lateral delimiting web 60. Between delimiting web 60 and a vertical web 61 which inclines upwardly at the same angle as delimiting web 60, is snugly guided the roller 23. As a result, lateral guidance of the pull-out rail 15 and thus of the drawer is ensured. Since the roller 22 is supported against the lower horizontal web 43 and the roller 23 is supported against the upper horizontal web 44, when the drawer is pulled out or pushed in there is no change n the direction of rotation of the running rollers 22, 23 and thus smooth running of the drawer is achieved.
At the front end of the lower profile 5' of the central rail 5 is secured a ramp block 4 of synthetic material. The ramp block 4 has an opening 62 in which the roller 6 is mounted. The roller 6 is mounted on rivet 7 which is held in flanges 67. The ramp block 4 extends over the front end of the lower profile 5' of the central rail 5 and includes a rail web 63 which has a straight portion 63' and a front, downwardly bent portion 63". When the drawer is suspended in place, the pull-out rails 15 are guided on the rail web 63 by way of their running webs 45, as a result of which suspension in place of the drawer is substantially facilitated.
All three adapters 16, 17, 18 have downwardly projecting holding webs 64. Each drawer frame 28 is constructed to be double-walled with an outer wall 65 and an inner wall 66. The outer wall 65 has, at its lower edge, a holding web 67 which is angled inwardly and upwardly in the manner of a hook and by means of which it can be suspended in place on the holding webs 64 of the adapters 16, 17, 18. The inner wall 66 has a horizontal web 68 which lies on the drawer bottom plate 38 when the drawer is mounted, and a vertical lateral web 69 which bears laterally against the drawer bottom plate 38. The transition from the horizontal web 68 to the inner wall 66 is rounded off.
Because the drawer frame 28 is welded or connected by tongue-and-groove connections neither to the adapters 16, 17, 18 nor to the pull-out rail 15, drawer frames of any material can be suspended in place on the adapters 16, 17, 18, from synthetic frames or aluminum frames to steel frames of a Nirosta material. The furniture manufacturer thus has the possibility of equipping even those drawers which are very different in price with the differential pull-out mechanism according to the invention.
The frontmost adapter 16 is provided with a holding plate 70 onto which a support part 32, 33 of a securing means 30, 31 for securing the front panel 39 can be screwed. Using securing means 30, the front panel 39 is pressed onto dowels 71 of a holding part 80, and support part 32 is secured to holding plate 70 by a screw 72, thus mounting the securing means 30 in its entirety on the pull-out rail 15. Using securing means 31, a holding part 34 is secured to the front panel 39 and the support part 33 is secured to the holding plate 70 by screw 72. Both the support part 33 of the securing means 31 and the support part 32 of the securing means 30 are provided with a lateral guide wall 73 which bears against a corresponding guide wall 74 of the holding plate 70.
Support part 32 of the securing means 30 has a rearwardly open slot 75 through which projects securing screw 72 which can be screwed into a female thread 70a in the holding plate 70. The securing means 30 has a holding part 80 which is secured to the front panel 39 by means of dowels 71. The support part 32, which is punched out of a steel sheet, has a tab or flange 76 which projects at a right angle from the support part 32. Support part 32 has top and bottom horizontal webs 77, each having a rearwardly open slot 78. Pegs 79 of the holding part 80 are guided in the slots 78. The holding part 80 is provided with a cutout 81. Furthermore mounted in the holding part 80 is an adjusting screw 82 for lateral adjustment of the front panel 39. When the fitting is mounted, an upper edge 83 of the support part 32 projects into an annular groove 84 in the adjusting screw 82, with the result that by turning the adjusting screw 82 the holding part 81 is moved laterally with respect to the support part 32. When the securing means 30 is mounted, the flange 76 of the support part 32 projects into the cutout 81 in the holding part 80. A pressure spring 85 is mounted in the cutout 81 and is supported at one end against a web 86 of the holding part 80 and at the other end against the tab 76 of the support part 32. As a result of the pressure spring 85, the holding part 80 is pushed rearwardly and thus the front panel 39 is tightened against the end edges of the drawer frames 28.
If the drawer is pushed into the furniture cabinet too vigorously, the front panel 39 strikes against the end edges of the side walls 36 of the furniture cabinet. However, the drawer can, with the drawer frames 28, the pull-out rails 15 and the support parts 32, move further in opposition to the pressure of the pressure springs 85 relative to the holding parts 80, with the result that a damping effect occurs and the seating of the dowels 71 in the front panel 39 is not over-stressed. Once the energy of inward movement is consumed, the drawer frames 28 are pushed, by way of the support part 32 and the holding plates 70, against the front panel 39 by the pressure springs 85.
When the drawer is assembled, the securing means 30 according to the invention is mounted in its entirety in the drawer frame 28. The holding part 80 is pushed to a rear end position by the pressure spring 85. The outer wall 65 of the front panel 28 is provided in the region of the securing means 30, 33 with a cutout 87 which enables access of tools to the securing means 30, 33. The cutout 87 is covered by a removable cover plate 29.
To mount the front panel 39, the holding part 80 is pushed somewhat outwardly of the drawer frame 28 by means of a pressure ram which engages in the cutout 81 and bears against a web 89 of the holding part 80, with the stop face 88 lying just in front of the end face of the drawer frame 28. In this position, the front panel 39 can be pressed against the dowels 71 of the holding part 80. Once the front panel 39 is anchored on the dowels 71 of the holding part 80, the pressure ram is withdrawn from the cutout 81 and the pressuring spring 85 pushes the holding part 80 into the drawer frame 28 to such an extent that the front panel 29 bears snugly against the end face of the drawer frame 28.
The securing means 31 has support part 33 which is secured to the holding plate 70 of the adapter 16 by screw 72. A tilt lever 90 is moved on the support part 33. At the rear, the support part 33 has a bent tab 76 against which the spring 85 is supported. The bent tab 76 is provided with a cross slot 91 through which there projects a rod 92 which supports the spring 85 and directly acts on the tilt lever 90. The support part 33 is secured by means of the screw 72, which projects through a vertical elongate hole 33a in the support part 32 and can be screwed into the holding plate 70. The tilt lever 90 has an upper notch 93 and a lower notch 94. Above the tilt lever 90 is locking bolt 95 which at its rear end is mounted on rod 92 by means of a punched-out slot 96 and which has a front locking web 97 which latches into the notch 93 on the tilt lever 90 when the front panel 39 is secured. The holding part 34 is secured directly to the front panel 39 and has mounted therein adjusting screw 82 for lateral adjustment. The support part 32 has upper and lower horizontal webs 77 defining therebetween a space into which the holding part 34 can be pushed. A lateral plate 98 is pushed onto the webs 77 and pegs 99 of the webs 77 project into openings in page 98. The support part 33 and the lateral plate 98 have punched holes 101 through which projects a pin 102 which forms an axle of the tilt lever 90. The holding part 34 is provided with a lug or hook 100.
Before the front panel 39 has been pushed onto the drawer frames 28 and the holding parts 34 have been pushed into the support parts 33, the tilt levers 90 are in the position shown in FIG. 13. That is, the spring 85 rotates lever 90 clockwise far enough for a lug 105 to bear against the upper web 77. Once the holding part 34 is pushed into the support part 33, the lug 100 latches into the notch 94 and turns the tilt lever 90 counterclockwise. Once the spring 85 has passed the dead center position, the tilt lever 90 is also turned counter-clockwise by the spring 85. Thus, the holding part 34 is pulled into the support part 33 and the front panel 39 is pushed against the drawer frame 28.
The tilt lever 90 is provided with a cross slot 108. The locking bolt 95 has a lateral web 107 which reaches laterally over the tilt lever 90. When the front panel 39 is to be released from the drawer frame 28, a Phillips screwdriver is inserted into the cross slot 108. This raises up the locking bolt 95, since the screwdriver bears against the lateral web 107. At the same time, the locking flange 97 is lifted out of the notch 93 in the tilt lever 90 and the tilt lever 90 is thus freed. The tilt lever 90 can now be turned clockwise, by the Phillips screwdriver projecting into the cross slot, as a result of which the holding part 34 is freed.
If a drawer is pushed into the furniture cabinet too forcefully, a shock absorber effect again occurs. When the front panel 39 strikes against the side walls 36 of the cabinet, the drawer frames 28 and the pull-out rails 15 can be lifted away from the front panel 39, in opposition to the action of the spring 85, to the extent permitted by a spacing between the locking flange 97 and a stop face 109 on the tilt lever 90. Then, the pull-out rails 15 and the drawer frame 28 are pushed against the front panel 39 again by the spring 85.
The holding part 34 can also be connected to a coupling part 103 (FIG. 1) for a front plate. Unlike a front panel 39, an end of which bears against the drawer frames 28, a front plate is located between the two drawer frames 28 and ends at the front thereof. As a result, the front plate does not project beyond the cabinet side walls 36 and the furniture cabinet can be closed using doors.
The rearmost adapter 18 supports, by screws 26, a coupling part 25 for the rear wall 27. The coupling part 25 is provided with pegs 105 which project into punched holes 106 of bent tabs 27a of the rear wall 27. Furthermore, the coupling part 25 has a downwardly projecting, preferably resilient hook 108 which hooks into the adapter 18 when the coupling part 25 is mounted. The rear wall 27 is furthermore provided with a lower horizontal web 27b on which lies the drawer bottom plate 38. | 1a
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to the safety measures required in the medical field to protect patients and operators from undesired radiation exposure.
2. Invention Disclosure Statement
Modern laser therapy has gained a well-accepted role in many classical parts of medical therapy methods. Nearly every procedure that employs conventional heat producing sources such as microwaves or electromagnetic field applications can also be performed using laser sources at a correct wavelength. Laser heat sources are an advantage over the prior art, because the area to be treated can be targeted specifically. The laser wavelength can be matched to the absorption wavelengths of water or hemoglobin to more accurately treat a medical problem. Suitable laser sources with sufficiently high output powers have become commercially available. Significant progress has been made in designing medical application lasers such as Q-switched Neodymium family lasers, compact carbon dioxide lasers, and in particular diode lasers.
Medical laser therapy methods are generally divided in two substantial classes: direct open treatment and interstitial treatment. In interstitial treatments, q-switched lasers are often coupled with optical fibers for use in surgery. Laser energy has also been used indirectly in treatments such as Photodynamic Therapy (PDT). In PDT, laser radiation is used to activate photo-reactive substances, which have been applied to a particular treatment zone.
There are many safety issues to be concerned with however, when using lasers in the place of conventional heat producing sources. With interstitial laser treatments such as ocular, vein treatment, hair removal, and other comparable treatments, there is less risk that the operator will be exposed to laser radiation. For many surface treatments however, many safety precautions must be taken to protect the operator and patient. State of the art systems often require cumbersome or expensive safety equipment. For example some laser systems include auto-locking doors for the operation room that cannot be opened from the outside while the laser source is running. These auto-locking doors prevent unprotected personnel from entering the treatment room. These safety requirements also mean that most laser equipment can only be used in a clinical setting. It would be advantageous if a system that fulfilled the safety requirements could be used in non-clinical settings.
U.S. Pat. No. 5,877,825 describes a type of protective eyewear for use with a pulsed laser radiation source. This protective device incorporates an electro optical shutter that causes the safety glasses' lens to become opaque during each pulse of radiation. The drawback to this invention is that every technician present must be tied into the protective system. Furthermore, this invention does not protect anyone who enters the treatment room by accident.
Many laser safety systems employ state of the art in situ visualization methods such as CCD cameras, image viewing, and processing units. This method eliminates an operator's exposure to laser radiation. Many surgeons and technicians however, prefer to operate using their own eyesight.
It is therefore the goal of the present invention to provide a method to protect medical personnel from exposure to laser radiation. The current invention will allow surgeons and technicians to use their own sight to perform operations, while still meeting safety requirements. The limitations of the prior art are overcome by the utilizing the current invention system.
BRIEF SUMMARY OF THE INVENTION
It is an object of the present invention to incorporate into a laser treatment system safety means that allow the laser system to be used more efficiently and safely.
It is another object of the present invention to provide a laser treatment system that can be used in a non-clinical setting while still meeting safety requirements.
It is also an object of the present invention to provide means by which laser treatment systems can be used more easily while still protecting the operator from laser radiation.
It is a further object of the present invention to allow the operator to visually observe the procedure without exposure to stray laser radiation.
It is yet another object of the present invention to provide a laser treatment system that protects technicians and patients from accidental exposure.
In the present invention a laser treatment system is provided that can be used in any clinical environment without the necessity of personal safety equipment. Furthermore, the present invention provides a large amount of control to the operator/technician and the patient. The present invention combines mechanical and optical methods to protect operators and patients from undesired exposure to laser radiation. According to this approach safe portable and stationary embodiments that are useful in a large variety of applications, are now possible. Several examples are described.
The above, and other objects, features and advantages of the present invention will become apparent from the following description read in conjunction with the accompanying drawings, in which like reference numbers in different drawings designate the same elements.
BRIEF DESCRIPTION OF FIGURES
FIG. 1 depicts a conical bell shaped safety treatment system of the present invention.
FIG. 1 a shows a variation of bell 1 in FIG. 1 .
FIG. 2 illustrates the present invention power control unit in greater detail.
FIG. 3 depicts a present invention device with alternative imaging optics.
FIG. 4 shows a present invention device that incorporates an optical fiber.
FIG. 5 illustrates a closed box embodiment of the present invention.
FIG. 6 shows another embodiment of safety means of the present invention.
FIG. 7 depicts yet another embodiment of a closed box safety measure of the present invention.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
The present invention provides an apparatus, which can be used in any clinical environment without the necessity of personal safety equipment. The present invention also gives a large amount of control to the operator as well as the patient. The present invention fulfills laser safety requirements and can be applied to emergency rescue operations or for veterinary applications as well. In these applications, the current precautions often are particularly difficult to sustain. By combining mechanical and optical methods, this approach can be applied to fixed as well as portable devices in a large range of medical applications. The present invention combines ease of use with flexibility. For example, in one embodiment a portable laser disinfecting system is used in ambulances because under the present invention it could be manufactured to meet safety requirements in such use.
FIG. 1 illustrates the basic design of a present invention embodiment. The interface towards the patient is formed by conical “bell” 1 . Alternatively, the specific form of bell 1 may vary depending upon the desired treatment method and the particular optical system chosen. Furthermore, varying sizes of bell 1 are used depending on the type of treatment application area. Bell 1 is made of a transparent material, which is manufactured with a filter coating on the inside. The filter coating inside bell 1 is chosen to be highly reflective for the particular laser wavelength used. The coating should reflect all angular variation that may occur. Conversely, the coating should allow any wavelength not being used in the medical procedure to transmit and pass though. In an alternative, the bell material absorbs a sufficient amount of laser radiation to protect the operator. The bell material can be a colored glass or plastic. Since bell 1 , filters out the laser radiation being used in treatment, the potential risk to patient and operator are eliminated. Bell 1 is pressed upon the body area to be treated. This means that anyone exterior to the bell is protected from the laser radiation produced in the interior. Furthermore, since the coating transmits most wavelengths other than the base wavelength, it is possible to visually inspect the treatment area during a medical procedure. Casual light will pass through the walls of the bell.
Inside the bell-shaped form of FIG. 1 are imaging optics for the radiation source. The setup presented in FIG. 1 includes lens 2 , which is mounted in glass tube 3 . Glass tube 3 is transparent to the radiation wavelength used in the desired application. Alternatively, glass tube 3 is antireflection coated. In yet another alternative glass tube 3 is in a stable wire frame unit. In another alternative embodiment, the lenses are exchangeable and can be mounted at different positions in the rod. This allows the radiation spot sizes to be varied. In yet another alternative, multiple lenses are used to achieve more complex irradiation profiles such as a cylindrical form or spread point images. These profiles can be achieved be using diffracting optics such as gratings. Holder 3 is passed through bell 1 and fastened to bell 1 using flexible fasteners 4 . Flexible fasteners 4 allow the laser to move during treatment instead of irradiating a fixed spot. The present invention allows the intensity focused upon any part of the treatment area to be controlled. This is an advantage considering that diseased areas are rarely homogenous. At the top of the unit described in FIG. 1, at least one optical fiber 5 transports the radiation produced by an appropriate beam source 6 . Beam source 6 is located elsewhere in the holder. In an alternative, multiple beam sources are used. The fiber is fixed in position to avoid altering the imaging to the treated body parts. The fiber travels completely through power control unit 7 of the invention.
FIG. 1 a shows a variation of bell 1 in FIG. 1 . Rim 20 of bell 1 has attached to it a soft deformable cushion 22 . Cushion 22 contacts the treatment surface. This cushion makes a better easier seal between rim 20 and the surface to be treated. Therefore any leakage of laser radiation is minimized. A hard surface with an irregular pattern in the perpendicular direction would especially create a problem for sealing the treatment area. Cushion 22 provides a tighter fitting interface without causing discomfort to the patient by increasing pressure on the rim. In an alternative cushion rings of varying diameter can be manufactured to fit different sized bell/cones. In another alternative, the cushions are manufactured with a temporary adhesive. This adhesive allows the cushion to be replaced after use or interchanged with a different thickness. Alternative to using a cushion, the entire bell is manufactured from a partially flexible substance. These variations on bell 1 also benefit present invention applications that require a partial vacuum on the enclosed volume within the bell/cone. The lower vacuum would cause less discomfort to the patient and potentially less damage to non-medical substrate requiring laser treatment.
FIG. 2 illustrates power control unit 7 of FIG. 1 in greater detail. The power control unit is fixed to the imaging optics holder. The power control unit consists of two basic parts: upper contact shaft 8 and lower contact shaft 9 . Lower contact shaft 9 is fixed to optical holder 3 shown in FIG. 1 . Upper contact shaft 8 shown in FIG. 2 is movable with reduced up and down friction due to roller bearing 10 . Roller bearing 10 is included in lower shaft 9 . The initial position of lower shaft 9 is an elevated state due to the pressure from compression spring 11 . This elevated position keeps upper contact shaft's 8 electrodes 12 separated from lower contact shaft's 9 electrodes 13 . Lower shaft electrodes 13 are electrically isolated from the shaft itself. When electrically connected, all of them have the same potential. Upper shaft electrodes 12 consist of at least two separated elements at a different potential, which are therefore electrically isolated. When upper shaft 8 is pressed down against compression springs 11 , upper shaft electrodes 12 will contact lower shaft electrodes 13 . This closes the optical switch, which is made up of electronics 14 (shown in FIG. 1 ). This switch mechanism is an integral part of the present invention safety mechanism. Upper contact shaft 8 of FIG. 2 is fixed to hand-piece 15 of FIG. 1 . Hand-piece 15 serves as a handle for the present invention laser tool. Bell shaped cone 1 (shown in FIG. 1) is positioned over the treatment zone. The laser operation cannot be started unless the operator presses down on hand-piece 15 . This pressing creates electrical contact in power control unit 7 to start the laser operation. This assures that no radiation can enter from the exterior, because the apparatus is pressed over the treatment area, which creates a tight enclosure. The included optical fiber must be slightly longer to match the path difference that occurs due to pressing the apparatus down. Means such as loop 16 of FIG. 2 solve this problem. If necessary, multiple fiber loops are created. Power control unit 7 is completely enclosed in a suitable flexible pipe to accommodate these dimension changes made by pressing.
Beam source 6 (shown in FIG. 1) is located within the hand-piece itself. Beam source 6 is a diode laser which is fiber coupled to at least one optical fiber. Alternatively beam source 6 is a miniaturized diode pumped solid-state laser operating at a fundamental wavelength between 1 μm and 3 μm. The latter alternative can further contain means for frequency conversion that allows visible wavelengths that may have different absorption characteristics as well. In another embodiment the invention further includes means for Q-switching of this laser. In an alternative (with any chosen beam source), the beam source parameters are set externally by switches (not shown) on hand-piece 15 . The parameters that are set externally include pulsed/cw operation, laser power level, duty cycle and repetition rate. Additionally switching system 14 of several relays is included. Switching system 14 is connected to power source 18 . In an alternative, a state of the art battery provides power source 18 . Wiring 17 connects battery power source 18 to beam sources 6 and switching unit 7 . Using standard electronics, the power control unit may be operated at non-critical levels, such as 5 Volts, and current peaks can be avoided. Alternatively, the battery can be taken out of the element for recharging, while a fully charged battery replaces it to ensure continuous operation of the apparatus. In yet another embodiment, a power supply (not shown) is connected to the battery port of the apparatus to provide equivalent power from a stationary plug.
FIG. 3 shows a variation of the above-described concept. There are two basic variations. First, the imaging optics are completely different. Optics holder 303 is similar in design to the one in FIG. 1 . Optics holder 303 holds curved mirror 319 . Mirror 319 is depicted as having a defocusing effect. In an alternative, mirror 319 has a focusing effect. The radiation emitted by the fiber is reflected from mirror 319 through transparent optics holder 303 to the reflecting bell. The exact form of the bell is determined by the optical requirements. Usually the bell form is either parabolic or spherical in shape. Both alternative shapes have the effect of collimating or focussing the incoming radiation to the treatment zone. While the parabolic shape has the advantage of lower imaging errors, the spherical shape has more flexibility in uses. In an alternative, additional lenses are added to optics holder/mount 303 . By varying the parameters of the lenses, the back reflecting mirror and the reflecting bell optics, the instrument can be used in a greater variety of applications/treatments.
Second, syringe 320 is added through a lumen 321 . Syringe 320 is added in a lower, non-irradiated portion of the bell. This allows the in situ addition of therapeutic substances, such as disinfectants, anaesthetic substances or PDT liquids. This allows the operator to apply therapeutic substances as needed during the operation. Furthermore, since the operator can visually inspect the treatment area, the operator can more accurately gauge the amount of therapeutic substance to apply. Alternatively, a vacuum line connects to the system through interface lumen 321 . This vacuum line can be used either as part of the treatment procedure or as an additional safety mechanism. In another alternative embodiment, the pressure within the bell is monitored. Once the bell is pressed onto a treatment site, the air is partly evacuated through this vacuum line. The apparatus is designed so that the laser can only be started once a specific reduced pressure level is reached. This mechanism ensures that the bell forms an isolated treatment chamber and that no radiation can leave the chamber. Using this method, prior art safety methods such as glasses, special clothes or gloves, or constructive safety means such as emergency locks at laboratory doors all become unnecessary.
FIG. 4 illustrates another basic design to the present invention. In order to reduce costs it is an advantage to directly apply the laser source instead of first coupling it to a fiber. This also enhances the electrical to optical efficiency and avoids the complications with coupling fiber to a laser source. The drawback to direct laser application in the past is that advanced constructional means were needed. In a present invention embodiment, a simple approach is taken. The beam source itself is included in optics holder 403 or 404 and images the radiation through working bell shaped cone 401 to the diseased body parts. In a preferred embodiment the laser source is placed with the aid of a transparent optics holder 403 , similar to the holder described in FIG. 1 . The laser source then radiates towards the bell surface. In one embodiment micro-optical elements 405 and standard optical elements 422 shape the radiation before it hits the inner bell surface. At the inner bell surface it is directed by mirror to the treatment zone. The bell shape is manufactured to obtain ideal irradiation intensity. Preferred forms for the bell are parabolic, hyperbolic or spherical shapes. Alternatively the bell shape may be x.y astigmatic bodies that combine the above shapes with different parameters or combinations of different ones. For example, an x-parabolic can be combined with a y-spherical shape in order to correct typical diode laser astigmatisms or to equalize differences in beam quality in the two directions. Electric circuitry 417 used to drive the beam source, is guided through shaft contact system 412 and transparent holder 403 to the beam source. All other details of this apparatus are manufactured similar to the description for FIG. 1 .
Another approach to resolve the problems described above concerning the laser safety during the treatment and the inspection of the treatment process, can also be solved by a stationary apparatus. This stationary apparatus satisfies the high safety demands for a system in a clinical environment. A system of this type must fulfill the highest safety standards for operator and patient, while still providing high ease of use, rapid device preparation and visual online inspection. FIG. 5 illustrates an apparatus designed to fulfill all of these requirements. This embodiment is comprised of closed box 523 made of a highly durable material. This material is chosen to be indestructible by any direct or indirect laser irradiation applied during a treatment procedure.
The part of the body to be treated is passed through holes 524 . Holes 524 enclose the body part with a rubber ring, so that the interior of the box is sealed from the outside. The rubber ring is designed so that it can either withstand an evacuation to a specified low pressure or withstand an air pressure created artificially within the chamber. In alternative embodiments the pressure changes can be used to contribute to the treatment process. The pressure change however, is preferably used as a safety mechanism. A vacuum line, resp., gas or air pipe is lead through pipe 529 to the chamber. The apparatus is designed so that electrical lines for any kind of control mechanisms are guided and introduced into the chamber in a way that preserves the isolation of the interior. In a preferred embodiment, one of the control lines incorporates a pressure measurement sensor (not shown). When an exterior laser supply mechanism is used, this element is connected to the general supply (not shown). The pressure inside the chamber is detected by measurement equipment. If the pressure has reached a specified critical value, the safety mechanism allows the operator to start the laser source. For example, a specific evacuation level is used as the criterion that allows the laser system to start.
The box in this embodiment contains at least one hole enclosed with coated window 525 . Coated window 525 is manufactured from any suitable glass, crystal or polymer material. The coating on window 525 is designed in a dichroitic way, so that it protects the outer environment from the application laser, while still allowing the visual inspection of the treatment area. The chromatic distortions are insignificant because typical illumination light consists of different wavelengths than most processing lasers. This is particularly true because many medical operation lasers operate in the infrared region. Even for lasers that operate in visible wavelengths, the chromatic distortions do not significantly effect affect treatment area visualization. Alternatively window 525 is manufactured from a colored material. The colored material absorbs the active laser wavelength to protect the operator from the particular visible or non-visible wavelength being used.
The application instrument itself is introduced into the box through isolating interface 526 . In this embodiment it consists basically of the same elements as the instrument in FIG. 1 . The application instrument is preferably hand-piece 527 which contains power control means. The power control means can be realized by switches, pressure controls or a foot-piece. The laser unit has a flexible interface, so that it can be moved over a large distance in the chamber. The flexibility allows the laser unit to cover large treatment areas or to perform the necessary movements in applications such as vessel treatments.
FIG. 6 illustrates yet another embodiment that overcomes the safety problem of the prior art. A transparent expandable sheet form creates the safety means. When applied, the form is blown up to a balloon through pipe 629 . An electrical connection is also included through pipe 629 . This serves as the control line for a pressure measurement system. A specific body part is inserted through hole 624 . The “balloon” isolates the chosen body part from the surrounding environment. In this embodiment, the pressure inside the balloon is then increased to a specific level. The pressure inside the balloon acts as a gate switch for the laser. If the pressure is sufficiently high, then the treatment site is sufficiently isolated and the laser operation can be started. If the pressure is not high enough, the laser safety switch will not allow the laser to function. Furthermore a safety mechanism is included to prevent over-pressurization and damage to the body part. For the laser safety switch to function, the laser source must also be connected to a central control unit (not shown) either by cable 628 or a wireless transmission method (not shown). The power source for the laser apparatus is included in the form of a battery. Alternatively it is positioned in a central control system and connected via a line in pipe 628 . The laser apparatus, itself, is formed by hand-piece 627 and application end 626 . The interior balloon surface is coated to ensure isolation from radiation. The application section of the apparatus is inside the balloon while the hand-piece remains outside. This enables the operator to position the device safely.
In another embodiment a pair of gloves is included (not shown). In this latter embodiment, the whole laser hand-piece is inside the balloon. The operator uses the gloves to work completely inside the balloon. This is an advantage for treatments requiring multi-spot treatment irradiation, where small areas distributed over a larger area of the body need treatment. Balloon foil ( 630 ) is coated in a dichroitic way. This coating completely reflects radiation generated by the laser source, but is still transparent to other wavelengths. The system in FIG. 6 is in particular constructed to irradiate human extremities. In an alternative, minor modifications are made to this design for the irradiation of a torso. In this alternative the dimensions and hole 624 sizes must be altered appropriately. To apply the radiation, a needle system is shown in FIG. 6, similar to that used in interstitial laser therapy. The needle system is guided into a lumen and used to irradiate specific parts of body.
FIG. 7 shows another solution to the general problem of combining laser safety with in situ inspection and ease of use. This embodiment consists of the setup illustrated in FIG. 5 of a closed box ( 523 ). One side however is replaced with dichroicly coated window 725 for an observation interface that prevents laser radiation from leaving the enclosed treatment area and entering the environment. At least one central line enters the chamber. Included in the central line are the supply lines for the laser system such as optical fibers, wire lines, vacuum lines and fluid lines as well as a pressure or vacuum safety system. The part of the body to be treated is inserted into the chamber through hole 724 . In the embodiment depicted in FIG. 7, hole 724 is specially designed for legs or arms. The whole setup can be scaled to include the patient's entire body. After the body part is inserted, the interface is then sealed and the chamber is evacuated or filled with air or gas to a predetermined pressure. This critical pressure, whether over pressurized or a vacuum, is the triggering criterion for the laser safety mechanism. If the predetermined pressure is not reached, the beam source cannot be started. This assures that the isolation process is complete and no radiation can exit the chamber. In a preferred embodiment, the laser source rests completely inside the chamber. The interface to the outside is realized through preferably a pair of gloves ( 731 ), which allow the operator to manipulate the instrument inside the chamber. These gloves are made of a durable material, which has a special coating to protect the practitioners' hands and arms from the irradiation. The advantage of this embodiment over the simple handle interface in FIG. 5 is that more complex operations can be performed. It is possible to perform several steps in a single treatment session without the need to depressurize/deflate the chamber and change setups.
In alternative embodiments to all the described alternatives, a plurality of additional elements can be lead into the treatment zone through the available interface. For some purposes, e.g. interstitial methods, it is particularly useful to include an endoscopic line through the interface that allows for visualization. This is necessary for in-body treatments, where visualization of the treatment area is not possible. In an alternative embodiment means are included that allow the basic parameters of the beam source to be adjusted.
In alternative embodiments a plurality of power source options can be utilized. In one embodiment the power source is at least one rechargeable battery. Alternatively the present invention includes a plug interface to allow batteries to be exchanged without interrupting the power flow. In yet another alternative the present invention includes a power adapter, which allows a direct plug connection.
Having described preferred embodiments of the invention with reference to the accompanying drawings, it is to be understood that the invention is not limited to the precise embodiments, and that various changes and modifications may be effected therein by those skilled in the art without departing from the scope or spirit of the invention as defined in the appended claims. | 1a
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TECHNICAL FIELD
The present invention relates to novel fungal isolates of potential medicinal value. More particularly, the invention relates to compounds isolated from cultures of the Fusarium genus, herein designated "fusacandins", which possesses antifungal activity, as well as to methods and cultures of microorganisms useful for the preparation of fusacandins, pharmaceutical compositions containing such compounds, and the use thereof in treating fungal infections.
BACKGROUND OF THE INVENTION
The compounds of the present invention are related to those of the papulacandin class, described in J. Antibiotics 33(9):967-977 (1980). Papulacandins include BE-29602, disclosed in a published Japanese patent application of Banyu Pharmaceutical Co. (No. JP05170784-A, published Jul. 9, 1993) and isolated from a Fusarium species of fungus, and chaetiacandin, disclosed in J. Antibiotics 38(4):455-459 (1985) and J. Antibiotics 38(4):544-546 (1985). The fusacandins are distinct from the papulacandin compounds, however, in that they contain three sugar moieties not previously described in connection with other members of this class.
SUMMARY OF THE INVENTION
It has now been found that novel antifungal agents of the papulacandin class, herein designated "fusacandins", may be obtained by the fermentation of certain cultures belonging to the fungal strain Fusarium sp. AB 1900A-1314.
Accordingly, in one aspect of the present invention are disclosed compounds of the formula: ##STR3## as well as pharmaceutically acceptable prodrugs thereof.
In the above formula (I), R may be a radical of the formula ##STR4## in which instance the compound is designated fusacandin A. Alternatively, the radical R may be hydrogen, in which instance the compound is designated fusacandin B.
In another aspect of the present invention are disclosed pharmaceutical compositions which comprise a compound of the invention in combination with a pharmaceutically acceptable carrier.
In a further aspect of the invention is disclosed a method of suppressing or inhibiting a fungal infection in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound of the invention.
In yet another aspect of the invention, a process for preparing the compounds of the invention is disclosed which comprises the steps of (a) culturing a microorganism having substantially all the characteristics of Fusarium species AB 1900A-1314 under suitable conditions in a fermentation medium containing assimilable sources of carbon and nitrogen; (b) allowing the desired compound to accumulate in the fermentation medium; and (c) isolating the compound from the fermentation medium. Preferably, the microorganism to be cultured is Fusarium strain NRRL 21252 or a mutant or derivative thereof.
Similarly, in an additional aspect of the present invention is disclosed a biologically pure culture of a microorganism capable of producing the compounds of the invention, namely, a microorganism having substantially all the characteristics of Fusarium species AB 1900A-1314. Preferably, the microorganism is Fusarium strain NRRL 21252 or a mutant or derivative thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
The present invention will be better understood in connection with the following figures, in which:
FIG. 1 is a proton nuclear magnetic resonance (NMR) spectrum of Fusacandin A in CD 3 OD;
FIG. 2 is a carbon NMR spectrum of Fusacandin A in CD 3 OD;
FIG. 3 is an infrared (IR) spectrum of Fusacandin A acquired in microscope mode;
FIG. 4 is a proton NMR spectrum of Fusacandin B in CD 3 OD;
FIG. 5 is a carbon NMR spectrum of Fusacandin B in CD 3 OD; and
FIG. 6 is an IR spectrum of Fusacandin B acquired in microscope mode.
DETAILED DESCRIPTION OF THE INVENTION
As used throughout this specification and in the appended claims, the following terms have the meanings specified:
The term "biologically pure" as used herein refers to fungal cultures which are substantially free from biologically active contaminants.
The term "mutant or derivative" as used herein refers to fungal strains which are obtained by mutagenization or genetic modification of Fusarium species strain NRRL 21252 by techniques readily known in the art.
The term "pharmaceutically acceptable prodrug" as used herein refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate With a reasonable benefit/risk ratio, and which are effective for their intended use.
The term "prodrug" refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carders in Drug Design, American Pharmaceutical Association and Pergamon Press (1987). (Both here and throughout the specification, it is intended that citations to the literature are expressly incorporated by reference.)
Where appropriate, prodrugs of derivatives of compounds of the present invention may be prepared by any suitable method. For those compounds in which the prodrug moiety is an amino acid or peptide functionality, the condensation of the amino group with amino acids and peptides may be effected in accordance with conventional condensation methods such as the azide method, the mixed acid anhydride method, the DCC (dicyclohexyl-carbodiimide) method, the active ester method (p-nitrophenyl ester method, N-hydroxy-succinic acid imide ester method, cyanomethyl ester method and the like), the Woodward reagent K method, the DCC-HOBT (1-hydroxy-benzotriazole) method and the like. Classical methods for amino acid condensation reactions are described in M. Bodansky, Y. S. Klausner and M. A. Ondetti, Peptide Synthesis, Second Edition (New York, 1976).
Asymmetric centers may exist in the compounds of the present invention. Except where otherwise noted, the present invention contemplates the various stereoisomers and mixtures thereof.
The compounds of the invention exhibit in vitro activity as antifungal agents against a variety of fungal organisms and inhibit (1,3)-β-glucan synthetase. They are therefore expected to be useful in the treatment of fungal infections in mammals. When used in such treatment, a therapeutically effective amount of the compound of the present invention may be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt, ester or prodrug form. Alternatively, the compound may be administered as pharmaceutical compositions containing the compound of interest in combination with one or more pharmaceutically acceptable excipients. By a "therapeutically effective amount" of the compound of the invention is meant a sufficient amount of the compound to treat the targeted disorder, at a reasonable benefit/risk ratio applicable to any medical treatment, which is administered in such quantities and such a period of time as is necessary to obtain the desired therapeutic effect. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgement. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
The total daily dose of the compound of this invention administered to a human or lower animal may range from about 0.1 to about 100 mg/kg/day. For purposes of oral administration, doses may be in the range of from about 1 to about 100 mg/kg/day or, more preferably, of from about 10 to about 20 mg/kg/day. If desired, the effective daily dose may be divided into multiple doses for purposes of administration; consequently, single dose compositions may contain such amounts or submultiples thereof as make up the daily dose.
The pharmaceutical compositions of the present invention comprise a compound of the invention and a pharmaceutically acceptable carrier or excipient, which may be administered orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray. By "pharmaceutically acceptable carrier" is meant a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. The term "parenteral" as used herein refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
Pharmaceutical compositions of this invention for parenteral injection include pharmaceutically acceptable sterile nonaqueous solutions or aqueous dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be deskable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides) Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols and sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
Topical administration includes administration to the skin or mucosa, including surfaces of the lung and eye. Compositions for topical administration, including those for inhalation, may be prepared as a dry powder which may be pressurized or non-pressurized. In non-pressurized powder compositions, the active ingredient in finely divided form may be used in admixture with a larger-sized pharmaceutically acceptable inert carrier comprising particles having a size, for example, of up to 100 micrometers in diameter. Suitable inert carders include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.
Alternatively, the composition may be pressurized and contain a compressed gas, such as nitrogen or a liquified gas propellant. The liquified propellant medium and indeed the total composition is preferably such that the active ingredient does not dissolve therein to any substantial extent. The pressurized composition may also contain a surface active agent. The surface active agent may be a liquid or solid non-ionic surface active agent or may be a solid anionic surface active agent. It is preferred to use the solid anionic surface active agent in the form of a sodium salt.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
The compound of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y., 1976, p. 33 et seq.
The compounds of the present invention may be produced by culturing, in appropriate media, fungal microorganisms which are capable of producing fusacandins. The compounds are produced when the culture is grown in a stationary fermentation with a culture medium containing a source of carbon and a source of nitrogen. Media which are useful include an assimilable source of carbon such as starch, sugar, molasses, glycerol, a combination of glucose plus molasses, etc.; an assimilable source of nitrogen such as protein, protein hydrolysate, polypeptides, amino acids, peptone plus yeast extract or whole yeast, etc.; and other optional organic and inorganic ingredients which can be added to stimulate production of the fusacandin compounds. For example, inorganic anions and cations including potassium, magnesium, calcium, ammonium, sulfate, carbonate, phosphate, chloride, etc. may be added to the medium. Further, buffers such as calcium carbonate can be added to aid in controlling the pH of the fermentation medium. The stationary fermentation may include a solid support to increase the surface area available for fungal growth. Suitable supports include Spoon Size Shredded Wheat, rolled oats, barley, cracked corn, flee, millet, corn bran, wheat bran, oat bran, vermiculite, etc. The culture may be incubated in stationary vessel (without movement) or in a cylindrical or other vessel which is rolled or agitated to increase aeration. Other culture methods, such as a liquid, submerged, agitated culture process are feasible. In these cases, aeration may be provided by forcing sterile air through the fermentation medium. Agitation can be provided by shaking the container or by stirring the culture, for example, with a mechanical stirrer. The fermentation is generally carried out in a temperature range of from about 15° C. to about 35° C. The pH of the fermentation is preferably maintained between 3 and 9. The compound is produced and accumulated between 3 and 28 days after inoculation of the fermentation medium.
Subsequent to the fermentation process, the fusacandin compounds can be extracted from the fermentation broth as for example with ethyl acetate/acetone solvent mixtures. Partial purification of the active components can be achieved by sequential trituration of the organic extract with organic solvents such as ethyl acetate, ethanol and methanol in order to selectively remove the desired organic compounds. The extracts may be further purified by use of various partitioning solvent systems such as, for example, chloroform/methanol/water, hexane/ethyl acetate/methanol/water, or ethanol/ethyl acetate/water. Further purification and separation of individual components can be achieved by countercurrent chromatography in solvent systems such as, for example, ethyl acetate/ethanol/water, chloroform/methanol/water, or chloroform/carbon tetrachloride/methanol/water, and/or by adsorption onto silica gel and subsequent elution with organic solvents and solvent mixtures such as ethyl acetate, chloroform and methanol. Size exclusion chromatography on resin such as SEPHADEX LH-20, developed in a solvent such as methanol, affords the pure compound.
The compounds, processes and uses of the present invention will be better understood in connection with the following examples, which are intended as an illustration of and not a limitation upon the scope of the invention. The following abbreviations were used: EtOAc for ethyl acetate, EtOH for ethanol, MeOH for methanol and TLC for thin layer chromatography.
EXAMPLE 1
Identification and Characterization of of the Fusacandin-Producing Strain Fusarium Sp. Strain AB 1900A-1314
The compounds of the present invention, "fusacandins", were first obtained from a fungus isolated from a conk (fruiting body of wood-attacking fungus) collected in Piatt County, Illinois. The culture, which was designated strain AB 1900A-1314, is a Fusarium species as indicated by the production of characteristic macroconidia. A subculture of this microorganism was deposited in the permanent collection of the National Center for Agricultural Utilization Research, United States Department of Agriculture, 1815 North University Street, Peoria, Ill. 61604, U.S.A., under the terms of the Budapest Treaty, and accorded accession number NRRL 21252.
Strain AB 1900A-1314 was examined at the Pennsylvania State University, Fusarium Research Center, and identified as a strain of Fusarium sambucinum. The morphological and cultural characteristics of this strain grown on two media at 25° C. for seven days were as described below. The colors and numbers shown in parenthesis were assigned based on the Inter-Society Color Council-National Bureau of Standards (ISCC-NBS) Centroid Color Charts, U.S. Dept. of Commerce supplement to NBS Cir. 553, Washington D.C., 1976.
Colonies of strain AB 1900A-1314 on Potato Dextrose agar (Difco) were dense, floccose, medium yellow-pink (29), grew rapidly to 75-80 mm in diameter and produced a clear exudate. Aerial mycelium was pale pink in color (7) and the reverse was light orange (52) to medium orange (53). Spore structures were not found on this medium at seven days. As the culture aged, many raised, round, light orange (52) structures, 1-3 mm in diameter, developed on the agar surface. These aggregates were hard but could be broken apart by moderate pressure with an inoculating loop. Fragments of the structures under light microscopy consisted of flattened, irregular cells mixed with a few strands of mycelia. The aggregates appear to be similar to the perithecia-bearing stromata which Fusarium sambucinum (Gibberella pulicaris) can form on woody host tissue (Booth, C.: The Genus Fusarium. pp. 168-172, Commonwealth Mycological Institute, Kew, Surrey, England, 1971). Perithecia or asci, however, were not observed.
Colonies grew rapidly on Cornmeal agar (Difco) and attained a diameter of 75-80 mm in seven days. The culture produced characteristic four to six septate, sickle-shaped macroconidia and one to two septate microconidia on this medium. The colonies had white (263), wispy aerial mycelia and the reverse was colorless. Macroconidia were produced abundantly, measuring 37.5-70×5-7 μm while microconidia measured 20-37.5×3.75-7.5 μm. The culture developed medium orange (53) sporodochia after 14 days incubation on Commeal agar.
EXAMPLE 2
Growth of Fusarium Sp. Strain AB 1900A-1314 in Stationary Culture
The fusacandin-producing culture, Fusarium sp. AB 1900A-1314, was maintained as a frozen inoculum stock by freezing a portion of the original inoculum and storing at -70° C. The medium S18 (Table 1) was used for seed growth and the medium F9 (Table 2) was used for stationary fermentations.
TABLE 1______________________________________Seed Medium S18Ingredients grams/liter______________________________________Corn steep powder (Roquette Corp., Gurnee, IL) 2.5Glucose monohydrate 10.0Oat flour (National Oats Co., Cedar Rapids, IA) 10.0Tomato paste (made by Contadina Foods, Inc. Los 40.0Angeles, CA)CaCl.sub.2.2H.sub.2 O 10.0Trace element solution 10 mL/L______________________________________
Distilled water was added to achieve a volume of 1 liter. The pH was adjusted to pH 6.8. Reference: Goetz et al., J. of Antibiotics 38: 1633-1637 (1985).
______________________________________Trace Element SolutionIngredients grams/liter______________________________________FeSO.sub.4.7H.sub.2 O 1.0MnCl.sub.2.4H.sub.2 O 1.0CuCl.sub.2.2H.sub.2 O 0.025CaCl.sub.2.2H.sub.2 O 0.1H.sub.3 BO.sub.3 0.56(NH.sub.4).sub.6 MoO.sub.2.4H.sub.2 O 0.019ZnSO.sub.4.7H.sub.2 O 0.2______________________________________
Distilled water was added to achieve a volume of 1 liter.
TABLE 2______________________________________Fermentation Medium F9Ingredients grams/liter______________________________________Lactose 24.0Peptone (made by Difco Laboratories, Detroit, MI) 16.0MgSO.sub.4.7H.sub.2 O 0.4KH.sub.2 PO.sub.4 2.08NaNO.sub.3 1.28ZnSO.sub.4.7H.sub.2 O 0.004______________________________________
Distilled water was added to achieve a volume of 1 liter without pH adjustment. Spoon Size Shredded Wheat (Nabisco Brands, Inc., East Hanover, N.J.) was used as solid growth support, following separate sterilization.
The seed flasks were prepared by dispensing 100 mL of the seed medium (Table 1 ) into 500 mL Erlenmeyer flasks. The flasks were sterilized for 30 minutes at 121° C., 15 psi. Inoculum for the fermentation was prepared by inoculating 1% of the frozen inoculum into each of several seed flasks. The seed flasks were incubated for 72 hours at 28° C. C on a rotary shaker, operated at 225 rpm, with a stroke of 2 inches (approximately 5 cm).
The fermentation was conducted in 3 glass 20-liter carboys. Each carboy, containing 300 grams of Spoon Size Shredded Wheat, was sterilized for 45 minutes at 121° C., 15 psi. The F9 fermentation medium was sterilized in 3 batches of 360 mL in 2-liter Erlenmeyer flasks. Sterilization was at 121° C., 15 psi.
The 360 mL of liquid medium was inoculated with 60 mL of 72 hour seed growth. The combination was mixed and added aseptically to a carboy containing 300 grams of Shredded Wheat. The mixture was again thoroughly mixed to distribute the inoculum. The carboys were incubated in an upright position at 20° C. for 21 days. Three carboys were prepared in this manner.
EXAMPLE 3
Growth of Fusarium Sp. Strain AB 1900A- 1314 in Submerged Culture
The seed flasks were prepared by dispensing 600 mL of the seed medium (Table 3) into 2-liter Erlenmeyer flasks. The flasks were sterilized for 30 minutes at 121° C., 15 psi. Inoculum for the fermentation was prepared by inoculating 1% of the frozen inoculum into each of 3 seed flasks. The seed flasks were incubated for 72 hours at 28° C. on a rotary shaker, operated at 225 rpm, with a stroke of 2 inches (approximately 5 cm).
Thirty liters of production medium (Table 4) were prepared in a 42-liter, stainless steel, stirred fermentor (LH Fermentation) and sterilized at 121° C. and 15 psi for 1 hour. The antifoam agent XFO-371 (Ivanhoe Chemical Co,. Mundelein, Ill.) was added initially at 0.01%, and then as needed. The fermentor was inoculated with 1500 mL of the seed flask growth. The temperature was controlled at 28° C. The agitation rate was 250 rpm and aeration was 1.5 vol/vol/min. The head pressure was maintained at 5 psi. The fermentation was terminated at seven days, with a harvest volume of about 13 liters.
TABLE 3______________________________________Seed medium for submerged fermentationIngredient grams/liter______________________________________Mannitol 20.0Soy flour 20.0Distilled water 1 liter______________________________________
Reference: Traxler et at., J. Antibiotics 30:289-296 (1977).
TABLE 4______________________________________Submerged fermentation mediumIngredient grams/liter______________________________________Glucose monohydrate 55.0Mannitol 10.0Glycine 2.0Dried lard water (Inland Molasses, Dubuque, IA) 5.0Soybean meal (Archer Daniels Midland Co., 5.0Decatur, IL)Sodium citrate 2.0KH.sub.2 PO.sub.4 2.0CoCl.sub.2.6H.sub.2 O 0.01______________________________________
Distilled water was added to achieve a volume of 1 liter without pH adjustment. Reference: VanMiddlesworth et al., J. Antibiotics 44:45-51 (1991).
EXAMPLE 4
Isolation of Fusacandin A from Stationary Culture
To 3 carboys containing stationary culture were added 3 liters of acetone. The resulting mixture was allowed to soak for 18 hours. This acetone extract was removed and an additional 6 liters of acetone added to the stationary culture, left to soak for 1 hour and removed. This procedure was repeated two additional times. The combined acetone extracts were concentrated to afford 29.7 grams of brown oil. This oil was triturated sequentially with 2 liters each of hexane, EtOAc, EtOH, MeOH and distilled water. The ethanol soluble material was concentrated to afford 400 mg of tan oil which was subjected to silica gel chromatography on 200 grams of VARIAN 40 μ silica gel eluted sequentially with 500 mL each of EtOAc, 5% MeOH in EtOAc, 10% MeOH in EtOAc, 25% MeOH in EtOAc, 50% MeOH in EtOAc, and 100% MeOH. The material which eluted with 10% MeOH in EtOAc was concentrated to afford 130 mg of a pale oil which was subjected to countercurrent chromatography on an Ito multi-layered coil planet centrifuge in a solvent system of CHCl 3 /MeOH/H 2 O (1:1:1), lower layer stationary. Fractions of 5mL each were collected from this countercurrent chromatography with a solvent front at fraction 19, and fractions 43-45 were combined to yield 3.0 mg of a clear oil. This oil was subjected to size exclusion chromatography on a SEPHADEX LH-20 resin column developed in MeOH. The active fractions from this column were combined and concentrated to yield 1.8 mg of pure fusacandin A.
EXAMPLE 5
Isolation of Fusacandin A from Submerged Fermentation
15 liters of whole culture broth were added to 8 liters of acetone and the mixture was agitated for 1 hour, after which 15 liters of EtOAc was added, the mixture was agitated and the upper layer was removed. An additional two 8-liter extractions were made, combined with the first and concentrated under reduced pressure to yield 15 grams of brown oil. This oil was triturated sequentially with 2 liters each of hexane, EtOAc and MeOH. The MeOH soluble material was concentrated in vacuo to yield 780 mg of brown oil which was subjected to silica gel chromatography on 500 grams of VARIAN 40 μ silica gel eluting sequentially with 1 liter each of EtOAc, 2% MeOH in EtOAc, 5% MeOH in EtOAc, 10% MeOH in EtOAc, 20% MeOH in EtOAc, 50% MeOH in EtOAc and 100% MeOH. The material which eluted with 50% MeOH in EtOAc was subjected to size exclusion chromatography on a SEPHADEX LH-20 resin column developed in MeOH. Active fractions from this column were combined to yield 160 mg of pure fusacandin A.
EXAMPLE 6
Isolation of Fusacandin B from Submerged Fermentation
To 4900 liters of whole broth were added 3350 liters of acetone and 3700 liters of ethyl acetate. The resulting mixture was agitated for approximately 12 hours after which time the upper layer was removed, concentrated under reduced pressure, and deposited onto 10 kg of silica gel. This was loaded onto the top of a 240 kg silica gel column developed sequentially with 300 liters of EtOAc 300 liters of 25% MeOH in EtOAc, 300 liter of 50% MeOH in EtOAc, 300 liters of 75% MeOH in EtOAc and finally 300 liters of MeOH. A portion (25 g) of the material which eluted with 25% MeOH in EtOAc was partitioned between 3:1:2 EtOAc/EtOH/H 2 O, and the upper layer from this partition was concentrated under reduced pressure to an oily solid residue. This residue was subjected to size exclusion chromatography on a SEPHADEX LH-20 resin column developed in MeOH. The active fractions from this column were combined based upon their behavior on thin layer chromatograph to yield fusacandin A (2.65 g) and fusacandin B (62 mg).
EXAMPLE 7
Physico-Chemical Characterization of the Fusacandins
Fusacandin A was characterized using IR, UV, 1 H and 13 C NMR spectroscopy. The resulting infrared, proton and carbon spectra are shown in FIGS. 1, 2 and 3. Fusacandin A has a molecular weight of 1020 (C 51 H 71 O 21 ) and is a clear oil. [α] D =+58° (c=0.67, MeOH). TLC characterization on Merck silica gel plates: Rf=0.00 in EtOAc, R f =0.71 in 1:1 MeOH-EtOAc, R f =0.52 in acetone, and R f 0.40 in 3:2 CHCl 3 -MeOH. An ultraviolet spectrum of fusacandin A acquired in MeOH/0.01M NaOH contained a band at δ max =254 nm (ε=35,000) and end absorption. An infrared spectrum of fusacandin A acquired in microscope mode contained bands at 3372, 2955, 2927, 2858, 1702, 1634, 1459, 1411, 1375, 1335, 1396, 1267, 1146, 1076, 1049, and 1003 cm -1 .
Fusacandin B was characterized using IR, UV, 1 H and 13 C NMR spectroscopy. The resulting infrared, proton and carbon spectra are shown in FIGS. 4, 5 and 6. Fusacandin B has a molecular weight of 872 (C 41 H 60 O 20 ) and is a white solid. m.p. 42-45° C. [α] D =+1° (c=0.4, MeOH). TLC characterization on Merck silica gel plates: R f =0.00 in EtOAc, R f =0.60 in 1:1 MeOH/EtOAc, R f =0.46 in acetone and R f =0.19 in 3:2 CHCl 3 /MeOH. An ultraviolet spectrum of fusacandin B acquired in MeOH or MeOH/0.01M HCl contained a band at δ max =263 nm (ε=18,000), 231 (21,000) and end absorption. An ultraviolet spectrum of fusacandin B acquired in MeOH/0.01M NaOH contained a band at δ max =256 nm (ε=22,000), and end absorption. An infrared spectrum of fusacandin B acquired in microscope mode contained bands at: 3305, 3040, 3005, 2880, 2850, 1708, 1645, 1625, 1570, 1465, 1410, 1380, 1315, 1265, 1155, 1080 and 1055 cm -1 .
EXAMPLE 8
In Vitro Assay of Antifungal Activity
Minimal inhibitory concentrations (MICs) were determined by an agar dilution method. The test compounds were serially diluted in MeOH and 0.2 mL portions were mixed with 20 mL of molten, cooled Sabouraud dextrose agar (Difco). Yeast cell inoculum was prepared by growing cultures on Sabouraud dextrose agar for 18 hours at 32° C. and suspending the cells in phosphate buffered saline. Filamentous fungi were grown under the same conditions for 4 days to obtain spores. The inoculum level for all cultures was adjusted to 10 4 cells using a Petroff-Hauser cell counter. The glutarimide antifungal compounds cycloheximide or amphotericin B were used as a control. Inoculated test plates were incubated at 32° C. and examined after 20 hours. The results, shown in Tables 5a and 5b, demonstrate that the compounds of the present invention possess significant antifungal activity.
TABLE 5a______________________________________In Vitro Antifungal Activity of Fusacandin AMIC (μg/ml) FusacandinMicroorganism A Cycloheximide______________________________________Candida albicans CCH 442 6.26 >100Candida albicans ATCC997 12.5 >100Candida albicans ATCC 623 6.25 >100Candida tropicalis NRRL-Y-1 6.25 0.4Candida kefyr ATTC 288 6.25Torulopsis glabrata ATCC 155 3.12 0.4Saccharomyces cereviseae GS 1-36 3.12 <0.05Aspergillus niger ATCC 164 6.25 1.6Nocardia asteroides ATTC 9970 12.5 1.6Streptococcus pyrogenes EES61 6.25 50Streptococcus bovis A-5169 12.5 25Staphylococcus aureus ATTC 6538p 50 0.8______________________________________
TABLE 5b______________________________________In Vitro Antifungal Activity of Fusacandin BMIC (μg/ml) FusacandinMicroorganism B Amphotericin B______________________________________Cryptococcus albidus ATCC 341 >100 3.12Saccharomyces cereviseae GS 1-36 50 1.56Aspergillus niger ATCC 164 >100 1.56Candida albicans ATCC 102 50 1.56Candida albicans 579a 50 1.56Candida albicans CCH 442 50 1.56Candida albicans ATCC 382 >100 50Candida albicans ATCC 623 100 1.56Candida tropicalis NRRL Y-1 50 1.56Candida kefyr ATCC 288 100 1.56Torulopsis glabrata ATCC 155 100 1.56______________________________________
EXAMPLE 9
In Vitro Inhibition of (1,3)-β-Glucan Synthase Activity
The fungal cell wall serves as a protective barrier and is essential for viability in a hypotonic environment. (1,3)-β-Glucan is a component of the Candida albicans cell wall, and the enzyme that biosynthesizes this polymer, glucan synthase, is not present in higher eukaryotes. (Glucan synthase is an integral plasma membrane protein that catalyzes polymerization of uridine diphosphate-glucose (UDP-Glc) into β-glucan.) Accordingly, glucan synthase represents an ideal target for the development of antifungal agents.
A microtiter screen was established to detect inhibitors of (1,3)-β-glucan formation in C. albicans cell free extracts. Microsomes isolated from mid-log phase grown yeast were incubated with [ 14 C]UDP-Glc, effectors and test compound (fusacandin A). The formation of the water-insoluble β-glucan product was measured on a filter after removing the substrate with water washes. The IC 50 for fusacandin A was shown to be 20.5 μg/mL compared to 3.6 μg/mL for papulacandin B. The minimum inhibitory concentration (MIC) for fusacandin was 0.5 μg/mL compared to 1.0 μg/mL for papulacandin B.
It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art, and may be made without departing from the spirit and scope thereof. | 1a
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CROSS REFERENCE
This application is a continuation of Ser. No. 08/075,048, filed Jun. 10, 1993.
FIELD OF THE INVENTION
The present invention provides novel methods for treating diseases of the nervous system, e.g., neuromuscular disorders and conditions, with botulinum toxins. In addition, the present invention provides methods useful in all tissue and organ systems which involve the release of neurotransmitters, especially acetylcholine. These cholinergic transmission systems include neuromuscular junctions (muscles), smooth muscles (gut, sphincters, etc.) and secretions (salivation and mucus).
BACKGROUND OF THE INVENTION
A bacterial toxin, botulinum toxin, in particular botulinum toxin type A, has been used in the treatment of a number of neuromuscular disorders and conditions involving muscular spasm; for example, strabismus, blepharospasm, spasmodic torticollis (cervical dystonia), oromandibular dystonia and spasmodic dysphonia (laryngeal dystonia). The toxin binds rapidly and strongly to presynaptic cholinergic nerve terminals and inhibits the exocytosis of acetylcholine by decreasing the frequency of acetylcholine release. This results in local paralysis and hence relaxation of the muscle afflicted by spasm.
For one example of treating neuromuscular disorders, see U.S. Pat. No. 5,053,005 to Borodic, which suggests treating curvature of the juvenile spine, i.e., scoliosis, with an acetylcholine release inhibitor, preferably botulinum toxin A.
For the treatment of strabismus with botulinum toxin type A, see Elston, J. S., et al., British Journal of Ophthalmology , 1985, 69, 718-724 and 891-896. For the treatment of blepharospasm with botulinum toxin type A, see Adenis, J. P., et al., J. Fr. Ophthalmol ., 1990, 13 (5) at pages 259-264. For treating squint, see Elston, J. S., Eye , 1990, 4(4):VII. For treating spasmodic and oromandibular dystonia torticollis, see Jankovic et al., Neurology, 1987, 37, 616-623.
Spasmodic dysphonia has been treated with botulinum toxin type A. See Blitzer et al., Ann. Otol. Rhino. Laryngol , 1985, 94, 591-594. Lingual dystonia was treated with botulinum toxin type A according to Brin et al., Adv. Neurol . (1987) 50, 599-608. Finally, Cohen et al., Neurology (1987) 37 (Suppl. 1), 123-4, discloses the treatment of writer's cramp with botulinum toxin type A.
The term botulinum toxin is a generic term embracing the family of toxins produced by the anaerobic bacterium Clostridium botulinum and, to date, seven immunologically distinct neurotoxins serotype have been identified. These have been given the designations A, B, C, D, E, F and G. For further information concerning the properties of the various botulinum toxins, reference is made to the article by Jankovic and Brin, The New England Journal of Medicine , No. 17, 1990, pp. 1186-1194, and to the review by Charles L. Hatheway in Chapter 1 of the book entitled Botulinum Neurotoxin and Tetanus Toxin , L. L. Simpson, Ed., published by Academic Press Inc. of San Diego, Calif., 1989, the disclosures in which are incorporated herein by reference.
The neurotoxic component of botulinum toxin has a molecular weight of about 150 kilodaltons and is thought to comprise a short polypeptide chain of about 50 kD which is considered to be responsible for the toxic properties of the toxin, i.e., by interfering with the exocytosis of acetylcholine, by decreasing the frequency of acetylcholine release, and a larger polypeptide chain of about 100 kD which is believed to be necessary to enable the toxin to bind to the pre-synaptic membrane. The “short” and “long” chains are linked together by means of a simple disulfid bridge. (It is noted that certain serotype of botulinum toxin, e.g., type E, may exist in the form of a single chain un-nicked protein, as opposed to a dichain. The single chain form is less active but may be converted to the corresponding dichain by nicking with a protease, e.g., trypsin. Both the single and the dichain are useful in the method of the present invention.)
Immunotoxin conjugates of ricin and antibodies, which are characterized as having enhanced cytotoxicity through improving cell surface affinity, are disclosed in European Patent Specification 0 129 434. The inventors note that botulinum may be utilized in place of ricin.
Botulinum toxin is obtained commercially by establishing and crowing cultures of C. botulinum in a fermenter and then harvesting and purifying the fermented mixture in accordance with known techniques.
Botulinum toxin type A, the toxin type generally utilized in treating neuromuscular conditions, is currently available commercially from several sources; for example, from Port Products Ltd. UK, under the trade name “DYSPORT,” and from Allergan, Inc., Irvine, Calif., under the trade name BOTOX®.
It has been found, however, that some patients experience a loss of clinical responsiveness to botulinum toxin injections. One explanation for this action is that the patient has developed neutralizing antibodies or an immune response to, for example, botulinum toxin type A. Alternatively, the type of immune response may be different from just neutralizing antibodies. These include: (1) Allergic reaction where there is immediate local swelling, redness and itching. This may also be associated with general flu-like symptoms. (2) A delayed-type hypersensitivity manifested as swelling and redness at the injection site 48 to 72 hours after injection. (3) Or, a serum sickness-like response where the patient experiences flu-like symptoms. All of these immune-based reactions to type A dictate alternate serotype therapy to maintain clinical benefits.
A further hypothesis may explain loss of clinical responsiveness to botulinum toxin injections. This does not include interaction of other medications which may interfere with the action of botulinum toxin (i.e., angiotensin converting enzyme inhibitor class of antihypertensives and other endopeptidase inhibitors, aminopyridines, acetylcholine esterase inhibitors, etc.). One possible explanation for the loss of responsiveness is an alteration in the neuronal binding of toxin to the presynaptic cholinergic nerve terminal. An alternation of gangliocides could reduce the binding efficacy of the toxin and thus reduce the amount of toxin internalized. Alternatively, an induction of proteases may cause an enhanced breakdown of the toxin either in the extracellular milieu or within the neuron. Finally, the neuron may change the amino acid composition of the target protein for the light chain of the toxin to reduce or eliminate its effect on the exocytotic mechanism.
It is one object of the invention to provide novel treatments of neuromuscular disorders and conditions with botulinum toxin type A followed with treatments of botulinum toxin types B, C, D, E, F and G.
SUMMARY OF THE INVENTION
The present invention provides a method of treating a neuromuscular disorder or condition such as strabismus and other disorders of ocular motility, e.g., comitant and vertical strabismus, lateral rectus palsy, nystagmus, dysthyroid myopathy, etc.; dystonia, e.g., focal dystonias such as spasmodic torticollis, writer's cramp, blepharospasm, oromandibular dystonia and the symptoms thereof, e.g., bruxism, Wilson's disease, tardive dystonia, laryngeal dystonia etc.; other dystonias, e.g., tremor, tics, segmental myoclonus; spasms, such as spasticity due to chronic multiple sclerosis, spasticity resulting in abnormal bladder control, e.g., in patients with spinal cord injury, animus, back spasm, charley horse etc.; tension headaches; levator pelvic syndrome; spina bifida, tardive dyskinesia; Parkinson's and limb (focal) dystonia and stuttering, etc. of a patient, which method comprises administering to the patient suffering from said disorder or condition a therapeutically effective amount of a botulinum A followed with a neurotoxin of a different serotype, i.e., one selected from the group consisting of botulinum toxin types B, C, D, E, F and G.
The clinical features of the above-listed neuromuscular disorders and conditions are described in Jankovic and Brin, cited above, and in Quinn, Disorders of Movement , Academic Press, 1989, all of which are incorporated herein by reference.
The present invention further provides compositions of said botulinum toxins in a vehicle suitable for injection of said toxins into the appropriate region of the patient to be treated. Alterations of the vehicle and excipient may include materials designed to retain the injected toxin in the local area.
The present invention further provides a method for treating neuromuscular disorders or conditions in which the patient experiences a loss of clinical response to an initial treatment of botulinum toxin.
More specifically, a method in accordance with the present invention includes administering to the patient a therapeutically effective amount of botulinum toxin of a different serotype until the patient experiences loss of clinical response to the administered botulinum toxin and thereafter administering to the patient another botulinum toxin of the selected serotype, said another botulinum toxin being administered in therapeutically effect amounts.
More particularly, the method in accordance with the present invention includes initial treatment with botulinum toxin type A followed by treatment with another botulinum toxin selected from the group consisting of types B, C, D, E and F.
Alternatively, the initial treatment may be with botulinum toxin type B followed by another botulinum toxin serotype selected from the group consisting of types A, C, D, E and F.
An alternative embodiment of the present invention includes the administration to a patient of a therapeutically effective amount of botulinum toxin of a selected serotype until the patient develops neutralizing antibodies and thereafter administration to the patient of another botulinum toxin of a different serotype, said another botulinum toxin being administered in a therapeutically effective amount.
DETAILED DESCRIPTION
The botulinum toxins used according to the present invention are botulinum toxin serotype A, B, C, D, E, F and G.
Each serotype of botulinum toxin has been identified as immunologically different proteins through the use of specific antibodies. For example, if the antibody (antitoxin) recognizes, that is, neutralizes the biological activity of, for example, type A it will not recognize types B, C, D, E, F or G.
While all of the botulinum toxins appear to be zinc endopeptidases, the mechanism of action of different serotypes, for example, A and E within the neuron appear to be different than that of type B. In addition, the neuronal surface “receptor” for the toxin appears to be different for the serotypes.
The physiologic groups of Clostridium botulinum types are listed in Table I.
TABLE I Physiologic Groups of Clostridium botulinum Phenotypically Toxin Glucose Phages Related Sero- Milk Fermen- & Clostridium Group Type Biochemistry Digest tation Lipase Plasmids (nontoxigenic) I A, B, F proteolytic saccharolytic + + + + C. sporogenes II B, E, F nonproteolytic saccharolytic − + + + psychotrophic III C, D nonproteolytic saccharolytic ± + + + C. novyi IV G proteolytic nonsaccharolytic + − − − C. subterminale
These toxin types may be produced by selection from the appropriate physiologic group of Clostridium botulinum organisms. The organisms designated as Group I are usually referred to as proteolytic and produce botulinum toxins of types A, B and F. The organisms designated as Group II are saccharolytic and produce botulinum toxins of types B, E and F. The organisms designated as Group III produce only botulinum toxin types C and D and are distinguished from organisms of Groups I and II by the production of significant amounts of propionic acid. Group IV organisms only produce neurotoxin of type G.
The production of any and all of the botulinum toxin types A, B, C, D, E, F and G are described in Chapter 1 of Botulinum Neurotoxin and Tetanus Toxin , cited above, and/or the references cited therein. Botulinum toxins types B, C, D, E, F and G are also available from various species of clostridia. Currently fourteen species of clostridia are considered pathogenic.
Most of the pathogenic strains produce toxins which are responsible for the various pathological signs and symptoms. Organisms which produce botulinum toxins have been isolated from botulism outbreaks in humans (types A, B, E and F) and animals (types C and D). Their identities were described through the use of specific antitoxins (antibodies) developed against the earlier toxins. Type G toxin was found in soil and has low toxigenicity. However, it has been isolated from autopsy specimens, but thus far there has not been adequate evidence that type G botulism has occurred in humans.
In general, four physiologic groups of C. botulinum are recognized (I, II, III, IV). The organisms capable of producing a serologically distinct toxin may come from more than one physiological group. For example, Type B and F toxins can be produced by strains from Group I or II. In addition, other strains of clostridial species ( C. baratii , type F; C. butyricum , type E; C. novyi , type C 1 or D) have been identified which can produce botulinum neurotoxins.
Preferably, the toxin is administered by means of intramuscular injection directly into a spastic muscle, in the region of the neuromuscular junction, although alternative types of administration (e.g., subcutaneous injection), which can deliver the toxin directly to the affected muscle region, may be employed where appropriate. The toxin can be presented as a sterile pyrogen-free aqueous solution or dispersion and as a sterile powder for reconstitution into a sterile solution or dispersion.
Where desired, tonicity adjusting agents such as sodium chloride, glycerol and various sugars can be added. Stabilizers such as human serum albumin may also be included. The formulation may be preserved by means of a suitable pharmaceutically acceptable preservative such as a paraben, although preferably it is unpreserved.
It is preferred that the toxin is formulated in unit dosage form; for example, it can be provided as a sterile solution in a vial or as a vial or sachet containing a lyophilized powder for reconstituting a suitable vehicle such as water for injection.
In one embodiment, the botulinum toxin is formulated in a solution containing saline and pasteurized human serum albumin, which stabilizes the toxin and minimizes loss through non-specific adsorption. The solution is sterile filtered (0.2 micron filter), filled into individual vials and then vacuum-dried to give a sterile lyophilized powder. In use, the powder can be reconstituted by the addition of sterile unpreserved normal saline (sodium chloride 0.9% for injection).
The dose of toxin administered to the patient will depend upon the severity of the condition; e.g., the number of muscle groups requiring treatment, the age and size of the patient and the potency of the toxin. The potency of the toxin is expressed as a multiple of the LD 50 value for the mouse, one unit (U) of toxin being defined as being the equivalent amount of toxin that kills 50% of a group of 18 to 20 female Swiss-Webster mice, weighing 20 grams each.
The dosages used in human therapeutic applications are roughly proportional to the mass of muscle being injected. Typically, the dose administered to the patient may be up to about 1,000 units; for example, up to about 500 units, and preferably in the range from about 80 to about 460 units per patient per treatment, although smaller of larger doses may be administered in appropriate circumstances.
As the physicians become more familiar with the use of this product, the dose may be changed. In the botulinum toxin type A, available from Porton, DYSPORT, 1 nanogram (ng) contains 40 U. 1 ng of the botulinum toxin type A, available from Allergan, Inc., i.e., BOTOX®, contains 4 U. The potency of botulinum toxin and its long duration of action mean that doses will tend to be administered on an infrequent basis.
Ultimately, however, both the quantity of toxin administered and the frequency of its administration will be at the discretion of the physician responsible for the treatment and will be commensurate with questions of safety and the effects produced by the toxin.
The invention will now be illustrated by reference to the following nonlimiting examples.
In each of the examples, the appropriate muscles of each patient are injected with sterile solutions containing the botulinum toxins. Total patient doses range from 80 U to 460 U. Before injecting any muscle group, careful consideration is given to the anatomy of the muscle group, the aim being to inject the area with the highest concentration of neuromuscular junctions, if known. Before injecting the muscle, the position of the needle in the muscle is confirmed by putting the muscle through its range of motion and observing the resultant motion of the needle end. General anaesthesia, local anaesthesia and sedation are used according to the age of the patient, the number of sites to be injected, and the particular needs of the patient. In accordance with the present invention, multiple injections are necessary to achieve the desired result, due to the patient's experiencing loss of clinical response to an initial treatment. Also, some injections, depending on the muscle to be injected, may require the use of fine, hollow, teflon-coated needles, guided by electromyography.
Following injection, it is noted that there are no systemic or local side effects and none of the patients are found to develop extensive local hypotonicity. The majority of patients show an improvement in function both subjectively and when measured objectively.
EXAMPLE 1
The Use of Botulinum Toxin Serotype A, B and F in the Treatment of Tardive Dyskinesia
A patient, suffering from tardive dyskinesia resulting from the treatment with an antipsychotic drug, such as haloperidol, is treated with an effective amount of botulinum toxin type A by direct injection of such toxin into the muscles identified by the physician. After two to four days, the symptoms of tardive dyskinesia, i.e., orofacial dyskinesia, athetosis, dystonia, chorea, tics and facial grimacing, etc., are markedly reduced. Upon continued administration of the botulinum toxin type A, a loss of clinical response is noted. Thereafter, an effective amount of botulinum toxin type B is injected and the symptoms of tardive dyskinesia continue to be markedly reduced.
EXAMPLE 1(a)
The method of Example 1 is repeated, except that a patient suffering from tardive dyskinesia is injected with an effective amount of botulinum toxin type A, followed by injection of an effective amount of botulinum toxin type C. Similar results are obtained.
EXAMPLE 1(b)
The method of Example 1 is repeated, except that a patient suffering from tardive dyskinesia is injected with an effective amount of botulinum toxin type A, followed by injection of an effective amount of botulinum toxin type D. Similar results are obtained.
EXAMPLE 1(c)
The method of Example 1 is repeated, except that a patient suffering from tardive dyskinesia is injected with an effective amount of botulinum toxin type A, followed by injection of an effective amount of botulinum toxin type E. Similar results are obtained.
EXAMPLE 1(d)
The method of Example 1 is repeated, except that a patient suffering from tardive dyskinesia is injected with an effective amount of botulinum toxin type A, followed by injection of an effective amount of botulinum toxin type F. Similar results are obtained.
EXAMPLE 2
Use of Botulinum Toxin in the Treatment of Spasmodic Torticollis
A male, suffering from spasmodic torticollis, as manifested by spasmodic or tonic contractions of the neck musculature, producing stereotyped abnormal deviations of the head, the chin being rotated to one side, and the shoulder being elevated toward the side at which the head is rotated, is treated by injection with up to about 300 units, or more, of botulinum toxin type E, (having an activity of one to four days) in the dystonic neck muscles. After the symptoms are substantially alleviated and the patient is able to hold his head and shoulder in a normal position, the patient develops antibodies. Thereafter the patient is injected with botulinum toxin type B and the symptoms continue to be substantially alleviated.
Although there has been hereinabove described a use of botulinum toxin serotype for treating neuromuscular disorders and conditions in accordance with the present invention, for the purpose of illustrating the manner in which the invention may be used to advantage, it should be appreciated that the invention is not limited thereto since many obvious modifications can be made, and it is intended to include within this invention any such modifications as will fall within the scope of the appended claims. Accordingly, any and all modifications, variations, or equivalent arrangements which may occur to those skilled in the art, should be considered to be within the scope of the present invention as defined in the appended claims. | 1a
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RELATED APPLICATION
[0001] The present invention claims the benefit of and priority to U.S. Provisional No. 61/783,110, filed Mar. 14, 2013, which is incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] The invention relates to delivery catheters, e.g., guide catheters, having imaging elements to facilitate placement of the catheter and to direct the flow of a delivered fluid.
BACKGROUND
[0003] Catheters are tubes used to perform medical procedures, remove materials, and deliver Fluids. For example, catheters are often used in the performance of medical procedures such as coronary angiography for injecting dye, or the like, into the cardiovascular system for diagnosis. A variety of catheters are also used in various cardiovascular procedures to widen the lumen of an artery or vein which has become at least partially blocked by a stenotic lesion.
[0004] In many intravascular procedures, the instruments used to perform the medical procedures are guided through the vasculature using contrast agents and real-time x-ray images, i.e., fluoroscopy. Often the contrast is introduced into the vasculature by placing a guide catheter through the heart and in proximity to an ostium (opening) leading to the coronary arteries, e.g., the left anterior descending coronary artery or the left circumflex coronary artery. In this configuration, contrast introduced via the guide catheter will be pushed through the coronary arteries with the natural pumping of the heart, thereby providing images of the arteries on the fluoroscope.
[0005] Placement of the guide catheter near an ostium is a delicate task, however. If the guide catheter is too far away, flushing is less complete and less effective. This can increase the need to add more contrast and to increase the length of the flushes. This results in increased contrast loading and increased ischemic in the tissues oxygenated by the arteries. On the other hand, if the catheter completely blocks the ostium, the arteries past the ostium will also be blocked, resulting in ischemia in the tissues oxygenated by the arteries. A better method for placing guide catheters is needed.
SUMMARY
[0006] The invention is a delivery catheter, e.g., a guide catheter, having an imaging element in proximity to the distal end of the catheter. Catheters of the invention are easier to place in proximity to an ostium, thereby increasing the efficiency of contrast delivery while reducing the risk of ischemia due to blocked blood supply. A particular benefit of the invention is that the imaging element provides visualization for initial placement of the catheter and during a procedure (including introducing flow contrast into the vessel and introduction of one or more interventional catheters through the guide catheter). The visualization allows an operator to ensure the catheter remains in a safe location during the procedure, thereby reducing risk of ischemia due to catheter placement. Because the placement of the guide catheter is visualized, an operator is better equipped to direct the flow of a fluid from the catheter, resulting in better performance with less fluid. For example, a catheter of the invention can be used to produce improved fluoroscopic images with less overall contrast. This improvement reduces the risk of an allergic reaction to the contrast while decreasing the length of time for a procedure, i.e., because of a need to re-contrast.
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] FIG. 1 is a generalized depiction of a catheter having distal ports for use in delivering agents, e.g., contrast agents, or guiding interventional catheters.
[0008] FIG. 2 depicts a rapid-exchange configuration of a delivery catheter according to certain embodiments.
[0009] FIG. 3 illustrates deployment of a guide catheter of the invention at an ostium.
[0010] FIGS. 4A-4C illustrate an alternative use of a delivery catheter of the invention in a biological lumen.
[0011] FIG. 5 depicts a system for use with catheters of the invention.
DETAILED DESCRIPTION
[0012] The invention is a delivery catheter having imaging elements that facilitate visualization of the vasculature and catheter placement. The visualization provided by the delivery catheter of the invention helps to direct the flow of a fluid delivered or guide an interventional catheter to a treatment site. The design of the delivery catheter is especially-suited to be used with guide catheters, such as the type used to deliver contrast agents or place interventional catheters during endovascular procedures. The imaging element is located at or near the distal end of the delivery catheter. The imaging element is a part of an imaging assembly, such an IVUS or photoacoustic imaging assembly. In certain embodiments, the imaging element is an ultrasound transducer, a piezoelectric micromachined ultrasound transducer, a capacitive micromachined ultrasound transducer, and a photoacoustic ultrasound transducer.
[0013] Catheters having the described imaging elements can be any type of catheter. Catheters include any elongated intraluminal device that comprises a tube or shaft that is configured to enter a body lumen. Many catheters for endovascular procedures are around 200 cm in total length and are administered via a cannula (introducer) that has been placed in an artery (e.g., the femoral, brachial, or radial artery). Catheters can be shorter, however, e.g., between 100 and 200 cm, or longer, e.g., between 200 and 400 cm. Often a vascular catheter is delivered along a guidewire. The catheter may have a lumen running the length of the catheter to accept a guidewire (over the rail) or only a portion of catheter, typically the distal tip 410 , will have a guidewire lumen (rapid exchange). An inner lumen diameter of catheters of the invention (including over the wire and rapid exchange configurations) may be configured to receive one or more interventional catheters.
[0014] In some instances, the catheters are placed with a guidewire. Access guidewires (generally “guidewires” herein) are known medical devices used in the vasculature or other anatomical passageway to act as a guide for other devices, e.g., a catheter. Typically, the guidewire is inserted into an artery or vein and guided through the vasculature under fluoroscopy (real time x-ray imaging) to the location of interest. In some procedures one or more devices are delivered over the guide wire to diagnose, image, or treat the condition. Guidewires typically have diameters of 0.010″ to 0.035″, with 0.014″ being the most common. Guidewires (and other intravascular objects) are also sized in units of French, each French being ⅓ of a mm or 0.013″. Guidewire lengths vary up to 400 cm, depending on the anatomy and work flow. The ends of the guidewire are denoted as distal (far from the user, i.e., inside the body) and proximal (near the user, i.e., outside the body). Often a guidewire has a flexible distal tip portion about 3 cm long and a slightly less flexible portion about 30 to 50 cm long leading up to the tip with the remainder of the guidewire being stiffer to assist in maneuvering the guidewire through tortuous vasculature, etc. The tip of a guidewire typically has a stop or a hook to prevent a guided device, e.g., a catheter from passing beyond the distal tip. In some embodiments, the tip can be deformed by a user to produce a desired shape.
[0015] In some instances, the catheter comprises a resilient inner coil, making it possible to shape the catheter and deliver it to targeted anatomy, e.g., the heart. Such catheters are generally known as guide catheters and are often used to deliver fluids, e.g., contrast agents to critical areas, or to deliver the catheter to tortuous locations, such as vasculature or the heart. Because the catheters are rather narrow, e.g., typically 8 French or less, it is also possible to guide a second catheter, for example, an imaging or therapeutic along the guide catheter to a desired location along the guide catheter.
[0016] An embodiment of a catheter system 10 for use with the invention is shown in FIG. 1 . FIG. 1 is merely exemplary, as many other configurations of the catheter system 10 are possible to achieve the principles of the invention. The catheter system 10 includes a guide catheter 12 having a catheter body 14 with a proximal end 16 and a distal end 18 . A luminal opening at the distal end 18 allows a fluid to be delivered to a patient or an interventional catheter to be placed at a target location. Catheter body 14 is flexible and defines a catheter axis 15 , and may include multiple lumens, such as a guidewire lumen, an inflation lumen, and a fluid delivery lumen. Catheter 12 includes an imaging element 19 , proximal to the distal end 18 , and a housing 29 adjacent proximal hub 16 . Typically, the imaging element 19 is placed on the external surface of the catheter body 14 . Although, the imaging element 19 may also be placed, for example, within catheter body 14 . In certain embodiments, the imaging element 19 is placed in a ring array around the catheter body 14 . In this manner, the imaging element surrounds one or more lumens of the catheter body. Preferably, the imaging element 19 is located right next to the distal end of 18 . Ideally, the distal end 18 is less than 1 cm from the imaging element, preferably now more than a few millimeters. Minimal distance d between the imaging element 19 and the distal end 18 allows the imaging element to image luminal surfaces and other objects that are substantially flush with the distal end 18 . Additional lumens may be provided for other treatments, such as irrigation, aspiration, perfusion, or delivery of a device, e.g., a stent.
[0017] According to certain embodiments, the imaging element 19 is coupled to one or more signal lines 17 . The signal lines 17 couple to the imaging element 19 and run along an inner lumen of the catheter body. In certain embodiments, the signal lines 17 are bonded of laminated into a wall of the inner lumen. The signal lines 117 run along the inner wall towards proximal hub 16 . At proximal hub 16 , the single lines 17 are incorporated into an external cable. As shown the signal lines 17 (as enclosed in an external cable) extend through an external housing 29 coupled to the proximal hub 16 and attached to a patient interface module (PIM) connector 31 . The PIM connector may couple to an imaging system (such as the imaging system 400 shown in FIG. 5 ). The imaging system 400 is configured to control treatment, send and receive imaging data, and process imaging data. The imaging system is described in more detail hereinafter.
[0018] In an embodiment, housing 29 includes a first connector 26 in communication with the guidewire lumen and optionally a second connector 28 in communication with e.g. a delivery lumen. The catheter 10 may be ridden over a guidewire running through the guidewire lumen to a position of interest. The guidewire lumen may be configured to receive a guidewire and an interventional catheter, which may also be riding over the guidewire. The interventional catheter may be for ablation, stent placement, angioplasty, imaging, pressure sensing, ect. Both first and second connectors 26 , 28 may optionally comprise standard connectors, such as Luer-Loc™ connectors.
[0019] In certain embodiments, the guide catheter 10 further includes a balloon 22 or other expandable member. In addition to the imaging element, the expandable members 22 can be used effectively and reliably place the distal tip 18 of the catheter inside an ostium 310 of an artery 330 (as shown in FIG. 3 ). This placement assures that the length d of the guide catheter inside the ostium is appropriate for the procedure. In some embodiments, the guide catheter will have markers distal to the balloon 22 , allowing a surgeon to modify the length of the distance d as needed for the procedure. An additional benefit of the balloons is that fluids flushed from the catheter will be directed distally away from the tip.
[0020] Housing 29 additionally provides a connection to a pump 38 coupled to a fluid source, e.g., saline or contrast. The pump 38 may be any pump suitable to deliver sufficient pressure to push the fluid. through the delivery lumen to be administered via the distal opening. In some embodiments, the pump 38 will be designed to give an initial burst of pressure to inflate a balloon 22 . The pump 38 may be a peristaltic pump, or the pump 38 may be a syringe. The reservoir 40 is any suitable reservoir to hold the fluid prior to delivery to the patient. The reservoir 40 may comprise pressure and temperature controls to maintain the fluid in optimum condition. In simple embodiments, both the pump 38 and the reservoir 40 take the form of a single syringe. In advanced embodiments, as shown in FIG. 1 , the pump 38 and the particle reservoir 40 may be controlled by a controller 42 that is interfaced with patient monitoring equipment, e.g., a blood oxygen sensor, or a pressure sensor.
[0021] The controller 42 may include a processor, or is coupled to a processor, used to control flow of fluid into the catheter. In certain embodiments, the controller 42 is a computer. The controller may be included in imaging system 400 . For example, the controller 42 may be computer 449 . In such aspect, one computer may be used to control image collection and related processes and control fluid flow through the catheter 12 .
[0022] As shown in FIG. 1 , the catheter 1 is an over-the-wire guide catheter. Over-the-wire guide catheters have a functional lumen that extends the entire length of the shaft, from the distal end to a proximal hub. Devices, such as interventional catheters, introduced into the guide catheter are placed into the proximal end of the guide catheter, which is extending out of the patients body. The devices are pushed guided through the length of the guidewire.
[0023] In addition to the over-the-wire guidewire configuration, catheters of the invention may alternatively have a rapid exchange configuration. Rapid exchange catheters are characterized by the distal catheter shaft being from about 10 cm to about 40 cm long. The catheter does not require that another device, such an interventional catheter, be pushed through the entire length of the catheter. Rather, an interventional catheter may ride along a guidewire, and enter the guide catheter through a catheter entry port located at a proximal end of the distal shaft. The rapid exchange guidewire allows one to more easily exchange varying interventional catheters into the delivery catheter. In addition, rapid exchange delivery catheters are compatible with virtually any length interventional catheter.
[0024] FIG. 2 depicts a catheter of the invention having a rapid exchange configuration. The catheter 300 has a distal shaft 50 defining a lumen 54 . The distal shaft is about 10 cm to about 40 cm in length. However, it is contemplated that the distal shaft 50 may be shorter or longer depending on the application. The distal shaft 50 includes an imaging element 119 located at or near the distal end 18 . Like the catheter of FIG. 1 , the distance between the imaging element 19 and the distal end 18 is preferably minimized such that the imaging plane is substantially flush with the absolute end of the catheter 300 . The distal shaft 50 includes proximal end 52 . The proximal end 52 terminates in a soft, atraumatic catheter port 53 leading to lumen 53 . Typically, the imaging element 19 is placed on the external surface of the distal shaft 50 . Although, the imaging element 19 may also be placed, for example, within distal shaft 50 . In certain embodiments, the imaging element 19 is placed in a ring array around the distal shaft 50 . The rapid exchange configuration may also include a balloon or expandable element.
[0025] A push rod 21 is coupled to the proximal end 52 . The push rod 21 may be made of any suitable material. Typically, the push rod 21 is made of stainless steel, such as 304 ss. The push rod 21 may be attached to the proximal end 52 via adhesive or thermal bonding. The push rod terminates at a proximal hub 83 . The proximal hub 83 may be used to control movement of the catheter 80 . Alternatively, a handle separate from the proximal hub 83 may be used to manipulate and control movement of the guide catheter.
[0026] According to certain embodiments, the imaging element 19 is coupled to one or more signal lines 17 . The signal lines 17 couple to the imaging element 19 and run along an inner lumen of the distal shaft 50 . In certain embodiments, the signal lines 17 are bonded of laminated into a wall of the distal shaft 50 . At the distal shaft, the signal lines 17 may transition to a sleeve 93 . The sleeve 93 may run next to a parallel to the push rod 21 . Preferably, the sleeve 93 is coupled to the push rod 21 . The signal lines 17 run within sleeve 93 towards proximal hub 83 . At proximal hub 83 , the single lines 17 are incorporated into an external cable. As shown, the signal lines 17 (as enclosed in an external cable) are attached to a patient interface module (PIM) connector 31 . The PIM connector 31 may couple to an imaging system (such as the imaging system 400 shown in FIG. 5 ). The imaging system 400 is configured to control treatment, send and receive imaging data, and process imaging data. The imaging system is described in more detail hereinafter.
[0027] As shown in FIG. 3 , the guide catheter having imaging element 19 can be used to effectively and reliably place the distal tip 18 of the catheter inside an ostium 310 of an artery 330 . This visualization assures the guide catheter is appropriately placed inside the ostium for the procedure.
[0028] FIG. 4A-4C further depicts a guide catheter of the invention in use. In this embodiment, the catheter 200 has been placed in a lumen 280 , which may be an artery or vein on the order of the same size as the catheter 200 . The catheter 200 includes an imaging element 210 , a catheter body 230 , a distal tip 235 , a fluid delivery lumen 250 , and optionally a balloon 212 . The imaging element is able to send and receive imaging data so that an operator can visualize the vessel during the procedure. This allows the delivery catheter to be appropriately placed and remain in the appropriate place during the procedure. Fluid contrast for external imaging is delivered, and then an interventional catheter is introduced through the delivery catheter. The interventional catheter may be used to ablate or morcellate tissue at a treatment site in the artery, for example.
[0029] The sequence of insertion, fluid delivery, and interventional catheter introduction is shown in FIGS. 4A-4C , respectively. As shown in FIG. 4A , prior to fluid delivery, the imaging element 210 , positioned near the distal tip 235 , is placed within a biological lumen 280 . The imaging element 210 allows one to maintain, through visualization, the proper positioning of the catheter 200 during a procedure. Once the catheter 200 is in place with the guidance of the imaging element 210 , a balloon 212 can be inflated in order to assist in maintaining the positioning of the guide catheter 200 . With the balloon 212 expanded, a fluid introduced via the distal end 235 can only travel to the distal side of balloon 212 . When used with a contrast agent, the inflated balloon 210 will result in sharp line on the fluoroscope detailing the exact location of the catheter end. This method will also be useful if the catheter is inserted against the normal flow of fluid in the lumen, e.g., blood flow. An interventional catheter 290 may then be introduced, as shown in FIG. 4C , while being imaged by an external modality. In addition, intraluminal images can be obtained with the imaging element 210 to ensure positioning of the delivery catheter throughout the procedure.
[0030] The methods of the invention can also be used with various interventional devices, such as catheters. Various interventional catheters are described in U.S. Pat. Nos. 8,187,267, 7,993,333, 7,981,151, 8,080,800, and 6,544,217.
[0031] As discussed, imaging elements of the invention may be placed on an outer catheter body/shaft or within a catheter body/shaft. The imaging element may have any suitable configuration for imaging a vessel surface. In certain embodiments, the imaging element is a ring transducer array wrapped around a distal end of the catheter shaft. This configuration allows one to image a cross-section of the vessel without having to rotate the catheter shaft.
[0032] In certain embodiments, the imaging elements of the array are transducers, such as ultrasound transducers, piezoelectric micromachined ultrasound transducers, capacitive micromachined ultrasound transducers, and photo-acoustic transducers. Each imaging elements of the array may include a signal transmitter and a signal collector (or image collector). The signal transducer and the signal collector may be the same or different. For example, a piezoelectric element that is used to transmit a signal may also be used to receive a signal. Ultrasound transducers produce ultrasound energy and receive echoes from which real time ultrasound images of a thin section of the blood vessel are produced. The transducers in the array may be constructed from piezoelectric components that produce sound energy at 20-50 MHz.
[0033] In yet another embodiment, the imaging element is an optical acoustic imaging element. Optical-acoustic imaging elements include at least one acoustic-to-optical transducer. In certain embodiments, the acoustic-to-optical transducer is a Fiber Bragg Grating within an optical fiber. The imaging element may one or more optical fibers with Fiber Bragg Gratings placed longitudinally along a length of the catheter shaft. For example, the imaging element may include two or more optical fibers aligned next to each other, and each with a plurality of Fiber Bragg Gratings. In another embodiment, an optical fiber having several Fiber Bragg Gratings may be wrapped around the distal end of the catheter. In some embodiments, the imaging elements may include an optical fiber with one or more Fiber Bragg Gratings (acoustic-to-optical transducer) and one or more other transducers. The at least one other transducer may be used to generate the acoustic energy for imaging. Acoustic generating transducers can be electric-to-acoustic transducers or optical-to-acoustic transducers.
[0034] Fiber Bragg Gratings for imaging provides a means for measuring the interference between two paths taken by an optical beam. A partially-reflecting Fiber Bragg Grating is used to split the incident beam of light into two parts, in which one part of the beam travels along a path that is kept constant (constant path) and another part travels a path for detecting a change (change path). The paths are then combined to detect any interferences in the beam. If the paths are identical, then the two paths combine to form the original beam. If the paths are different, then the two parts will add or subtract from each other and form an interference. The Fiber Bragg Grating elements are thus able to sense a change wavelength between the constant path and the change path based on received ultrasound or acoustic energy. The detected optical signal interferences can be used to generate an image using any conventional means.
[0035] Exemplary optical-acoustic imaging elements are disclosed in more detail in U.S. Pat. Nos. 6,659,957 and 7,527,594, 7,245.789, 7447,388, 7,660,492, 8,059,923 and in U.S. Patent Publication Nos. 2008/0119739, 2010/0087732 and 2012/0108943.
[0036] In another embodiment, the imaging element of the invention is a capacitive micromachined ultrasound transducer array (CMUT). CMUT elements generally include at least a pair of electrodes separated by a uniform air or vacuum gap, with the upper electrode suspended on a flexible membrane. Impinging acoustic signals cause the membrane to deflect, resulting in capacitive changes between the electrodes, which produce electronic signals usable for ultrasonic imaging. Exemplary CMUT arrays are described in more detail in U.S. Pat. Nos. 8,309,428 and 6,328,696, and U.S. Publication No. 2007/0161896.
[0037] In another embodiment, the imaging element of the invention is a piezoelectric micromachined ultrasound transducer array (PMUT). In PMUTs the sound-radiating element is a micromachined multi-layer membrane that is activated by a piezoactive layer (such as a PZT thin film). The PZT thin film is poled in the thickness direction. Application of an electric field across the thickness direction causes a strain in the film and induces membrane bending, thereby propagating a sound wave. reflected sound waves are received on the membrane, which causes a detectable charge displacement in the electrode PZT. PMUT arrays are described in more detail in U.S. Pat. No. 8,148,877, U.S. Publication No. 2003/0085635, and Akasheh, Firas, et al. “Development of piezoelectric micromachined ultrasonic transducers.” Sensors and Actuators A: Physical 111.2 (2004): 275-287.
[0038] While the invention is described as delivering fluids, e.g., contrast, to the vasculature and or delivering interventional catheters, it is understood that similar methods could be used to deliver fluids to a number of tissues that are accessible via the various lumen of the body, including, but not limited to vasculature of the lymphatic and nervous systems, various structures of the gastrointestinal tract including lumen of the small intestine, large intestine, stomach, esophagus, colon, pancreatic duct, bile duct, hepatic duct, lumen of the reproductive tract including the vas deferens, uterus and fallopian tubes, structures of the urinary tract including urinary collecting ducts, renal tubules, urethra, and bladder, and structures of the head and neck and pulmonary system including sinuses, parotid, trachea, bronchi, and lungs.
[0039] In some embodiments, a catheter of the invention includes imaging element that sends and receives imaging data through the operation of IVUS, or other imaging hardware. In some embodiments, a catheter of the invention is coupled to a processing device. A processing device of the invention is a computer device such as a laptop, desktop, or tablet computer, and obtains a three-dimensional data set by retrieving it from a tangible storage medium, such as a disk drive on a server using a network or as an email attachment.
[0040] Methods of the invention can be performed using software, hardware, firmware, hardwiring, or combinations of any of these. Features implementing functions can also be physically located at various positions, including being distributed such that portions of functions are implemented at different physical locations (e.g., imaging apparatus in one room and host workstation in another, or in separate buildings, for example, with wireless or wired connections).
[0041] In some embodiments, a user interacts with a visual interface to view images from the imaging system. Input from a user (e.g., parameters or a selection) are received by a processor in an electronic device (such as a computer 449 ). The selection can be rendered into a visible display. An exemplary imaging system is illustrated in FIG. 5 . As shown in FIG. 5 , an imaging engine 859 of the imaging assembly communicates with host workstation 433 as well as optionally server 413 over network 409 . The data acquisition element 855 (DAQ) of the imaging engine receives imaging data from one or more imaging element. In some embodiments, an operator uses computer 449 or terminal 467 to control system 400 or to receive images. An image may be displayed using an I/O 454 , 437 , or 471 , which may include a monitor. Any I/O may include a keyboard, mouse or touchscreen to communicate with any of processor 421 , 459 , 441 , or 475 , for example, to cause data to be stored in any tangible, nontransitory memory 463 , 445 , 479 , or 429 . Server 413 generally includes an interface module 425 to effectuate communication over network 409 or write data to data file 417 .
[0042] Processors suitable for the execution of computer program include, by way of example, both general and special purpose microprocessors, and any one or more processor of any kind of digital computer. Generally, a processor will receive instructions and data from a read-only memory or a random access memory or both. The essential elements of computer are a processor for executing instructions and one or more memory devices for storing instructions and data. Generally, a computer will also include, or be operatively coupled to receive data from or transfer data to, or both, one or more mass storage devices for storing data, e.g., magnetic, magneto-optical disks, or optical disks. Information carriers suitable for embodying computer program instructions and data include all forms of non-volatile memory, including by way of example semiconductor memory devices, (e.g., EPROM, EEPROM, solid state drive (SSD), and flash memory devices); magnetic disks, (e.g., internal hard disks or removable disks); magneto-optical disks; and optical disks (e.g., CD and DVD disks). The processor and the memory can be supplemented by, or incorporated in, special purpose logic circuitry.
[0043] To provide for interaction with a user, the subject matter described herein can be implemented on a computer having an I/O device, e.g., a CRT, LCD, LED, or projection device for displaying information to the user and an input or output device such as a keyboard and a pointing device, (e.g., a mouse or a trackball), by which the user can provide input to the computer. Other kinds of devices can be used to provide for interaction with a user as well. For example, feedback provided to the user can be any form of sensory feedback, (e.g., visual feedback, auditory feedback, or tactile feedback), and input from the user can be received in any form, including acoustic, speech, or tactile input.
[0044] The subject matter described herein can be implemented in a computing system that includes a back-end component (e.g., a data server 413 ), a middleware component (e.g., an application server), or a front-end component (e.g., a client computer 449 having a graphical user interface 454 or a web browser through which a user can interact with an implementation of the subject matter described herein), or any combination of such back-end, middleware, and front-end components. The components of the system can be interconnected through network 409 by any form or medium of digital data communication, e.g., a communication network. Examples of communication networks include cell network (e.g., 3G or 4G), a local area network (LAN), and a wide area network (WAN), e.g., the Internet.
[0045] The subject matter described herein can be implemented as one or more computer program products, such as one or more computer programs tangibly embodied in an information carrier (e.g., in a non-transitory computer-readable medium) for execution by, or to control the operation of, data processing apparatus (e.g., a programmable processor, a computer, or multiple computers). A computer program (also known as a program, software, software application, app, macro, or code) can be written in any form of programming language, including compiled or interpreted languages (e.g., C, C++, Perl), and it can be deployed in any form, including as a stand-alone program or as a module, component, subroutine, or other unit suitable for use in a computing environment. Systems and methods of the invention can include instructions written in any suitable programming language known in the art, including, without limitation, C, C++, Perl, Java, ActiveX, HTML5, Visual Basic, or JavaScript.
[0046] A computer program does not necessarily correspond to a file. A program can be stored in a portion of file 417 that holds other programs or data, in a single file dedicated to the program in question, or in multiple coordinated files (e.g., files that store one or more modules, sub-programs, or portions of code). A computer program can be deployed to be executed on one computer or on multiple computers at one site or distributed across multiple sites and interconnected by a communication network.
[0047] A file can be a digital file, for example, stored on a hard drive, SSD, CD, or other tangible, non-transitory medium. A file can be sent from one device to another over network 409 (e.g., as packets being sent from a server to a client, for example, through a Network Interface Card, modem, wireless card, or similar).
[0048] Writing a file according to the invention involves transforming a tangible, non-transitory computer-readable medium, for example, by adding, removing, or rearranging particles (e.g., with a net charge or dipole moment into patterns of magnetization by read/write heads), the patterns then representing new collocations of information about objective physical phenomena desired by, and useful to, the user. In some embodiments, writing involves a physical transformation of material in tangible, non-transitory computer readable media (e.g., with certain optical properties so that optical read/write devices can then read the new and useful collocation of information, e.g., burning a CD-ROM). In some embodiments, writing a file includes transforming a physical flash memory apparatus such as NAND flash memory device and storing information by transforming physical elements in an array of memory cells made from floating-gate transistors. Methods of writing a file are well-known in the art and, for example, can be invoked manually or automatically by a program or by a save command from software or a write command from a programming language.
INCORPORATION BY REFERENCE
[0049] References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made throughout this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes.
EQUIVALENTS
[0050] The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting on the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein | 1a
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This application is a divisional of application Ser. No. 08/340,358, filed Nov. 14, 1994, now U.S. Pat. No. ,486,630.
FIELD OF THE INVENTION
The present invention is directed to a novel Legionella specific antibiotic AL072, a novel Streptomyces sp. AL91 producing the same, and a process for producing the said antibiotic.
BACKGROUND OF THE INVENTION
Legionella pneumophila, which is the causal agent of Legionella infections, has been known to cause Legionnaires' disease or Pontiac fever. Since the bacteria was first isolated in Philadelpia, USA, it has been reported that many isolations of a species of Legionella were made from various patients and environments in all parts of the world, including the USA, and 10 or more species were identified. Legionella pneumophila is one of the pathogens capable of causing pneumonia and it is presumed that 5% of the occurences of pneumonia are due to Legionella pneumophila. Legionella pneumophila grows in air-conditioning cooling towers, water service pipes, drain pipes, etc., and infections are believed to occur in respiratory organs by inhalation of contaminated aerosols. In July, 1984, criticism was caused by the surprising fact that ill-defined symptoms of pneumonia which occurred in patients as well as medical teams at intensive care units of Koryo Hospital in Seoul appeared to be caused by Legionella species.
According to a result of investigation completed in 1985 by the National Health Institute, at least 90% of air-conditioning cooling towers within Seoul were contaminated with Legionella species and 93% of the isolated Legionella were identified as Legionella pneumophila. An additional investigation completed by the National Health Institute in major cities throughout the country, for example Seoul, Pusan, Daejeon, etc., between June and September, 1988 revealed that 83% of the isolated Legionella were classified to Legionella pneumophila serogroup 1.
Macrolide antibiotics, such as erythromycin, and quinolone antibiotics, such as rifampin, are known to be active against Legionella species and have been used for the treatment of the Legionella infections. However, these antibiotics have a wide spectrum of activity against a variety of microbes, in addition to the Legionella species. In this regard, an abuse of such antibiotics for extended periods may not only generate resistance to various microbes but also cause harmful problems such as the collapse of the balance of microbes occurring in a human body.
Additionally, there have been serious problems in that chemical agents for disinfecting air-conditioning cooling towers, which are contamination sources of Legionella species, may result in the contamination of the environment and the corrosion of the air-conditioning device.
Therefore, the development of novel Legionella specific antibiotics which are specifically active against only Legionella species, is needed and thereby may minimize the undesired problems. We have intensively investigated soil microbes over several years for the purpose of developing such antibiotics. Eventually, we succeeded in isolating a species of Streptomyces producing Legionella specific antibiotics and purifying a novel antibiotic specifically active against only Legionella species, which is designated Antibiotic AL072.
SUMMARY OF THE INVENTION
Cultivation of the novel microorganism Streptomyces sp. AL91 yields a novel antibiotic substance AL072 which is active exclusively against Legionella species, whose structure is represented as follows:
DESCRIPTION OF THE DRAWINGS
FIG. 1 shows the ultraviolet absorption spectrum of antibiotic substance AL072.
FIG. 2 shows the infrared absorption spectrum of antibiotic substance AL072.
FIG. 3 shows the mass spectrum of antibiotic substance AL072 measured by FAB/MS.
FIG. 4 shows the 400 MHz proton nuclear magnetic resonance spectrum of antibiotic substance AL072.
FIG. 5 shows the 100 MHz carbon nuclear magnetic resonance spectrum of antibiotic substance AL072.
DETAILED DESCRIPTION OF THE INVENTION
The Microorganism
The microorganism used for the production of Legionella specific antibiotic substance AL072 is Streptomyces sp. AL91. The microorganism was deposited at the permanent collection of the Korean Culture Center of Microorganisms, Seoul, Korea, on Jun. 2, 1994 under the Budapest Treaty on the international recognition of the deposit of microorganisms for the purposes of patent procedure, and a subculture of the organism can be obtained from the repository under the accession number KCCM 10055. In addition to the specific microorganism described and characterized herein, it should be understood that mutants of the microorganism (e.g., mutants produced through the use of X-ray, ultraviolet radiation or nitrogen mustards) can also be cultivated to produce the antibiotic substance AL072.
Isolation of Streptomyces sp. AL91 was accomplished by shaking 1.0 g of dried soil sample in 10 ml of sterile distilled water, plating 0.1 ml of dilutions of the soil suspension on a Humic acid-Vitamin agar supplemented with Cycloheximide (50 μg/ml) and Nalidixic acid (200 μg/ml), and cultivating the -plate at the temperature of 28° C. for 14-21 days. The medium was sterilized at 121° C. for 15 minutes before the antifungal agent Cycloheximide and the antibacterial agent Nalidixic acid, seperately sterilzed by filtration, were added. The composition of Humic acid-Vitamin agar is described in Table I.
TABLE I______________________________________Humic acid 1.0 g(dissolved in 10 ml of 0.2N NaOH)Na.sub.2 HPO.sub.4 0.5 gKCl 1.71 gMgSO.sub.4.7H.sub.2 O 0.05 gFeSO.sub.4.7H.sub.2 O 0.01 gThiamin-HCl 0.5 mgVitamin B.sub.2 0.5 mgNiacin 0.5 mgPyridoxine-HCl 0.5 mgInositol 0.5 mgPantothenic Acid Ca-salt 0.5 mgp-Aminobenzoic Acid 0.5 mgBiotin 0.25 mgCycloheximide 50 mgNalidixic acid 200 g/mLAgar 20 gDistilled water (pH 7.0) 1 L______________________________________
Characteristics of Streptomyces sp. AL91 KCCM 10055
Morphology: Spores are formed by spiral, branched chains. The surface of spores is smooth.
Biochemical characteristics: The ability to liquefy gelatin is negative and the ability to degrade starch is positive.
Cultural characteristics:
__________________________________________________________________________ Color of Reverse SolubleMedia Growth aerial mycelium color pigments__________________________________________________________________________Trypton-yeast good brown brown brownextract agarYeast extract- good white brown --malt extractagarOat meal good pale orange -- --extract agar or whiteInorganic salt- good white -- --starch agarGlycerol- good dense yellow dense yellow --asparagine agarPeptone-yeast poor dense brown brown dense brownextract-ironagarTyrosine agar good white-brown dense brown --Bennett' medium good white yellow-brown --__________________________________________________________________________
Carbon utilization:
Positive: D-Glucose, sucrose, D-xylose, D-mannitol, D-fructose, rhamnose, raffinose, cellulose.
Negative: L-Arabinose, I-inositol.
Susceptibility to antibiotics:
______________________________________ Size of ring occured Concentrations by inhibition of growthantibiotics (μg/mL) (mm, in diameter)______________________________________Carbenicillin 100 --Chloramphenicol 30 27.7Neomycin 30 12.0Nalidixic acid 30 --Vancomycin 30 22.0Clindamycin 2 --Ampicillin 10 12.0Kanamycin 30 17.0Tetracycline 30 17.0Cephalothin 30 24.0Erythromycin 15 40.0Rifampin 5 --Gentamycin 10 10.0Streptomycin 10 17.0______________________________________
Production of the Antibiotic substance AL072
Streptomyces sp. AL91 KCCM 10055 was grown on a nutrient agar containing the components listed in Table II for 3 days. The cultures were inoculated into 200 mL of a liquid medium containing the components listed in Table III and cultivated at the temperature of 28° C. under aerobic conditions for 3 days. Subsequently, the culture solution was inoculated into 6 L of a liquid medium containing the components listed in Table IV and cultivated at the temperature of 28° C. under aerobic conditions for 5 days. The antibiotic AL072 was isolated and purified from the final culture solution by the procedures described below.
TABLE II______________________________________Sucrose 20.0 gGlucose 10.0 gCorn steep liquor 5 mgYeast extracts 4.9 gSoybean flour 20.0 gCaCO.sub.3 4.0 gNaCl 2.0 gK.sub.2 HPO.sub.4 0.05 gAgar 15 gDistilled water (pH 7.3) 1 L______________________________________
TABLE III______________________________________Glucose 1 gSoluble starch 24 gPeptone 3 gMalt extract 5 gCaCO.sub.3 4 gDistilled water (pH 7.0) 1 L______________________________________
TABLE IV______________________________________Sucrose 20.0 gGlucose 10.0 gCorn steep liquor 5 mLYeast extract 4.9 gSoybean flour 20.0 gCaCO.sub.3 4.0 gNaCl 2.0 gK.sub.2 HPO.sub.4 0.05 gDistilled water (pH 7.3) 1 L______________________________________
After cultivation was completed, 6 L of the culture solution was mixed with an equivalent amount of isopropyl alcohol by stirring. After standing over night, the mixture was centrifuged and the resulting supernatant was taken. The supernatant was filted through the passage of diatomaceous earth and the filtrate was then concentrated under reduced pressure to remove the isopropyl alcohol. The resulting concentrate was three times extracted with ethylacetate, which was then removed under reduced pressure. The residue was dissolved in 50% isopropyl alcohol and the resulting solution was then concentrated under reduced pressure to remove the isopropyl alcohol. The residual aqueous solution was passed on a column filled with octadecyl silica gel and the passed solution was discarded. Legionella specific antibiotics adhered to the ODS resin were eluted with 70% ethyl alcohol and the elutes were then concentrated under reduced pressure to dryness. After the dried concentrates were dissolved in 80% isopropyl alcohol, preparative high pressure liquid chromatography (206 nm) on silica gel, eluting with acetonitrile-distilled water, 68:32 at the rate of 30 mL/min, gave crude Leginella specific antibiotic substance AL072. Subsequently, the crude antibiotics were concentrated under a reduced pressure to dryness, the dried concentrates were dissolved in 50% isopropyl and the resulting solution was again concentrated under reduced pressure. The isopropyl alcohol was removed and the residue was three times extracted with chloroform. The chloroform was removed and the residue was dissolved in 80% isopropyl alcohol. High pressure liquid chromatography, run in the same conditions as used in the first chromatography, gave pure antibiotic AL072.
Physico-chemical properties of Antibiotic substance AL072
1. Thin-layer chromatography was conducted on Merck & Co. No. 5642 HPTLC silica gel plate with the development of chloroform-methyl alcohol, 19:1. Antibiotic AL072 samples were spotted on the silica gel plate and developed in a sealed container. After development, an aqueous 10% sulfuric acid solution containing 5% ammonium molybdate and eerie ammonium sulfate was sprayed on the silica gel plate which was then heated to 10013 for 10 minutes to develop a colour. As a result of this, the Rf value of antibiotic AL072 was 0.58.
2. Antibiotic AL072 is soluble in alcohols such as methyl alcohol, ethyl alcohol, isopropyl alcohol, etc., and organic solvents such as ethyl acetate, chloroform, etc., whereas it is not or poorly soluble in water.
3. Antibiotic AL072 is very stable in aqueous solutions with pH values between pH 2 and pH 12. The activity of antibiotic AL072 is unchanged by heat of 9513 for 1 hour.
4. As a result of ultraviolet spectrometry, antibiotic AL072 in methyl alcohol is shown to have a maximum absorption in 242 nm (FIG. 1).
5. The infrared absorption spectrum of antibiotic AL072 in potassium bromide using Bruker FT-IR spectrometer is shown in FIG. 2.
6. The proton nuclear magnetic resonance spectrum of antibiotic AL072 in CDCl 3 using Bruker ARX400 spectrometer is shown in FIG. 4. H-NMR δ(400MHz): 0.86(3H,m); 0.87(3H,m); 0.88(3H,m); 0.91(3H,m); 1.29(43H,m); 1.61(4H,m); 2.03(2H,m); 2.31(4H,m); 2.75(1H,m); 3.62(1H, dd, 12Hz, 6Hz); 3.72(1H,dd,4Hz, 12Hz); 3.96(1H,m); 4.14(2H,m); 5.35(4H,m) ppm.
7. The carbon nuclear magnetic resonance spectrum of antibiotic AL072 in CDCl 3 using Bruker ARX400 spectrometer is shown in FIG. 5. C-NMR δ(100MHz): 12.01(q); 14.67(q); 19.85(q); 23.23(q); 23.28(q); 25.34(t); 25.36(t); 26.29(q); 27.78(t); 27.84(t); 27.87(t); 28.10(t); 28.63(d); 29.72(t); 29.75(t); 29.82(t); 29.93(t); 30.02(t); 30.17(t); 30.26(t); 30.29(t); 20.33(t); 30.36(t); 30.38(t); 30.62(t); 30.69(t); 32.20(t); 24.79(t); 34.81(t); 35.08(d); 37.33(t); 39.75(t); 63.90(t); 25.95(t); 70.96(d); 128.50(d); 128.70(d); 130.60(d); 30.70(d); 174.90(s); 181.00(s)ppm.
Biological Activity of Antibiotic substance AL072
The effects of antibiotic substance AL072 obtained according to the above procedures on growth of various microbes were shown in Table V below. It is evident that while the antibiotic substance AL072 is powerfully active against Legionella pheumophila, it is not or only slighly active against the other microbes tested.
TABLE V______________________________________ Diameter of ring produced by inhibitionMicroorganism of growth (mm)______________________________________Legionella pneumophila ATCC 33152 108Staphylococcus aureus 11Streptococcus pyogenes --Streptococcus 20Streptococcus agalactiae --Streptococcus equi 21Streptococcus durans 24Listeria monocytogenes 12Corynebacterium diphtheriae 9Bacillus subtilis 8Bacillus megaterium 6Escherichia coli 6Citrobacter freundii --Salmonella typhimurium 14Shigella flexneri --Klebsiella pneumoniae --Klebsiella oxytoca --Klebsiella aerogenes --Enterobacter cloacae --Enterobacter aerogenes 9Serratia marcescens --Proteus mirabilis --Proteus vulgaris 12Proteus rettgeri --Proteus morgani --Pseudomonas aeruginosa --Pseudomonas cepacia --______________________________________ | 1a
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FIELD OF THE INVENTION
[0001] The invention relates to an abutment for connecting a dental prosthesis to a dental implant, the abutment comprising a body portion for supporting the dental prosthesis and a contact surface apical to said body portion for contacting the dental implant.
BACKGROUND OF THE INVENTION
[0002] Prosthodontic restorations replacing a natural tooth in a patient's dentition are commonly fixed on a dental implant that is surgically implanted into the patient's jawbone. Typically, since the early work of Per-Ingvar Brånemark of Sweden in 1952, such an implant consists of a titanium screw which resembles a tooth root and comprises a roughened or smooth surface. The majority of dental implants are made out of pure titanium, which is commercially available in four grades depending upon the amount of contained carbon and iron.
[0003] An abutment is usually anchored at the coronal end of the dental implant. A dental prosthesis, such as a crown, a fixed bridge retainer or a removable denture, can be attached on the abutment serving as an interface between the dental prosthesis and the dental implant. The abutment is typically held in place with a screw. Abutments can be custom-made in a dental laboratory or purchased as a prefabricated part from a dental implant supplier.
[0004] Current abutments are typically made of titanium, stainless steel, gold or ceramic. All these materials have the disadvantage of being too stiff and brittle as compared to the natural dentine they are supposed to replace and mimic. In consequence, the masticatory stresses exerted on the artificial tooth structure cannot be adequately absorbed. This leads to a number of undesirable side effects including an unnatural feeling of pressure while chewing, increased bruxism, and an increased risk of breakage of the artificial tooth structure. Another disadvantage lies in the different refractive index of these materials as compared to the enamel and dentine of a natural tooth, resulting in an unnatural and unaesthetic appearance of the replacement structure. Moreover, these materials are difficult to rework, in particular to cut or grind or trim. In consequence, they are usually fabricated in specific standardized shapes which complicates an individual adaption to the shape of crown or bridge restorations.
OBJECTS AND SUMMARY OF THE INVENTION
[0005] It is an object of the present invention to avoid at least one of the above mentioned disadvantages and to provide an improved abutment which allows an adjustment of the tooth restoration structure to properties of a natural tooth.
[0006] Accordingly, the invention suggests that the abutment is composed of a resin that is reinforced with fibers substantially extending over the total length of the body portion towards the contact surface with the dental implant. The proposed material composition of the abutment allows to mimic the properties of natural dentine in a number of ways, in particular with respect to the modulus of elasticity and/or the refractive index. Such a material can also provide an excellent biocompatibilty of the abutment. Moreover, the shape and size of the abutment can be easily reworked, even after its application on a dental implant, since the proposed material can be trimmed or cut similar to natural dentine.
[0007] Despite its smooth workability, a high flexural strength of the body portion can be achieved, in particular in the range of 1500 MPa or higher, due to the continous longitudinal arrangement of the fibers. Thus, the abutment can be highly resistant against fracture, bending or rupture and can provide a long durability.
[0008] Generally, a number of different materials of the fiber and/or resin constituents of the abutment are conceivable. For instance, the material of the resin may be selected from methyl metacrylate (MMA), urethane dimethacrylate (UDMA), bisgma, epoxy, peek optima, polyester, polyvinyl ester or a mixture thereof. The material of the fibers may be selected from glass, quartz, carbon, aramide, kevlar or a mixture thereof. Moreover, a wide range of different compositions of the fiber content with respect to the resin content of the abutment is conceivable. Advantageously, the individual properties of these materials and of their relative composition can be exploited to adapt the abutment with respect to the specific requirements of the respective dental structure to be replaced.
[0009] In order to reduce the risk of breakage of the abutment, said body portion preferably exhibits a modulus of elasticity of at least 10 GPa and at most 50 GPa. In this way, the elastic properties of natural dentine can be imitated.
[0010] Preferably, the longitudinal extension of the fibers within the resin is exploited in such a way, that an anisotropic modulus of elasticity is achieved within the body portion. Thus, the body portion preferably exhibits a modulus of elasticity that varies in dependence of the direction of a force applied on the body portion with respect to the orientation of a longitudinal axis extending in the apical direction of the body portion. In this way, the inherent properties of the natural two-layer system between the enamel and the dentine can be further assimilated.
[0011] More precisely, an anisotropic behavior of the modulus of elasticity of natural enamel and dentine has been reported in various scientific studies. Such an anisotropic behavior of at least one layer of a multilayered biological system is believed to contribute to a protection against breakage or rupture of the system. Advantageously, the abutment according to the invention can be used to mimic the anistropic elastic modulus of one layer of such a natural system.
[0012] Preferably, the modulus of elasticity is lower for a force applied perpendicular to the longitudinal axis of the abutment as compared to a force applied in parallel with respect to its longitudinal axis. In this way, a homogenous and therefore predictable behavior can be achieved over the whole length of the body portion of the abutment. Preferably, the fiber content is chosen in such a way, that a variation of the elastic modulus of at least 10 GPa, more preferred at least 30 GPa is achieved. Furthermore, the fiber content is preferably chosen in such a way, that a variation of the elastic modulus of at most 100 GPa, more preferred at most 40 GPa is achieved. More specifically, the modulus of elasticity preferably varies in between a value of at most 20 GPa for a force applied perpendicular to said longitudinal axis and a value of at least 30 GPa for a force applied in parallel with respect to said longitudinal axis.
[0013] Various possibilities of the arrangement of the fibers within the resin are conceivable. According to a first preferred configuration, at least part of said fibers are substantially uniformly directed in parallel with respect to a longitudinal axis of said body portion. According to a second preferred configuration, at least part of said fibers are arranged in the manner of a braided netting in a biaxial or multiaxial orientation. Such an arrangement of the fibers can further contribute to improve the flexural strength of the abutment. In particular, an arrangement of the fibers can be applied as described in patent application No. EP 1 078 608 A1, which is herewith incorporated by reference.
[0014] A highly preferred material composition of the abutment comprises a resin that is derived from at least one methacrylate monomer, in particular methyl methacrylate (MMA) and/or urethane dimethacrylate (UDMA). Besides a high biocompatibility, an excellent bonding interaction between the abutment and the prosthetic structure can be expected from this material selection due to a chemical composition that resembles currently used composite resin cements that are used for fixing prosthetic devices in dentistry.
[0015] To provide an abutment that optically resembles to the properties of natural dentine, in particular to render the abutment aesthetically more pleasing, the fibers are preferably constituted by glass fibers. For instance, E glass, S glass and/or AR Glass fibers are conceivable for that purpose. To further assimilate the abutment to the optical properties of natural dentine, mineral particles are preferably embedded in said resin, wherein the content by volume of said mineral particles is matched in such a way that the index of refraction of said body portion is in between 1.3 and 1.8, more preferred in between 1.4 and 1.6. Most preferred, an index of refraction in between 1.50 and 1.55 is achieved by an appropriate composition of said resin, fibers and mineral particles in order to closely imitate the appearance of natural dentine.
[0016] In use, a basic prerequisite of the abutment is its radiopacity to allow a dentist to monitor the artificial tooth structure by X-ray analysis. In order to provide this property of the abutment, X-ray absorbing particles are preferably embedded in said resin, said X-ray absorbing particles being selected from a chemical compound comprising an element of an atomic number of at least 37, more preferred at least 57. Advantageously, the X-ray absorbing particles may be provided in the form of mineral particles for matching the refractive index of said body portion, as described above. Preferably, particles selected from an ytterbium compound are employed for this purpose, in particular ytterbium flouride and/or ytterbium oxide.
[0017] In order to achieve the above described properties with respect to an adaption of the abutment to natural dentine and by still ensuring a high flexural strength of the abutment, a fraction of at least 40% in volume of the total content of said body portion is constituted by said fibers. More preferred, the fiber content represents ideally at least 70% of the total volume, more preferred about 80% of the total volume. This material exceeds currently used abutment materials with respect to its fatigue properties under repeated stress, in particular by at least a factor of five. A further improvement of the flexural strength and the elastic properties of the abutment can be achieved by pretensing the fibers during the manufacturing process, in particular by a tension force of at least 100 N, more preferred at least 300 N. Such a tensioning of the fibers can be advantageously implemented during a fabrication process that is carried out by means of pultrusion.
[0018] In order to improve the bonding interaction between the fibers and the resin, the circumferential surface of the fibers is preferably covered with a coupling agent, in particular silane, for enhancing the adhesion of said fibers to the resin. On the one hand, such a treatment of the fibers contributes to increase the interlaminate shear strength (ISS) of the abutment. In this way, an ISS-value of at least 80 MPa, in particular about 90 MPa or higher, can be achieved, resulting in a further improvement of the fatigue properties under repeated stress. On the other hand, a delamination of the abutment can be effectively avoided, in particular during a reworking of the prefabricated abutment shape, for instance by grinding or cutting the surface of the body portion by means of diamond burs or discs. This advantageously allows to adapt the shape of the abutment to specific local requirements, even after it is fixed on a dental implant that is anchored in a jawbone.
[0019] Preferably, the shape of the body portion is substantially symmetrical with respect to a longitudinal axis of the abutment. In particular a cylindrical, cylindro-conical, conical, spherical or hyperbolic shape or a combination thereof is conceivable. More preferred, the body portion has a substantially hyperbolic form. Such a hyperboloid may be geometricaly described in a x-y-z coordinate system by the general equation x 2 /a 2 +y 2 /b 2 −z 2 /c 2 =1, wherein a, b, c are predefined constant values. More preferred, a circular hyperboloid is applied, wherein a substantially equals b in the above equation. Such a hyperbolic body portion has the advantage of strengthening the overall tooth structure, in particular providing a reduced risk of breakage, combined with a better distribution a lateral forces that are transmitted from the prosthetic structure. Another advantage is provided in conjunction with the reworkability of the abutment by means of commonly used cuting tools, such as diamond burs and/or disks, since the hyperbolic form allows an easier adaption to a specific shape and reduces the tendency of fracture of the abutment during the cutting or grinding procedure.
[0020] In order to further improve the bonding interaction between the abutment and the prosthetic structure, mechanical retention structures are preferably applied at the surface of the body portion. According to a first preferred configuration, the mechanical retentions can be provided in a micrometer sized range by trimming the surface of the body portion with appropriate cutting burs or tools.
[0021] According to a second preferred configuration, the mechanical retentions can be provided by means of at least one retention groove that is provided at the circumferential surface of the body portion. Preferably, at least two longitudinal grooves are provided extending in the apical direction of the body portion, wherein the course of each groove extends over a different portion of the circumference of the body portion. In this way, an improved retention can be achieved, wherein the danger of a structural weakening of the abutment is minimised. More preferred, the groove extends over the whole length of the body portion in order to increase mechanical retention along its total length. Moreover, the groove preferably exhibits an inclined course with respect to the longitudinal axis of the body portion for allowing an improved retention, in particular a substantially helical form that is at least partially winding or wrapped around the body portion. The preferred width and/or depth of the grooves is at least 0.01 mm and at most 1 mm, wherein a range in between 0.1 mm and 0.5 mm is more preferred. Preferably, at most ten, more preferred at most five, retention grooves are provided in order to minimize a structural weaking of the body portion. Other preferred characteristics of such a retention groove are described in patent application No. EP 2 281 525 A2, which is herewith enclosed by reference.
[0022] According to a third preferred configuration, an improved retention of the dental prosthesis on the abutment is achieved by combining both types of retention structures.
[0023] Preferably, the contact surface is constituted by a substantially flat bottom surface at the apical end of the body portion. This allows an easy application and positioning of the abutment on the dental implant before its actual fixation. Various fixation methods of the abutment on the implant are conceivable, in particular cementing, screwing or clipping or a combination thereof. Fixation by screwing can be achieved by means of an inward thread or an outward thread in or on the abutment. A particularly advantageous fixation of the abutment on the implant can be achieved in that a receiving bore is provided at the contact surface for receiving a connector portion of the dental implant. Alternatively, a connector portion can be provided at the contact surface configured for insertion into a receiving bore an the dental implant. In particular the cross section of the receiving bore may exhibit a circular, squared, triangular, hexagonal or octogonal shape. In this way, a cost efficient and yet easy applicable and reliable fixation can be realized.
[0024] According to a preferred implementation of the abutment, the optical properties of the fiber-reinforced resin structure are exploited for an advantageous light conduction through the body portion, which can be applied to achieve a proper polymerization of a setting product, such as resin cement. Advantageously, the ordered arrangement of the fibers extending over the total length of the body portion can be exploited to allow a superior light conduction both through the resin and through the optical fibers. Preferably, the optical fibers are glass fibers, in particular to provide an optical resemblance to natural dentine. Preferably, the apical surface of the body portion is used as a light entering surface. In particular, a planar cutting or grinding of the fibers may be applied for achieving an effective coupling of light into the fibers. Preferably, a light conduction to the contact surface is exploited for cementing the abutment to the dental implant.
[0025] Various fabrication methods can be applied for producing the described abutment, in particular extrusion, injection molding, wetting or pultrusion. Preferably, a pultrusion process is applied in which the fibers are pulled through a resin bath containing above described mineral particles. Before the pultrusion, the fibers are preferably treated with a coupling agent, in particular silane, for enhancing the adhesion of said fibers to the resin. During the pultrusion process, the fibers are preferably tensed by applying a force of at least 50 N, more preferred at least 100 N, to increase the flexural strength and the elastic properties of the abutment according to the above description. After the pultrusion process, the shaping of the abutment can be achieved by molding and/or turning and/or grinding. Preferably, a turning lathe is used for this purpose.
BRIEF DESCRIPTION OF THE DRAWINGS
[0026] The invention will be described in more detail in the following description of preferred exemplary embodiments with reference to the accompanying drawings. In the drawings:
[0027] FIG. 1-4 are schematic views of various embodiments of an artificial tooth structure in a longitudinal section; and
[0028] FIG. 5-11 are schematic perspective views of various embodiments of the body portion of an abutment for a dental implant.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0029] FIG. 1 depicts an artificial tooth structure 1 comprising a dental implant 2 , an abutment 3 and a dental prosthesis 4 . The dental implant 2 is anchored into a jaw bone 5 and consists, for instance, of titanium, stainless steel, ceramics or another osseointegratable material.
[0030] The abutment 3 is arranged on the dental implant 2 in such a way that the abutment 3 has a contact surface 6 at its apical end with the coronal side of the implant 2 . The abutment 3 is rigidly connected to the implant 2 by means of a connector portion 7 protruding from the center of the contact surface 6 . The connector portion 7 is cylindrically shaped and has an outer thread that is engaged with an inner thread of a receiving bore in the implant 2 .
[0031] The abutment 3 further comprises a body portion 8 which constitutes a prolongation of the implant 2 in a coronal direction along the longitudinal axis L. At the surface of the body portion 8 the dental prosthesis 4 is attached.
[0032] The abutment 3 is composed of a resin that is reinforced with fibers extending over the total length of the body portion 8 to the contact surface 6 . According to a first embodiment, the fibers are uniformly directed in parallel with respect to the longitudinal axis L of the body portion 8 . According to a second embodiment, the fibers are arranged in the manner of a braided netting in a biaxial or multiaxial orientation. The resin consists of a polymer derived from a methacrylate monomer, preferably methyl methacrylate (MMA) or urethane dimethacrylate (UDMA). Mineral particles, preferably ytterbium flouride and or ytterbium oxide, are homogenuosly distributed within the resin. The fibers are constituted by glass fibers, wherein the fiber content represents ideally 80% of the volume of the body portion 8 . The fibers are treated with silane as a coupling agent to the resin matrix.
[0033] The abutment 3 exhibits several advantageous mechanical properties, in particular an elastic modulus similar to natural dentine that is anisotropic with respect to the longitudinal axis L and varying in between 13 to 45 GPa. Yet the abutment 3 has a high flexural strength of ca. 1600 MPa for fracture resistance and durability. Moreover, the interlaminate shear strength (ISS) of the bond between the fibers and the resin matrix is larger than 90 Mpa, leading to an improved value of its fatigue under stress as compared to competing materials such as titanium, stainless steel or ceramics. The shape of abutment 3 can be easily reworked by means of common cutting tools such as diamond burs and/or discs.
[0034] Furthermore, the abutment 3 has several advantageous optical properties. First, the incorporation of the mineral particles is chosen so that the material composition of glass fibers, resin and mineral particles yields an index of refraction of 1.52. This value corresponds closely to the refractive index of natural dentine (1.540). Secondly, the particular arrangement of the fibers in the resin allows good light conduction through the body portion 8 . This can be exploited for a proper polymerization of a setting product, such as resin cement, in particular for fixing the abutment at its contact surface 6 .
[0035] The mineral particles with a high atomic number embedded in the resin lead to a radiopacity of the body portion 8 that is larger than 200% to the value of Aluminium, more preferred above a value of 400% of Aluminium. The chemical composition of the resin material similar to composite resin cement permits a chemically profound bonding-interaction between the abutment 3 and the dental prosthesis 4 and/or the implant 2 .
[0036] The artificial tooth structures shown in FIG. 2-4 comprise the dental implant 2 , the dental prosthesis 4 and an abutment with essentially identical properties with respect to the material and shape of its body portion 8 as the abutment of FIG. 1 . The connection means at the contact surface 6 of the abutment is modified.
[0037] FIG. 2 depicts an abutment 11 of an artificial tooth structure 10 that is rigidly connected to the implant 2 by means of a receiving bore 12 at the center of the contact surface 6 . The receiving bore 12 is cylindrically shaped and has an inner thread that is engaged with a connector portion protruding from the coronal end of implant 2 .
[0038] FIG. 3 depicts an abutment 16 of an artificial tooth structure 15 that is connected to the implant 2 by means of a receiving bore 17 at the center of the contact surface 6 . The receiving bore 17 is octogonally shaped and receives an adequately shaped connector portion of the implant 2 in a form-fitted manner. A rigid connection in between the abutment 16 and implant 2 at the contact surface 6 is established by means of resin cement.
[0039] FIG. 4 depicts an abutment 21 of an artificial tooth structure 20 that is connected to the implant 2 by means of a connector portion 22 protruding from the center of the contact surface 6 . The connector portion 22 is octogonally shaped and is inserted in a adequately shaped receiving bore in the implant 2 in a form-fitted manner. A rigid connection in between the abutment 21 and implant 2 at the contact surface 6 is established by means of resin cement.
[0040] In FIG. 5-9 various abutments with a different shape of the body portion are depicted, which is symmetrical along the longitudinal axis of the abutment.
[0041] FIG. 5 shows an abutment 25 with a cylindrical shaped body portion 26 .
[0042] FIG. 6 shows an abutment 27 with a hyperboloidal body portion 28 .
[0043] FIG. 7 shows an abutment 29 with a conical body portion 30 .
[0044] FIG. 8 shows an abutment 31 with a substantially spherical body portion 32 . The body portion 32 comprises a cylindrical apical end 33 to be contacted with the implant 2 .
[0045] FIG. 9 shows an abutment 34 with a cono-cylindrically shaped body portion 35 . The body portion 35 comprises a conical coronal part 36 and a cylindrical apical part 37 .
[0046] In FIGS. 10 and 11 an alternative embodiment of the abutments 25 , 27 is depicted. Three retention grooves 40 , 41 , 42 are provided at the lateral surface of the body portion 26 , 28 . Each of the retention grooves 30 , 31 , 32 extends over a different circumferential portion of this surface in order to avoid a weakening of the structure and a risk of breakage. The course of retention grooves 30 , 31 , 32 substantially extends in the apical direction and over part of the circumference of the body portion 26 , 28 such that they are partially wrapped around the surface. In this way, the retention properties can be greatly improved when the filling member 10 is fixed in the cavity by means of resin cement. Preferably, the grooves 30 , 31 , 32 extend over the total length of the body portion 26 , 28 to increase mechanical retention along the total device length. The retention grooves 30 , 31 , 32 can be analogously applied on the body portion 30 , 32 , 35 of the abutments 29 , 31 , 34 .
[0047] The above described preferred embodiments are intended to illustrate the principles of the invention, but not to limit the scope of the invention. Various other embodiments and modifications to those preferred embodiments may be made by those skilled in the art without departing from the scope of the present invention. | 1a
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This application is a divisional of U.S. patent application Ser. No. 09/899,300 filed on Jul. 6, 2001, entitled “Air-In-Line and Pressure Detection,” now issued as U.S. Pat. No. 7,232,430, which is based on and claims priority from U.S. Provisional Patent Application No. 60/216,772, filed on Jul. 7, 2000, the entire subject matter of these applications being incorporated herein by reference.
FIELD OF THE INVENTION
The present invention relates to a system and methods of determining air content and pressure in fluid, especially in association with an infusion pump.
BACKGROUND OF THE INVENTION
There is a need in the field for methods of measuring air content and pressure of a sample fluid. Particularly in an infusion pump, it is critical to determine the air content of the infusion fluid and the fluid pressure down stream of the outlet valve of the infusion pump.
SUMMARY OF THE INVENTION
The present invention is directed in part to unique methods of content measurement of a sample fluid. The present invention is based on the discovery that volume change in a chamber, as the chamber transitions between negative and positive pressure relates to the air content in the chamber. In particular, in an infusion pump, the volume change of infusion fluid as it transitions between being under negative pressure and positive pressure within a cassette central chamber, e.g., pumping chamber, relates to the air content in the infusion fluid. In addition, the present invention provides methods for determining pressure of a sample fluid.
BRIEF DESCRIPTION OF THE DRAWINGS
These and other objects and advantages of the invention will become more apparent and more readily appreciated from the following detailed description of an exemplary embodiment of the invention taken in combination with the accompanying drawings, of which:
FIG. 1 is a block diagram illustrating the fluid delivery system topology of an infusion pump.
FIG. 2 is a block diagram illustrating a cross-sectional view of the cassette assembly of an infusion pump.
FIG. 3 illustrates changes in cassette central chamber volume as a function of pressure.
FIG. 4 illustrates changes in piston position as a function of time.
DETAILED DESCRIPTION
Infusion pumps are widely used for administering medications to patients over an extended time period. During an infusion of medication, it is critical to monitor the air content of the fluid medication administered to a patient. In addition, it is often convenient/helpful to measure the pressure on the patient side of the pump, e. g. measure the blood pressure of the patient. One of the applications of the methods for air content measurement of a sample fluid is to measure the air content in a cassette central chamber in an infusion pump. In addition, the mechanism for air content measurement also provides means to monitor the blood pressure of a patient connected to an infusion pump.
FIG. 1 is a block diagram illustrating one embodiment of the present invention. The fluid delivery system 100 includes a cassette assembly 20 and a shuttle mechanism 40 . A suitable cassette assembly is described in patent application No. 60/216,658, filed Jul. 7, 2000, entitled “Cassette”, to Carlisle, Costa, Holmes, Kirkman, Thompson and Semler, the entire contents of which are incorporated herein by reference. Within the cassette assembly 20 is a cassette piston 60 and a cassette central chamber 80 . A spring 120 biases shuttle mechanism 40 which is connected to the cassette piston 60 . Piston 60 slides freely in the cassette central chamber 80 to draw fluid into central chamber 80 and pump fluid out of central chamber 80 . A motor 140 is activated in one direction to draw the cassette piston 60 out of cassette central chamber 80 via cam 160 and shuttle 40 . When the cassette piston 60 is fully withdrawn, shuttle 40 disengages from cam 160 and motor 140 , so that spring 120 pushes the cassette piston 60 into the cassette central chamber 80 via shuttle 40 to apply positive pressure to the fluid in the cassette central chamber 80 . The shuttle mechanism 40 is also operably linked to an optical position sensor 180 . A suitable position sensor is described in patent application No. 60/217,885, filed Jul. 7, 2000, entitled “Optical Position Sensor and Position Determination Method”, to Carlisle, Kaplan and Kirkman, the entire contents of which are incorporated herein by reference. A processor 220 is connected to motor 140 and the position sensor 180 .
FIG. 2 is a diagram illustrating a cross-sectional view of a cassette assembly 20 . The cassette assembly 20 contains an inlet valve 200 , an outlet valve 210 , a cassette central chamber 80 , and a cassette piston 60 . Cassette piston 60 is connected to shuttle 40 .
In operation, the motor 140 is activated in one direction to withdraw the cassette piston 60 against the force of spring 120 via cam 160 , creating a relative vacuum in the cassette central chamber 80 and pulling fluid through a one-way passive inlet valve 200 into the cassette central chamber 80 . During this fill stroke, the pressure in the cassette central chamber 80 is negative, e.g., between 0 and −10 psi. The amount of negative pressure depends on the withdrawal speed of the piston, fluid resistance, fluid viscosity, etc. Once the cassette piston 60 has been withdrawn, cam 160 disengages from the shuttle 40 , enabling the spring mechanism 120 to urge shuttle 40 to drive piston 60 into the cassette central chamber 80 . The pressure in the chamber then moves from a negative value through zero to a positive value. The one-way passive inlet valve 200 is now fully closed. The positive pressure in the cassette central chamber 80 is typically between +2 and +7 psi depending on the spring force applied to the cassette piston 60 through the shuttle 40 which is directly related to the length of the withdrawal stroke, e.g., the further the withdrawal stroke the stronger the spring force.
In a closed cassette central chamber, the volume changes as a function of cassette central chamber pressure. In theory, when the cassette central chamber 80 is closed and contains only liquid, i.e., air free fluid, the cassette central chamber is not compressible, thus no volume change occurs. Nevertheless in practice, a “base volume change” exists when the chamber contains just air free fluid (as shown in FIG. 3 ). Such “base volume change” is irrelevant to the air content in the fluid and is mostly due to system designs such as the shape of a sealing member of the cassette piston 60 or the flexing of elastomeric inlet and outlet valve elements connected to the cassette central chamber 80 .
For example, the cassette piston 60 in the cassette central chamber 80 acts as a nearly ideal piston when under positive pressure from the spring mechanism 120 ; thus a change in the axial position of the piston represents a fluid volume change in the cassette central chamber. Nevertheless, when cassette central chamber pressure changes from negative to positive, the shape of a sealing member of the cassette piston changes and results in piston travel without any change in central chamber fluid volume. This amount of travel contributes to the “base volume change”; it is significant, however, that this travel is a relative constant of the system design and does not change over time. In addition, the elastomeric valve elements connected to the cassette central chamber have some inherent displacement determined by their geometry and material properties. When under pressure, these elements move and to an insignificant degree, continue to move (creep) over time. The movement of these elements also contributes to the “base volume change”.
The “base volume change” of the cassette central chamber 80 can be determined by detecting the volume change of a control fluid under the pressure change of the cassette central chamber. The volume change can be measured by determining the change of shuttle position, i.e., the piston travel position when the cassette central chamber pressure changes from negative to positive. The change of shuttle position is determined by the precision position sensor 180 linked to the shuttle mechanism 60 . For example, one can compare the shuttle position in two states: the peak position during piston withdrawal and the shuttle position after the spring pressure is applied (as shown in FIG. 4 ). This net displacement change of the shuttle position as a result of the pressure change in the cassette central chamber 80 filled with control fluid is a measure of the “base volume change” of the system 100 , e.g., the volume change that is inherent in the system 100 .
In one embodiment, the “base volume change” of a control fluid is determined more than once and statistically conservative limits of “base volume change”, e.g., lower than average, is selected as the “base volume change” for calculating the fluid air content. In another embodiment, the base volume change of a control fluid for a sample infusion fluid is determined by measuring the median volume change of more than one sample of the same infusion fluid, e.g., over more than one fill stroke, resulting from the pressure change of the cassette central chamber. In yet another embodiment, the base volume change is the median volume change of an infusion fluid over eleven (11) contiguous fill strokes, and is updated or modified periodically throughout an infusion therapy; and such base volume change is used to measure the sample fluid air content of the same infusion fluid.
In a closed cassette central chamber, e.g., both inlet and outlet valves are closed, any cassette central chamber volume-versus-pressure changes above the “base volume change” are interpreted as volume changes in the cassette central chamber due to the presence of air (as shown in FIG. 3 ). The air content of fluid contributes to the total volume change of the cassette central chamber and is proportional to the total volume change, e.g., sample volume change minus the base volume change.
For example, one can fill the cassette central chamber 80 with a sample fluid until the volume (gVolMax) in the chamber is greater than the desired volume of fluid to be delivered in a single pump stroke (gVdue) plus the “base volume change” (Vbase). During the fill cycle, the fill volume can be monitored through the piston position, i.e., the shuttle position which is determined by the optical position sensor 180 . As a result of the geometry and design of the cassette assembly 20 , there is a linear relationship between the shuttle position and the fill volume. Once the fill volume (gVolMax) is achieved, the motor direction is reversed so that the shuttle 40 falls off the cam 160 and rides freely on the spring mechanism 120 . Similarly the end-diastolic volume (gVolEnd) can be determined from the stabilized shuttle position after the cam 160 releases shuttle 40 . The sample volume change is the difference between the gVolMax and gVolEnd. The air content of the sample fluid is calculated in processor 220 as follows:
Air content (Volair)˜Sample volume change−Base volume change
˜(gVolmax−gVolEnd)−Base volume change
The air content measured according to the present invention is independent of the size and shape of the air bubble contained in a sample fluid, e.g., the air content includes the content of big bubbles, small bubbles, integrated bubbles, and unintegrated bubbles.
In one embodiment, the effective amount of fluid that is pumped out of cassette central chamber 80 is calculated based on the air content of a sample fluid. For example, for a given stroke, the effective amount of fluid that is infused is calculated in processor 220 as follows:
effective amount of fluid infused˜gVolmax−Volair
In another embodiment, the proportion of air content and volume content in a given stroke is calculated directly on the change of position of the piston. Specifically the proportion is calculated in processor 220 as follows:
proportion of air/fluid content=(position change due to pressure change)/(max. position under neg. pressure)
The processor 220 adjusts subsequent fluid flow rate based on the air/fluid content proportion in a given stroke to compensation for the air content detected in a sample fluid.
In yet another embodiment, processor 220 compares the air content of a sample fluid to a predetermined value stored in the processor 220 ; the processor 220 activates an alarming device if the air content of the sample fluid is close to or beyond the predetermined value. Alternatively, the processor 220 activates an alarming device as well as shuts down the out flow of sample fluid from the cassette central chamber 80 , e.g., closes the outlet valve 210 of the cassette central chamber 80 and shuts down infusion process by the fluid delivery system 100 .
According to another feature of the invention, sample fluid continuously passes through cassette central chamber 80 and the air content of the sample fluid is determined at different time points and stored in processor 220 . The processor 220 calculates accumulated air content of the sample fluid by adding the air content values collected at different time points. Such accumulated air content over a period of time is compared to a threshold air content value stored in the processor 220 ; the processor 220 triggers a notifying device, e.g., an alarm, if the accumulated air content is close or beyond a predetermined limitation. Alternatively, the processor 220 activates a notifying device as well as shuts down the out flow of sample fluid from the cassette central chamber 80 , e.g., closes the outlet valve 210 of the cassette central chamber 80 and shuts down infusion process by the fluid delivery system 100 .
In one embodiment, the outlet pressure of the cassette central chamber, e.g., the blood pressure of a mammal such as a human connected to the infusion pump is monitored. For example, during the fluid displacement, the outlet valve 210 of the cassette central chamber 80 is opened via external actuation. Fluid then flows from the higher pressure in the cassette central chamber 80 to the outlet via the outlet valve 210 . If the outlet valve 210 remains open, the cassette piston 60 will stop when the cassette central chamber pressure equals the outlet pressure. The position of the piston on the spring load is associated with a known spring force. Processor 220 then calculates the outlet pressure from the fixed geometry of the cassette central chamber 80 . With the outlet valve 210 open, the outlet pressure including even rapid changes in arterial, vein, or capillary pressure of a patient can be measured.
For example, the spring rate, k (in units of force/distance), of the shuttle mechanism 40 and the piston cross-sectional area, A, are known system design constants. Such system design constants, i.e., k/A are pre-calculated and stored in the processor 220 as Design_Constant. During the empty cycle, the outlet valve 210 of the cassette central chamber remains open. Once the spring 120 reaches a stabilized position, the system reaches equilibrium, e.g., the outlet pressure equals the cassette central chamber pressure. Subsequently the shuttle position, i.e., X, is measured by the optical position sensor 180 and processor 220 calculates the outlet pressure as the following:
Outlet pressure=Design_Constant* X
In another embodiment, processor 220 monitors the outlet pressure of the cassette central chamber and compares it to a predetermined value over a period of time. An increase of the outlet pressure indicates a partial or complete blockage of the cassette central chamber outlet, i.e., blockage of the outlet pathway or a body fluid pathway receiving fluid displaced from the cassette central chamber 80 . Depending on the degree of outlet pressure increase, processor 220 generates a signal to either alert the pressure increase or stop the fluid displacement of the system 100 .
Other Embodiments
Although several exemplary embodiments of this invention have been described in detail above, those skilled in the art will readily appreciate that many modifications are possible in the exemplary embodiment without materially departing from the novel teachings and advantages of this invention. Accordingly, all such modifications are intended to be included within the scope of this invention as defined in the following claims. | 1a
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PRIORITY
Priority as a continuation application is claimed to U.S. application Ser. No. 10/269,340, now U.S. Pat. No. 6,992,765, filed Oct. 11, 2002. The disclosure of the priority application is incorporated herein by reference as if set forth in full.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The field of the present invention is laser focusing systems and methods.
2. Background
Various laser procedures or operations require that a laser beam be properly focused to a specific focal point. For example, in ophthalmic laser surgery wherein eye tissue is to be photodisrupted or ablated in or on the tissue that is to be affected, the correct positioning of a focusing assembly used to focus a laser beam is very critical. Such ophthalmic surgical procedures include those in cornea, sclera, iris, the crystalline lens and related structures, vitreous, and retina, and for treatment of glaucoma. Focal depth precision is also required in many non-ophthalmic laser surgical procedures, such as applications in dermatology and even “surgery” in DNA to excise portions of chromosomes. Also, non-biologic applications, such as photolithography and micromachining require focal depth precision.
With presently used laser systems, however, it is a critical concern that the object be positioned in a known relationship relative to the laser system. For example, in eye surgery, it is only when the eye can be positioned in a known relationship relative to the laser system that the laser beam can be directed to the desired area inside the eye with a high degree of accuracy. This is important because an inaccurately or improperly directed laser beam could affect an area of the eye not desired to be treated and cause permanent damage to the eye.
One way to accurately position the eye relative to a laser system for the purposes of performing laser ophthalmic procedures is to use a contact lens to stabilize the eye. To do this, however, the alignment of the contact lens (glass plate or “aplanation lens”) relative to the laser system must be known. As indicated above, if the lens alignment relative to the laser beam is not known, errors in accurate positioning of the laser beam can result.
In order to ensure that the alignment of a contact lens is known relative to a laser system, it is possible to permanently mount the lens on the laser system in a fixed orientation. If the contact lens is to remain mounted on the laser system, however, sterilization of the lens after each laser ophthalmic procedure could be time consuming, difficult to accomplish and, most likely, very uneconomical. Alternatively, the contact lens could be removed from the laser system, sterilized, and replaced. Further, a disposable contact lens could be used for the laser ophthalmic procedure. For either of these last two alternatives, however, the contact lens will require realignment with the laser system after the lens is mounted on the laser system.
U.S. Pat. No. 6,373,571 (incorporated herein by reference for all purposes) issued to Juhasz et al., discloses a system and method for aligning an aplanation lens with a laser system. In particular, Juhasz discloses that in order to properly align the aplanation lens to a laser system, reference marks on the contact lens are brought into coincidence with predetermined focal points along the laser beam paths. To this end, the laser system successively directs a laser beam along at least three predetermined paths to respective predetermined focal points, and the contact lens is positioned across these predetermined paths. Along each predetermined path, the laser beam is activated to establish a series of laser marks on the contact lens. If the laser marks, predetermined focal points, and reference marks are all coincident, then the contact lens is properly aligned with the laser system. If there is any displacement between any laser mark and reference mark, however, a retainer ring holding the aplanation lens is adjusted to align all reference marks with all predetermined focal points to align the lens to the laser system.
Because of the foregoing, it is however desirable to have alternative system and methods to determine the position and alignment of a plane of an object in relation to an intersecting axis and using that known position and alignment to allow for corrections to be made when using the plane as a reference plane.
SUMMARY OF THE INVENTION
The present invention generally relates to a method and system for determining the position and alignment (including the angle and orientation of tilt) of a plane of an object in relation to an intersecting axis and using that known position and alignment to allow for corrections to be made when using the plane as a reference plane. More particularly, the invention relates to a method and system for determining the position and alignment of a planar surface of an object in relation to a laser beam, and using the determined position and alignment to calculate a correction factor to be applied to the laser beam focal point. The method and system can also be adapted for objects with curved surfaces. Briefly stated, the method and system ultimately calculates a correction factor, z-offset, that is applied when using the laser beam in a procedure, such as photodisrupting corneal tissue below an aplanation lens.
Once the position and alignment of the aplanation lens is determined, the positioning of the laser beam can be corrected to take the alignment into account when using the laser beam to photodisrupt corneal tissue. In general the method can be broken into two steps: first, determining the position and alignment of the aplanation lens relative to the laser beam; second, determining the corrected position of the laser beam z-offset for later use in a procedure.
In one aspect of the inventive system, the movement of the focal point of the laser beam is controlled by a CPU and software instructions. The software instructions may be contained on storage media such as CDs, hard drives, diskettes, or other electronic storage media devices. Additionally, the computer software (instruction sets) may be stored in ROM, RAM or other storage devices capable of storing computer instructions. A software program may be configured to capture the z-axis location of the occurrence of detected plasma sparks. In addition to the z-axis location, the position of the x-axis and y-axis location may be captured.
Various laser sources may be used with the inventive method and system, including infrared, visible, and UV lasers. Further, laser sources to be used with the inventive method and system may be continuous wave, Q-switched pulse, and mode-locked ultrashort pulse lasers. Although the foregoing is not an exhaustive list, lasers of the foregoing type may be used with the present invention. In one aspect of the invention the laser beam is formed of a continuously repeating train of short optical pulses in the range of femtoseconds or picoseconds. In one embodiment, the laser source is an infrared ultrashort pulse laser with a pulse duration of less than 10 picoseconds. While various laser sources may be utilized, in one femtosecond laser system, the laser energy per pulse to photodisrupt the object and create a plasma spark is about 1-5 μJ for a focus of 2.5 μm.
The object used with the present invention is a material capable of producing a detectable plasma spark when contacted with the focal point of a laser beam. Some materials where a plasma spark may be created include glass, silicon, or plastic (including medical grade plastic), and biologic materials. The object is either permanently or temporarily affixed to the laser system such that the object falls within the path of the laser beam. A cage, base, frame, or other holding device may be used to position the object in place. For example, an aplanation lens composed of highly purified fused silica is placed in a cone shaped frame which is connected to the laser system as described in co-pending U.S. application Ser. No. 09/772,539 (Publication No. US2002/0103481) and Ser. No. 09/896,429 (Publication No. US2002/0103482) (the disclosures of which are incorporated herein for all purposes). Another example is a microscope slide positioned in place by using pressure to hold the slide in place.
In one aspect of the invention, there is a method and system for determining the occurrence of a plasma spark about the surface of an object, or within the object. The method and system utilizes a photodetector to detect the occurrence of the plasma spark when the focal point of the laser beam contacts the surface of the object, or when the laser beam is focused within the object. The photodetector identifies when a plasma spark occurs. The photodetector may be any one of a photodiode, CCD, photomultiplier, phototransistor, or any device suited for detecting the occurrence of a plasma spark.
In one aspect of the invention, there is a method and system for determining the position and alignment of a surface of an object in relation to a laser beam. A laser system for generating a laser beam and an object having a substantially planar surface are provided. The method and system may also be adapted for objects with a curved surface. The object is positioned in the path of the laser beam. The object may be permanently or temporarily affixed to the laser system. The focal point of the laser beam is repeatedly moved along a predetermined pattern in a plane perpendicular to a z-axis of the laser beam. Plasma sparks are detected when the laser beam focal point contacts the object. The position and alignment of the surface of the object in relation to the laser beam is determined.
In one aspect of the invention, moving the focal point of the laser beam includes starting at a starting point on a z-axis plane such that the focus of the laser beam is not in contact with the object; repeatedly moving the focal point of the laser beam along a predetermined pattern in at least one plane perpendicular to the z-axis; and after an occurrence of the completion of movement of the laser beam along the predetermined pattern, repositioning the focal point of the laser beam on the z-axis a set distance Δz from the previous z-axis location. The predetermined pattern is preferably circular in shape. In one embodiment, the focal point of the laser beam may be positioned below the object and the laser beam moved up towards the object. Or in another embodiment, the focal point of the laser beam may be focused somewhere between the laser source and the object, and the laser beam moved towards (or downward) to the object.
In another aspect of the invention, detection of plasma sparks includes identifying a first plasma spark when the laser beam comes into contact with the object; recording a first z-axis location of the first plasma spark; identifying the completion of the predetermined pattern by identifying a second plasma spark along the complete predetermined pattern; and recording a second z-axis location of the second plasma spark.
Further to detecting the plasma sparks, the position and alignment of the object in relation to the z-axis using the first z-axis location and the second z-axis location is calculated. In one embodiment, calculation of the tilt angle (alignment) of a surface of an object is performed by utilizing the formula θ=tan −1 (Δz/D), where Δz is the difference between the first z-axis location and the second z-axis location, and D is the diameter of the predetermined pattern.
In one embodiment of the invention, plasma sparks are visually detected by the operator. The occurrence of a first plasma spark and the occurrence of a second plasma spark at the completion of a predetermined pattern are detected. An input device such as a foot switch interconnected with the laser system is manually operated. When the operator of the laser system visually identifies the first occurrence of a plasma spark, then the input device is triggered to signal to the computer to record the first z-axis position. The laser focal point continues through the object in iterative predetermined patterns. When the operator of the laser system visually identifies the completion of the predetermined pattern, then the operator actuates the input device, which in turn triggers the computer to record the second z-axis position.
In another embodiment of the invention, the detection of the plasma spark includes providing a photodetector for detecting plasma sparks, and identifying the occurrence of the plasma spark with the photodetector. The photodetector may be any one of a photodiode, CCD, photomultiplier, phototransistor, or any device suited for detecting the occurrence of a plasma spark.
In one embodiment of the invention, the detection of the plasma spark includes providing a video camera for taking images of the object and capturing a series of images of the object. The position and alignment of the surface can be determined by subtracting the pixels of a previous image from the pixels of a current image and subsequently adding all the resulting pixels that exceed a certain threshold to become a final number for that image which correlates with the plasma intensity for that image. The final number for each calculation may be plotted on a graph to establish a plasma intensity curve.
The step of determining the alignment of the aplanation lens relative to the laser beam can be broken into several substeps, as follows. First, if the z-axis is defined as the path of the laser beam, the focal point of the laser is directed on the z-axis below the aplanation lens, at a point z 0 . The focal point of the laser beam is then moved along a closed pattern, for example, a circle with a fixed diameter less than the diameter of the aplanation lens, in a plane perpendicular to the z-axis. After the focal point has completed the closed pattern, the focal point is adjusted at a set distance (also referred to as a separation layer), z x , above to z 1 , and the moving step is repeated. These last two steps, adjusting the focal point up the z-axis to Z 2 and moving the focal point in the closed pattern, are repeated i times until the focal point of the laser is adjusted up the z-axis to z i and the focal point makes contact with the aplanation lens, causing a plasma spark. When this occurs, the position of the focal point, z i is recorded. The focal point is then adjusted z x above the previous starting point and the focal point is moved along the closed pattern in a plane perpendicular to the z-axis until the laser makes contact with the aplanation lens along the entire closed pattern, causing a plasma spark along the entire closed pattern. When this occurs, the position of the focal point, z j , is again recorded. A Δz can be determined, by calculating the distance between z 0 and z j . Using the diameter of the closed pattern and the total distance along the z-axis the focal point traveled, trigonometry can be used to determine the angle, θ, of the aplanation lens relative to the z-axis.
In one aspect of the invention, a method and system for determining the alignment of a surface of an object in relation to a laser beam is disclosed. An object having a substantially planar surface is provided. A laser system for generating a laser beam is utilized to create at least three plasma sparks at the surface of the object. The laser system has a CPU with software configured to carry out the process and computations. The plasma sparks may be detected in any manner, including those described previously, such as manually/visually, a photodetector, or the video image analysis. By detecting three points about the planar surface of the object, it is possible to identify a plane in relation to a z-axis of the laser beam and the plane's tilt relative to the laser beam z-axis. Additionally, the curvature of a surface may be detected if the surface is not planar. In this case, multiple points would be identified with plasma sparks and their x-,y-,z-coordinates recorded. The curvature of the surface may then be computed.
In one aspect of the invention, a method and system for determining a focal point of a laser beam upon an object having a substantially planar surface is disclosed. The novel system and method utilizes an interferometer to determine a fringe pattern of a reflection of a laser beam from the object. In this particular system and method, an object having a substantially planar surface is provided. A laser system for generating a laser beam is provided. The laser system has a central processing unit configured for instructing movement of the laser beam. The interferometer is interconnected with the laser system. The laser beam is focused at or near the substantially planar surface. The laser beam is reflected back from the planar surface. A fringe pattern is detected. Based on the analysis of the fringe pattern, the laser beam is determined to be in or out of focus. A software program for execution on the central processing unit may be configured for focusing the laser beam at or near the substantially planar surface of the object, detecting a fringe pattern of the laser beam, and determining whether the laser beam is in focus based on the fringe pattern. If the fringe pattern lines are substantially parallel to one another, then the laser beam is focused on the planar surface.
In yet another aspect of the invention, another method and system for determining a focal point of a laser beam upon an object having a substantially planar surface is disclosed. The laser system computer monitors the dependence of the signal on depth. Change in the signal indicates the interface between the lower surfaces of the aplanation glass and the cornea. A laser system for generating a laser beam has a central processing unit configured for instructing movement of the laser beam. A photomultiplier with a band pass filter for detecting a nonlinear frequency signal generated by the laser beam is interconnected with the laser system. A software program for execution on the central processing unit is configured for monitoring a nonlinear frequency signal generated by the laser beam, and determining whether the laser beam is in focus. The nonlinear frequency signal may be any one of second harmonic generation, third harmonic generation, stimulated Raman, or white light generation and others.
In yet another aspect of the invention, a method and system for determining the distance between two objects is disclosed. A laser system for generating a laser beam having a central processing unit configured for instructing movement of the laser beam is utilized to create and detect a first plasma spark at the surface of a first object, and to create and detect a second plasma spark at the surface of a second object. A software program is configured for identifying a first point at the outer surface of a first object by detecting the occurrence of a first plasma spark; identifying a second point at the outer surface of the second object by detecting the occurrence of a second plasma spark; and determining the distance between the first point and the second point. The software program records the x-,y, z-axis location of the first and second points, and then calculates the distance between the points. The detection of the plasma spark may be done by any device capable of detecting a plasma spark. In one embodiment, the plasma spark is detected by a photodetector. Some examples of a photodetector includeany one of a photodiode, CCD, photomultiplier, phototransistor, or any device suited for detecting the occurrence of a plasma spark.
BRIEF DESCRIPTION OF THE DRAWINGS
For a more complete understanding of the present invention, reference is now made to the following descriptions taken in conjunction with the accompanying drawings, in which:
FIG. 1 is a perspective view of the system used to determine position and alignment of the aplanation lens relative to the laser system illustrating an embodiment of the present invention;
FIG. 2 is a schematic view of the aplanation lens and the laser beam;
FIG. 3 is a flowchart illustrating a method for determining the position, alignment, and orientation of the aplanation lens relative to the focal plane of the laser beam;
FIG. 4 is a graph illustrating a video image analysis for determining the position, alignment, and orientation of an aplanation lens relative to laser beam;
FIG. 5A-5C are drawings illustrating detected pattern fringes while using an interferometer for focusing a laser beam; and
FIG. 6 is a graph illustrating dependence of second harmonic signal on beam waist position in pig eye where the positive sign on the Depth axis corresponds to the position inside the cornea and the zero position corresponds to the cornea-glass interface.
DETAILED DESCRIPTION OF THE INVENTION
Although the present invention and its advantages have been described in detail, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims. Moreover, the scope of the present application is not intended to be limited to the particular embodiments of the process, machine, manufacture, composition of matter, means, methods and steps described in the specification. As one of ordinary skill in the art will readily appreciate from the disclosure of the present invention, processes, machines, manufacture, compositions of matter, means, methods, or steps, presently existing or later to be developed that perform substantially the same function or achieve substantially the same result as the corresponding embodiments described herein may be utilized according to the present invention. Accordingly, the appended claims are intended to include within their scope such processes, machines, manufacture, compositions of matter, means, methods, or steps.
Referring now to FIG. 1 , a schematic view of one embodiment of an aplanation lens position and alignment system according to the present invention is depicted. The major components of the system 10 are a laser system 12 and an aplanation lens 14 . To accomplish laser ophthalmic surgery, the laser system 12 includes a laser source 16 which is mounted on the system housing (not shown). This laser source 16 generates a laser beam 20 from an origination point 22 , as shown in FIG. 1 . In one embodiment of the invention, the laser beam 20 has a pulse duration less than three hundred picoseconds (<300 ps) and a wavelength of between approximately 400-3000 nm. Preferably, the laser operates at 1053 nm, with a pulse duration of approximately 600-800 femtoseconds, and a repetition rate of 10 kHz. FIG. 1 shows that the laser beam 20 is used to define a z-axis 24 that is parallel to the path of the laser beam. As discussed herein, the inventive system and method are shown through the use of an aplanation lens. However, the position and alignment of other objects may be determined. Thus, the inventive system and method should be construed to cover any other object for which one wants to determine its position and alignment in relation to a laser beam.
Determination of Object Alignment
Referring to FIG. 2 , a schematic view of a laser beam 20 and tilted aplanation lens 14 is shown. To determine the position and alignment of the aplanation lens 14 in relation to the z-axis 24 of the laser beam, the focal point of the laser beam is first directed to a point on the z-axis 24 that is below the aplanation lens 14 . This first point is referred to as z 0 26 . The focal point of the laser beam is then moved along a closed pattern. The closed pattern is a shape where the laser beam focal point will travel. As the laser beam focal point travels along the closed pattern, the laser beam is fired. A spot distance of the laser beam may be set by the laser system such that the laser beam is fired on the closed pattern for a particular distance. For example, in one embodiment, the spot distance may be set to 1 μm-30 μm. For a particular object and laser source being utilized, the spot distance may be different than the aforementioned example.
In a preferred embodiment, the closed pattern is a circular shape having a diameter (“D”) 28 . The closed pattern is made in a plane perpendicular to the z-axis 24 . For an ophthalmic procedure using the aplanation lens, the closed pattern should have a diameter sufficiently wide, such that after the position of the aplanation lens and alignment determination is completed, a cornea then pressed against the aplanation lens does not contact an area of the closed pattern. In certain tests using an aplanation lens, a 7-9.5 mm diameter was utilized for the closed pattern and was found sufficiently wide. Other diameters of course may be utilized depending on the type of procedure and the particular object for which alignment is being determined.
After the first closed pattern is completed, the focal point of the laser beam is then adjusted up the z-axis 24 a set distance z x 30 to another starting point z 1 32 where z 1 =z 0 +z x . The value for the z x distance between each successive closed pattern is also referred as a separation layer distance. For each pass of the closed pattern, the laser beam focal point will move a distance along the z-axis based on the separation layer setting.
The focal point of the laser beam is then again moved along a similar closed pattern in a plane perpendicular to the z-axis 24 and then adjusted up the z-axis to z 2 34 where Z 2 =z 1 +z x . The steps of moving the focal point along the closed pattern and adjusting the starting point of the focal point of the laser beam up the z-axis 24 are repeated n times, until the focal point of the laser along the closed pattern makes contact with the aplanation lens 14 , causing a first plasma spark, at z n 36 , which may be detected. The particular manner in which the plasma sparks are detected is described below.
A CPU utilizing software preferably instructs the movement of the focal point of the laser beam. While moving the laser beam, the software may record the coordinates of the focal point. For example, as the closed pattern is followed, the specific x-, y- and z-coordinates of the laser beam focal point will be known. This is true because it is the software instructing the movement of the focal point through the closed pattern at particular coordinates. Thus, the laser system software may be configured or programmed to record the x, y, and/or z-coordinates based on certain defined events.
The particular z n when the first plasma spark occurs is recorded. The steps of moving the focal point along the closed pattern and adjusting the starting point of the focal point of the laser beam up the z-axis 24 are repeated m times, until the focal point of the laser contacts the aplanation lens 14 along the entire closed pattern, causing a plasma spark along the entire closed pattern, at z j 38 , where j=m+n, which is detected. The point z j is recorded. The particular manner in which detection of the completion of the closed pattern occurs is later described below.
For a better understanding of the inventive method, FIG. 3 sets out in flowchart form certain steps of the present invention. In step 201 , the focal point of the laser beam is set at a point on the z-axis below the aplanation lens, z 0 . Next in step 202 , the focal point of the laser beam is moved along a pattern, preferably in the shape of a circle having a diameter D, in a plane perpendicular to the z-axis. During the movement of the laser beam along the pattern, a check is made for the occurrence of a plasma spark. If a plasma spark is detected, then in Step 204 , the z n location is recorded. Likewise, the x n and y n coordinates may also be recorded. If no spark is detected, when the pattern is complete, then in Step 203 the focal point of the laser beam is moved up the z-axis a determined distance, z x . Step 202 is repeated until a plasma spark is detected.
In Step 205 , the focal point of the laser beam is moved up the z-axis a determined distance, z x . Then in Step 206 , the focal point of the laser beam is moved along a predetermined pattern, preferably in the shape of a circle having a diameter D, in a plane perpendicular to the z-axis. During the movement of the laser beam along the pattern, a check is made for the occurrence of a completion of a plasma spark for the circumference of the circle. If a completion of the entire circle is detected, then in Step 207 , the z j location is record. Also, the location of the x n and y n coordinates may also be recorded. If the completion of the plasma spark for the circumference of the circle is not completed, then Step 205 repeats. Lastly, in Step 208 , the tilt of the aplanation lens can be determined.
Visual Detection of Plasma Spark
The plasma spark may be visually detected by the operator. For example, a foot switch operated by the user of the laser system may identify when the plasma spark occurs. The movement of the focal point along the closed pattern is performed as discussed above. When the user first detects the plasma spark, a foot switch may be activated. The activation of the switch signals the computer to record the z-axis coordinate of the first plasma spark. When the user detects completion of the closed pattern by watching a complete plasma spark along the closed pattern, the user activates the foot switch again. Thus, the second z-axis coordinate is obtained. With both coordinates the tilt of the lens may then be determined.
Electronic Detection of Plasma Spark
In another embodiment, a photodetector connected with the laser system may be utilized to detect the occurrence of plasma sparks. The photodetector can be any device capable of determining such an event. For example, a photodetector may include a photodiode, CCD, photomultiplier, phototransistor, or any device suited for detecting the occurrence of a plasma spark.
The photodetector can be utilized to determine a first occurrence of the plasma spark and the completion of the closed pattern, thereby giving first and second z-axis coordinates which then may be used to calculate the tilt of the aplanation lens.
In one embodiment, a photodetector is connected with the laser system. The photodetector is placed in a position on, adjacent to, or near the laser system where the photodetector can detect the plasma spark. The photodetector generates a voltage or signal when the laser beam creates a plasma spark in the aplanation lens. When the photodetector first detects a plasma spark, then the laser system software records the first z-axis coordinate.
For the second z-axis position at the completion of the plasma spark along all of the closed pattern, the identification of the completion may be determined in different ways. One way to determine the completion of the closed pattern is to evaluate the voltage or signal from the photodetector and compare it with a known time for completion of the closed pattern. The laser system software may be configured to calculate the duration of time necessary to complete a given closed pattern. At the completion of the closed pattern, the voltage or signal of the photodetector can be evaluated. If the voltage or signal of the photodetector indicates that a plasma spark is occurring at the end of the closed pattern, then we know that a plasma spark has occurred at the end of the closed pattern. With this known completion point, then the second z-axis position can be determined.
Information about the orientation of tilt can be obtained by determining the x-y coordinate where the most intense plasma spark is detected within the object. The strongest signals from the plasma spark correspond to the deepest position within the object.
Video Image Detection of Plasma Spark
In an alternative embodiment, a video camera is utilized to capture images of the aplanation lens as plasma sparks are being generated. By comparing sequences of captured images, it is then possible to use the image information to determine the tilt of the aplanation lens. In one embodiment, an NTSC camera with a rate of 30 frames per second was utilized. However, other video cameras with different frame rates may be utilized.
In general, video images are searched for plasma spark as the laser beam focal point is scanned upwards toward the bottom surface of the aplanation lens. Similar to the visual/manual and photodetector methods described above, the laser beam focal point is set at a beginning point such that the focal point of the laser beam does not create a plasma spark. The laser beam focal point is then moved through successive closed patterns whilst first and second z-axis coordinates are determined.
In one embodiment, 8-bit grey scale images are captured and evaluated. A grey scale image has pixels with a grey scale value between 0 (black) and 255 (white). The grey scale values ranging between 0-255 indicates the brightness for a particular pixel. For example, if an area of certain pixels of an image had a value of zero or near zero, this would indicate that portion of the image was dark. If an area of certain pixels had a value of 255 or near 255, this would indicate that portion of the image was very light. Thus the higher the number for the pixels of a certain area of an image, the brighter (or whiter) that area would be. Based on this pixel valuation model, the occurrence of a plasma spark can be detected. When a plasma spark occurs and an image is taken, more higher-ranging pixels would exist than would exist if the plasma spark was not occurring. This is because the plasma spark creates a very bright light that would be noted in the image.
Referring now to FIG. 4 , a graph is shown illustrating an aplanation lens tilt determination utilizing the iterative image comparison method. The frequency of image frames to be captured is set at a periodic time interval. The x-axis on the graph represents the frame number of a captured video image. In the illustrated example, a focal point of the laser beam was set in a circular pattern with a diameter of 7.8 mm. The spot distance of the laser was set at 3 μm. An energy level of 3 μJ energy for the laser source was utilized. The y-axis on the graph represents the Total Compared Image Value, for those pixels above a certain threshold number. In the experiment, the threshold number was set at a value of 20.
The plasma spark line 60 shows the processing of several frames of images before, during and after the occurrence of plasma sparks. The video image process begins with the capture of a first video image. After a preset time interval, the next image is captured. The first video image and the second video image are then compared to one another.
Each pixel value (0-255) from the first image is added together to obtain a first image value. Also, each pixel value (0-255) from the second image is added together to obtain a second image value. If a threshold value is set, then only those pixel values having a value higher than the threshold value would be added together. Utilizing a threshold value reduces the light noise dramatically and allows the process to run at full room light and high illumination of the aplanation lens.
The first image value is subtracted from the second image value giving a Total Compared Image Value. The Total Compared Image Value, which is stored in memory of the CPU, may be plotted on a graph. Although not shown on the graph, for a Total Compared Image Value, the laser system software would also know or have stored the x-,y-, and z-coordinates for the particular image frame. Thus, for a particular Total Compared Image Value, the x-, y-, and z-coordinates may be associated with the particular Total Compared Image Value.
As illustrated in FIG. 4 , prior to about frame 860 , no plasma spark has occurred. On the y-axis, the plasma spark line is shown as a linear line having a Total Compared Image Value of zero. During the process the ambient light is preferably maintained at a consistent level. As shown in FIG. 4 , literally no noise signal exists before the plasma starts, even at full room light. As the plasma spark starts, from about frame 860 , the increasing mountains of signals occur as is shown on plasma spark line 60 .
The spacing between each side of a mountain on the plasma spark line 60 represents the completion of one full circle. The first mountain 64 indicates the first occurrence of a plasma spark. The exact x-y coordinates at any mountain top gives the tilt axis. The first time the mountain does not go down to 0 (or some low threshold), the plasma circle is completed (second or final contact).
To more easily detect the first and the second contact, the plasma spark line 60 is further processed in the following way. A binary signal (or plasma spark state) may be created with the following process. The binary signal or plasma spark state is set to one 1 if the Total Compared Image Value is over a certain value. If for a particular image frame, the Total Compared Image Value is greater than the set value (in the example it was set to 1), then for that frame the plasma spark state would be set to 1 or True. If the Total Compared Image Value is below the set value, then the plasma spark state would be set to 0 or False. In this manner, as shown on the graphed plasma spark state line 62 , the state of the plasma spark for a particular image frame and time would be known.
The distance between two consecutive mountain peaks is equivalent to the layer separation parameter defined by the laser software. This is usually in the order of 2-10 micrometers but may vary according to the desired accuracy. For each mountain peak, the closed pattern makes one revolution and for each revolution, the focus position moves upward in the z-direction in the amount of the layer separation. The amount of peaks contained between the first plasma spark 64 and the full closure of the pattern 61 determines the following Δz=|z (1st plasma) −z (Full closure) |. The determination of the tilt axis is dependent on the position of the x-y coordinate at the time the mountain peak is present. An axis line can be drawn 180° from the x-y position of the mountain peak, relative to the center of the circular pattern. The determination of tilt is as follows θ=tan −1 (Δz/D) where Δz is the difference of z position between the first plasma spark 64 and the full closure of the pattern 61 as detected by the CCD camera and D is the diameter of the circular pattern.
Calculation of Tilt of the Lens and Z-Coordinate Offset
The alignment of the aplanation lens 14 in relation to the z-axis 24 is then calculated by using the following equation: θ=tan −1 (Δz/D); where θ 40 is the angle between the aplanation lens 14 and a plane perpendicular to the z-axis 24 , and wherein Δz is the difference between the first z-axis location and the second z-axis location, and D is the diameter of the predetermined pattern. The angle φ42 between the z-axis 24 and the aplanation lens 14 is 90−θ.
Although the methods above discuss obtaining a second z-axis location by electronic or manual means, the second z-axis may be calculated. After the first z-axis location is found, then the second z-axis is calculated. The second z-axis location would be the point on a circular predetermined pattern opposite the first z-axis location. This holds true since, by using a circular predetermined pattern, the first z-axis location is the lowest point of the tilt (if scanning the laser from the below the aplanation lens upwards) and the highest point would always be the point on the predetermined pattern opposite the first z-axis location. Thus, the first z-axis location may be determined (along with the x-,y-coordinates) and then using the known diameter of the circular pattern, the second z-axis location may be determined.
Utilizing the circular predetermined pattern, by finding the first and second z-axis location, the plane of the contact surface of the aplanation lens can be determined along with the orientation of the plane about the z-axis.
Determining the tilt of the aplanation lens 14 in relation to the laser beam is very useful. In the field of ophthalmic surgery, a more precise photodisruption of tissue of the eye can be achieved. For example, it is important in ophthalmic laser surgery procedures that photodisruption be very precise. Whilst utilizing an aplanation lens, a patient's cornea is pressed against the lens, thereby flattening the cornea against the glass surface of the lens. With a perfectly calibrated laser system, using a perfectly formed aplanation lens, the contact surface (the contact plane) of the aplanation lens would be perpendicular to the laser beam. This would allow the focusing of the laser beam at a z-coordinate in the cornea in one x-y location to be the same z-coordinate if the laser focus was moved to another x-y location. But if the aplanation lens were tilted, this would cause the focus of the laser at one x-y location in the tissue of eye to actually be different than another x-y location in the tissue of the eye. But if the tilt of the aplanation lens were known, then the z-coordinate (or focal depth) for a particular x-y location could be offset or compensated for to take into consideration the lens tilt.
Three-Point Method to Determine Tilt of an Object
An alternative way to determine the tilt of a surface of an object in relation to a z-axis of a laser beam is to determine three points of an object. A laser beam may be focused at a z-axis point such that the focal point of the laser beam does not contact the object. This may be at any x-,y-coordinate. The laser beam z-axis focal point is incrementally moved a specified distance and the laser fired. The focal point is moved again a set distance and fired. This continues until a first plasma spark is detected. The detection may be by any manner, including the method described above, manually, via photodetector, and video image comparison. The first point (its x-,y-, and z-coordinates) is recorded or saved in memory or storage by the laser system.
The laser system then directs the laser beam to a second x,y-coordinate. The focal point of the laser is then moved to a z-axis point such that the focal point of the laser beam does not contact the object. Then again, the laser beam z-axis focal point is incrementally moved a specified distance and the laser fired. This continues until a second plasma spark is detected. The second point (its x-,y-, and z-coordinates) is recorded or saved in memory or storage by the laser system.
The laser system then directs the laser beam to a third x,y-coordinate. The focal point of the laser beam is then moved to a z-axis point such that the focal point of the laser beam does not contact the object. Then again, the laser beam z-axis focal point is incrementally moved a specified distance and the laser fired. This continues until third plasma spark is detected. The third point (its x-,y-, and z-coordinates) is recorded or saved in memory or storage by the laser system.
Having now determined three surface points of a surface of the object, a plane of the surface in relation to a z-axis of the laser be would be known. Knowing the plane of the object, then subsequent procedures can use the plane as a reference plane for z-offset.
Also, the distance between two points may be calculated by detecting a first plasma spark at the surface of a first object, and detecting a second plasma spark at the surface of a second object. The detection of the first and second plasma spark may be detected by the methods described above. The z-axis coordinate of each plasma spark is then used the determined the distance between the surface of each object where the plasma spark is detected.
Z-offset and Gain Calibration Procedure
By determining the alignment (or tilt) of a surface of an object in relation to a laser beam (or z-axis of the laser beam), a z-offset value may be utilized for subsequent laser system operations. For a particular x-,y-coordinate, the z-coordinate may be offset a particular distance to allow the focus of the laser beam to be at a plane parallel to the plane of the tilt of the object.
In one embodiment, a software program commands a displacement of a focusing assembly of a laser system by writing a voltage to a Digital/Analog card. A z-Galvo will in turn move the focusing assembly to the desired focal depth position based upon the commanded voltage by directing a current to the motor-driven focusing assembly. A linear encoder positioned within the laser system senses the linear movement of the focusing assembly. An intelligent controller interoperating with the host computer and software program utilizes a sensor to read an encoder strip attached to the focusing assembly. As the lens is moved into position, encoder feedback is provided by an intelligent controller and an actual focusing assembly position is obtained.
To measure the z-gain, a second point needs to be measured. Measurement of the z-gain may be achieved by utilizing a second object, such as glass that has a substantially planar top and bottom surface that are substantially parallel to one another.
In one experiment, a 160 μm thick microscope slide was mounted against the contact glass of the aplanation lens contact plane. The slide was made out of borosilicate glass (Corning 0211) with a refractive index of 1.521 at 1060 nm. The flatness of the slide was measured. It had parallel top and bottom planar surface within ±1 μm over the whole slide (22×22 mm). The slide is pressed against the contact glass by slightly pushing from below with a rod and a round plastic screw head on top of it. This results in an air gap below the slide at the circle diameter of the closed pattern. The circular closed patterns are now cut like in the z-offset procedure except that the starting depth is set at 200 μm. This simulates focusing the laser beam into the corneal tissue. To correct for the human cornea (n=1.377), the 160 μm thick borosilicate glass corresponds to a 146 μm thick cornea layer. This was simulated with the WinLase™ 3.0 Pro software using a Gaussian beam with an f#=1.48 focusing number of the objective lens.
With the correction in place, the software is expected to report an offset of 146 μm if the z-offset was zeroed before a procedure. If the number is off, then the z-scale factor (z-gain) is off by the following amount: New z-scale factor=(146 μm/measured offset)*old z-scale factor
After correcting the z-scale factor in the laser system settings, the z-offset needs to be redone because it might not fall together with a O-voltage on the z-scanner and therefore can be affected by a gain change.
Interferometric Laser Focus Detection
Another way to measure the position of a surface of an object relative to a laser beam is utilizing an interferometer. After measurement, the laser system may then account for variances of height dimensions of the object and set offset parameters for the focal depth. Offset parameters in software allow canceling the effect of variances of height dimensions of the aplanation lens, thereby delivering consistent surgical depths.
This method utilizes the curvature of the wave front of a laser reflected back from the glass surface of the aplanation lens. The curvature of the wave front is measured by an interferometer.
There are two ways to relate fringe curvatures to focal depth. First, by knowing the geometry of the optics and the interferometer, the fringe patterns can be exactly calculated and related to focal depths. However this method would require a precise knowledge of the beam geometry.
A second, more practical method is to calibrate the machine to measurable focal positions. This is the approach we followed with our implementation. In one implementation the machine is set to cut patterns in a glass sample at different depths while the interference patterns are simultaneously recorded. Then the cutting depths in the sample are measured with the help of a microscope and related to the curvatures of the fringes as previously recorded.
The interferometer utilizes a reference beam, which is split directly from the laser beam before entering the delivery system, and a measured beam, which passes through the delivery system. The reference beam is essentially a parallel beam. The measured beam is part of the laser beam that reflects back from the optical surface of the aplanation lens. The reflected beam retraces the optical path through the laser focusing optics and the scanner system in a backward direction.
If the reflecting surface is at the focal point, then the back-reflected beam retraces the same path all the way through the delivery system and leaves it as a parallel beam. This beam can be interfered with a reference beam. In this case, both beams are parallel and they make an interference pattern with straight fringes. On the other hand, if the aplanation lens is out of focus, then the back-reflected beam does not trace the very same path backwards, and it leaves the delivery system as a convergent or divergent beam. Convergent or divergent beams combined with parallel beams produce curved fringe patterns. The position information of the focus can be extracted from the interference pattern, essentially from the sign and magnitude of the curvature of the fringes.
In one embodiment an image processing method is followed. A raw image is first captured then filtered and enhanced by convoluting the image with a spatially periodic kernel. This process smoothes imperfections of the image which are of random nature for example due to dust particles on the optics. At the same time the spatial periodicity of the kernel enhances the contrast of the interference pattern with the right periodicity.
The next step of the image processing is edge detection by Canny Edge Detection algorithm. (Canny, A. (1986) A computational approach to edge detection. IEEE Trans. PAMI, 8:769-698.)
The edge fragments are then analyzed. Fragments shorter than a given length are discarded. The longer fragments are fitted with a polynomial curve. The second order coefficient of the polynomial gives the curvatures of the individual fringes. Finally curvatures from individual fringes are averaged.
In one embodiment, the interference pattern is captured by a video camera and frame capture software described above. The pattern may be analyzed by computer software. The curvature of the fringe pattern is extracted and the focal position calculated. To determine the focal position, when the fringe pattern has parallel beams, then the laser beam is focused. One way to determine how much the laser beam is out of focus, is the mass calibrate various curvatures of the fringe pattern and measure the focal distance. For example, a micrometer may be used to determine the various focal distance for a particular fringe curvature. For a particular fringe curvature, a focal depth value may be stored in a table. Then for subsequent uses of the laser system, a particular fringe pattern curvature, may be determined and then looked up in the table to determine the focal position. Alternatively, for the curvature behavior could be evaluated to determine an algorithm, such that for a particular fringe curve a focal position could be derived.
Various experiments were performed to determine the fringe patterns and the relation to the focus of the laser beam. In one experiment, the measured interference fringe pattern curved downwards. This is shown in FIG. 5A . The focus of the laser beam was found to be 20 μm above the contact plane of the aplanation lens. In another experiment, the measured interference fringe pattern formed straight lines. This is shown in FIG. 5B . The focus of the laser beam was found to be on the glass surface of the aplanation lens. In a third experiment, the measured fringe pattern curved upwards. This is shown in FIG. 5C . The focus of the laser beam was found to be 10 μm below the contact plane of the aplanation lens.
Measuring one point at the optical center of the field of view of the aplanation lens provides a z-offset number. This method may be used to measure three point measurements of the contact plane of the aplanation lens to determine the tilt of the focal plane.
This interferometric method not only has the advantage of determining the focal point of a plane of an aplanation lens, but also may be used to detect laser beam distortions. Some of these distortions may be i) inherent to the design of the laser system optics, such as spherical and chromatic aberrations, ii) coming from the laser, such as spatial chirp, iii) distortions from component level aberrations, such as out of spec mirror flatness, or iv) distortions due to system misalignment.
If the measured focal position of the laser is outside of a pre-determined acceptable range, the laser system software may be configured to instruct the servo system to modify offset values for the z-axis focal position and then bring the laser system into an acceptable range. Also, the software parameters for a surgical pattern may be configured to accommodate hardware offset and tilt of the laser focal plane relative to a surgical plane.
Nonlinear Frequency Conversion
Another method to determine the depth of focus of a laser beam is utilizing a photo multiplier with band pass filter to monitor the nonlinear frequency signal generated by laser beam. The laser system computer monitors the dependence of the signal on depth of focal point. Change in the signal indicates the interface between the lower surfaces of the aplanation glass and the cornea. Nonlinear frequency conversion method is noninvasive. The depth calibration can be performed while the aplanation lens is docked on a patient's eye thus reducing the error introduced by mechanical backlashes.
This method is based on usage of different nonlinear effects in glass and the cornea to generate light at frequencies other than the frequency of the laser beam. The effects can include, but not be limited to, second harmonic generation, third harmonic generation, stimulated Raman, white light generation and others. At laser beam intensities close to photodisruption threshold, conversion efficiencies of mentioned nonlinear processes are high enough to generate a detectable signal. These signals have quadratic or higher order dependence on input intensity and will be confined in space to the beam waist and will therefore increase the accuracy of interface detection.
A photo multiplier with a band pass filter is attached to the laser system. The computer of the laser system monitors the dependence of the signal on focal point depth. A change in the signal indicates the interface between the lower surface of the aplanation lens and cornea. Accuracy of better than 5 microns may be achieved.
Referring to FIG. 6 , the method may be further described. FIG. 6 is a graph illustrating dependence of second harmonic signal on beam waist position in pig eye where the positive sign on the Depth axis corresponds to the position inside the cornea and the zero position corresponds to the cornea-glass interface. To determine the focal point of the laser beam at the interface of the aplanation lens and the cornea, one takes half the max of the signal. This is shown on the graph on at the point of 0 microns. If the focal spot moves out into the aplanation lens, then the signal decreases, if the focal point goes into the cornea, then the signal increases. This can be done because, with certain laser beams, such as a femtosecond mode-locked laser beam can be described by its confocal parameter. In other words, the laser beam has a focal point with a particular length range. It is when half the length of the focal point range is inside the cornea that the signal would be at the half max of the signal.
In one experiment, the method was tested with an aplanation lens in contact with a pig eye. The energy level of laser was reduced to 0.2 □J so that the fluence is below the optical damage threshold of the glass or pig eye, but high enough to generate second harmonic in cornea. While scanning the depth of the focal point, the intensity of second harmonic decreases by factor of 50 from cornea to glass interface. This enabled localization of the focal point at the cornea-glass interface with accuracy of better than +/−5.0 microns. Results are presented on FIG. 6
In another experiment, the method was tested with an aplanation lens having a piece of plastic attached to the lens. The piece of plastic was used to simulate a cornea being in contact with the aplanation lens. The energy level of the laser system was reduced to 0.7 μJ so that the fluence is below the optical damage of the glass, but high enough to generate white light. While scanning the depth of the focal point, the intensity of while light changes by factor of two from glass to plastic. This enable the localization of the focal spot position at the glass-plastic interference with an accuracy of 5 micron.
The inventive systems and methods described above are well adapted for a system to determine the position and alignment of an aplanation lens in relation to a laser system. However, it shall be noted that the foregoing description is presented for purposes of illustration and description, and is not intended to limit the invention to the form disclosed herein. Consequently, variations and modifications to the systems and processes commensurate with the above teachings and teaching of the relevant art are within the scope of the invention. These variations will readily suggest themselves to those skilled in the relevant art and are encompassed within the spirit of the invention and the scope of the following claims.
Moreover, the embodiments described are further intended to explain the best modes for practicing the invention, and to enable others skilled in the art to utilize the invention in such, or other, embodiments and with various modifications required by the particular applications or uses of the present invention. It is intended that the appending claims be construed to included alternative embodiments to the extent that it is permitted by the prior art. | 1a
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[0001] This application claims the benefit of U.S. Provisional Application Ser. No. 60/937,788 filed on Jun. 29, 2007. This invention concerns a synergistic herbicidal composition containing (a) a substituted phenoxy alkanoic acid derivative and (b) a glyphosate derivative. More particularly, the invention concerns a synergistic herbicidal composition containing (a) a 2,4-dichlorophenoxy acetic acid (2,4-D) or 2,4-dichlorophenoxy propionic acid (dichlorprop) derivative and (b) a glyphosate salt.
FIELD OF THE INVENTION
Background of the Invention
[0002] The protection of crops from weeds and other vegetation which inhibit crop growth is a constantly recurring problem in agriculture. To help combat this problem, researchers in the field of synthetic chemistry have produced an extensive variety of chemicals and chemical formulations effective in the control of such unwanted growth. Chemical herbicides of many types have been disclosed in the literature and a large number are in commercial use.
[0003] In some cases, herbicidal active ingredients have been shown to be more effective in combination than when applied individually and this is referred to as “synergism.” As described in the Herbicide Handbook of the Weed Science Society of America, Seventh Edition, 1994, p. 318, “‘synergism’ [is] an interaction of two or more factors such that the effect when combined is greater than the predicted effect based on the response of each factor applied separately.” The present invention is based on the discovery that substituted phenoxy alkanoic acid derivatives and glyphosate derivatives, already known individually for their herbicidal efficacy, display a synergistic effect when applied in combination.
[0004] The herbicidal compounds forming the synergistic composition of this invention are independently known in the art for their effects on plant growth.
[0005] For example, 2,4-D, 2,4-dichlorophenoxy acetic acid, is a selective systemic herbicide used to control annual and perennial broad-leaved weeds in various crops as well as in non-crop land, including areas adjacent to water. It is commercially available, for example, as an ester such as Esteron™ herbicide from Dow AgroSciences and as a salt such as DMA-4™ herbicide from Dow AgroSciences. Dichlorprop, 2,4-dichlorophenoxy propionic acid, is a selective systemic herbicide used to control annual and perennial broad-leaved weeds in various crops as well as in non-crop land. It is commercially available, for example, as a salt such as Dicopur™ DP herbicide or Duplosan™ DP herbicide from Nufarm.
[0006] Glyphosate, N-(phosphonomethyl)glycine, is a non-selective systemic herbicide used to control annual and perennial grasses and broad-leaved weeds, particularly in crops that have been genetically modified to be tolerant of glyphosate. It is commercially available, for example, as Roundup™ herbicide from Monsanto or Glyphomax Plus™ herbicide from Dow AgroSciences.
SUMMARY OF THE INVENTION
[0007] The present invention concerns a synergistic herbicidal mixture comprising an herbicidally effective amount of (a) a substituted phenoxy alkanoic acid derivative of the formula
[0000]
[0008] wherein
X represents Cl or CH 3 ; R independently represents H or CH 3 ; and n is an integer from 1-3;
and (b) a glyphosate derivative. Preferred substituted phenoxy alkanoic acids are 2,4-D and dichlorprop. The compositions may also contain an agriculturally acceptable adjuvant or carrier.
[0012] The present invention also concerns a method of controlling the growth of undesirable vegetation, particularly in crops that are tolerant, either naturally or through genetic modification, to the active herbicides of the synergistic mixture, and the use of this synergistic composition.
[0013] The species spectrums of the compounds of the synergistic mixture, i.e., the weed species which the respective compounds control, are broad and highly complimentary. While glyphosate is a non-selective herbicide, resistance to glyphosate by several weed species, for example, horseweed ( Conyza canadensis , ERICA), has been well documented. The synergistic mixture of 2,4-D or dichlorpropand glyphosate is particularly effective at controlling these glyphosate resistant weeds. Other weeds which the mixture of 2,4-D or dichlorpropand glyphosate synergistically control include ivyleaf morning glory ( Ipomoea hederacea ; IPOHE), Canada thistle ( Cirsium arvense ; CIRAR), prickly sida ( Sida spinosa ; SIDSP), velvetleaf ( Abutilon theophrasti ; ABUTH), common ragweed ( Ambrosia artemesifolia ; AMBEL), spiderwort ( Commelina benghalensis ; COMBE), hemp sesbania ( Sesbania exaltata ; SEBEX), field bindweed ( Polygonum convolvulus ; POLCO), and common waterhemp ( Amaranthus rudis ; AMATA).
DETAILED DESCRIPTION OF THE INVENTION
[0014] The term herbicide is used herein to mean an active ingredient that kills, controls or otherwise adversely modifies the growth of plants. An herbicidally effective or vegetation controlling amount is an amount of active ingredient which causes an adversely modifying effect and includes deviations from natural development, killing, regulation, desiccation, retardation, and the like. The terms plants and vegetation include germinating seeds, emerging seedlings and established vegetation.
[0015] Herbicidal activity is exhibited by the compounds of the synergistic mixture when they are applied directly to the plant or to the locus of the plant at any stage of growth or before planting or emergence. The effect observed depends upon the plant species to be controlled, the stage of growth of the plant, the application parameters of dilution and spray drop size, the particle size of solid components, the environmental conditions at the time of use, the specific compound employed, the specific adjuvants and carriers employed, the soil type, and the like, as well as the amount of chemical applied. These and other factors can be adjusted as is known in the art to promote non-selective or selective herbicidal action. Generally, it is preferred to apply the composition of the present invention postemergence to relatively immature undesirable vegetation to achieve the maximum control of weeds.
[0016] The substituted phenoxy alkanoic acid derivatives in which R is CH 3 contain asymmetric carbon atoms and are capable of existing as a racemic mixture such as dichlorprop or as an individual enantiomer or an enriched enantiomeric mixture such as dichlorprop-P
[0017] By substituted phenoxy alkanoic acid derivatives and glyphosate derivatives is meant the acids themselves and their agriculturally acceptable esters and salts.
[0018] Suitable salts include those derived from alkali or alkaline earth metals and those derived from ammonia and amines. Preferred cations include sodium, potassium, magnesium, and aminium cations of the formula:
[0000] R 1 R 2 R 3 NH +
[0000] wherein R 1 , R 2 , and R 3 each, independently represents hydrogen or C 1 -C 12 alkyl, C 3 -C 12 alkenyl or C 3 -C 12 alkynyl, each of which is optionally substituted by one or more hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio or phenyl groups, provided that R 1 , R 2 , and R 3 are sterically compatible. Preferred amine salts are those derived from ammonia, methylamine, dimethylamine, trimethylamine, isopropylamine, monoethanolamine, diethanolamine, triethanolamine, triisopropanolamine, 2-methylthiopropylamine, bisallylamine, 2-butoxyethylamine, morpholine, cyclo-dodecylamine, or benzylamine. Amine salts are often preferred because they are water-soluble and lend themselves to the preparation of desirable aqueous based herbicidal compositions.
[0019] Suitable esters include those derived from C 1 -C 12 alkyl, C 3 -C 12 alkenyl or C 3 -C 12 alkynyl alcohols, such as methanol, iso-propanol, butanol, 2-ethylhexanol, butoxyethanol, methoxypropanol, allyl alcohol, propargyl alcohol or cyclohexanol.
[0020] In the composition of this invention, the weight ratio on an acid equivalent basis of the substituted phenoxy alkanoic acid component to glyphosate component at which the herbicidal effect is synergistic lies within the range of between about 5:1 and about 1:48. Preferably the weight ratio of the substituted phenoxy alkanoic acid component to the glyphosate component lies within the range of between about 3:1 and about 1:12 with a weight ratio of between about 1:1 and about 1:12 being especially preferred.
[0021] The rate at which the synergistic composition is applied will depend upon the particular type of weed to be controlled, the degree of control required, and the timing and method of application. In general, the composition of the invention can be applied at an application rate of between about 100 grams of acid equivalents per hectare (g ae/ha) and about 2000 g ae/ha based on the total amount of active ingredients in the composition. An application rate between about 200 g ae/ha and about 1000 g ae/ha is preferred. In an especially preferred embodiment of the invention, the 2,4-D component is applied at a rate between about 35 g ae/ha and about 560 g ae/ha, the dichlorprop component is applied at a rate between about 35 g ae/ha and about 280 g ae/ha and the glyphosate component is applied at a rate between about 100 g ae/ha and about 750 g ae/ha.
[0022] The components of the synergistic mixture of the present invention can be applied either separately or as part of a multipart herbicidal system.
[0023] The synergistic mixture of the present invention can be applied in conjunction with one or more other herbicides to control a wider variety of undesirable vegetation. When used in conjunction with other herbicides, the composition can be formulated with the other herbicide or herbicides, tank mixed with the other herbicide or herbicides or applied sequentially with the other herbicide or herbicides. Some of the herbicides that can be employed in conjunction with the synergistic composition of the present invention include: amide herbicides such as allidochlor, beflubutamid, benzadox, benzipram, bromobutide, cafenstrole, CDEA, chlorthiamid, cyprazole, dimethenamid, dimethenamid-P, diphenamid, epronaz, etnipromid, fentrazamide, flupoxam, fomesafen, halosafen, isocarbamid, isoxaben, napropamide, naptalam, pethoxamid, propyzamide, quinonamid and tebutam; anilide herbicides such as chloranocryl, cisanilide, clomeprop, cypromid, diflufenican, etobenzanid, fenasulam, flufenacet, flufenican, mefenacet, mefluidide, metamifop, monalide, naproanilide, pentanochlor, picolinafen and propanil; arylalanine herbicides such as benzoylprop, flampropand flamprop-M; chloroacetanilide herbicides such as acetochlor, alachlor, butachlor, butenachlor, delachlor, diethatyl, dimethachlor, metazachlor, metolachlor, S-metolachlor, pretilachlor, propachlor, propisochlor, prynachlor, terbuchlor, thenylchlor and xylachlor; sulfonanilide herbicides such as benzofluor, perfluidone, pyrimisulfan and profluazol; sulfonamide herbicides such as asulam, carbasulam, fenasulam and oryzalin; antibiotic herbicides such as bilanafos; benzoic acid herbicides such as chloramben, dicamba, 2,3,6-TBA and tricamba; pyrimidinyloxybenzoic acid herbicides such as bispyribac and pyriminobac; pyrimidinylthiobenzoic acid herbicides such as pyrithiobac; phthalic acid herbicides such as chlorthal; picolinic acid herbicides such as aminopyralid, clopyralid and picloram; quinolinecarboxylic acid herbicides such as quinclorac and quinmerac; arsenical herbicides such as cacodylic acid, CMA, DSMA, hexaflurate, MAA, MAMA, MSMA, potassium arsenite and sodium arsenite; benzoylcyclohexanedione herbicides such as mesotrione, sulcotrione, tefuryltrione and tembotrione; benzofuranyl alkylsulfonate herbicides such as benfuresate and ethofumesate; carbamate herbicides such as asulam, carboxazole chlorprocarb, dichlormate, fenasulam, karbutilate and terbucarb; carbanilate herbicides such as barban, BCPC, carbasulam, carbetamide, CEPC, chlorbufam, chlorpropham, CPPC, desmedipham, phenisopham, phenmedipham, phenmedipham-ethyl, propham and swep; cyclohexene oxime herbicides such as alloxydim, butroxydim, clethodim, cloproxydim, cycloxydim, profoxydim, sethoxydim, tepraloxydim and tralkoxydim; cyclopropylisoxazole herbicides such as isoxachlortole and isoxaflutole; dicarboximide herbicides such as benzfendizone, cinidon-ethyl, flumezin, flumiclorac, flumioxazin and flumipropyn; dinitroaniline herbicides such as benfluralin, butralin, dinitramine, ethalfluralin, fluchloralin, isopropalin, methalpropalin, nitralin, oryzalin, pendimethalin, prodiamine, profluralin and trifluralin; dinitrophenol herbicides such as dinofenate, dinoprop, dinosam, dinoseb, dinoterb, DNOC, etinofen and medinoterb; diphenyl ether herbicides such as ethoxyfen; nitrophenyl ether herbicides such as acifluorfen, aclonifen, bifenox, chlomethoxyfen, chlomitrofen, etnipromid, fluorodifen, fluoroglycofen, fluoronitrofen, fomesafen, furyloxyfen, halosafen, lactofen, nitrofen, nitrofluorfen and oxyfluorfen; dithiocarbamate herbicides such as dazomet and metam; halogenated aliphatic herbicides such as alorac, chloropon, dalapon, flupropanate, hexachloroacetone, iodomethane, methyl bromide, monochloroacetic acid, SMA and TCA; imidazolinone herbicides such as imazamethabenz, imazamox, imazapic, imazapyr, imazaquin and imazethapyr; inorganic herbicides such as ammonium sulfamate, borax, calcium chlorate, copper sulfate, ferrous sulfate, potassium azide, potassium cyanate, sodium azide, sodium chlorate and sulfuric acid; nitrile herbicides such as bromobonil, bromoxynil, chloroxynil, dichlobenil, iodobonil, ioxynil and pyraclonil; organophosphorus herbicides such as amiprofos-methyl, anilofos, bensulide, bilanafos, butamifos, 2,4-DEP, DMPA, EBEP, fosamine, glufosinate and piperophos; phenoxy herbicides such as bromofenoxim, clomeprop, 2,4-DEB, 2,4-DEP, difenopenten, disul, erbon, etnipromid, fenteracol and trifopsime; phenoxyacetic herbicides such as 4-CPA, 3,4-DA, MCPA-thioethyl and 2,4,5-T; phenoxybutyric herbicides such as 4-CPB, 3,4-DB, and 2,4,5-TB; phenoxypropionic herbicides such as cloprop, 4-CPP, 3,4-DP and fenoprop,; aryloxyphenoxypropionic herbicides such as chlorazifop, clodinafop, clofop, cyhalofop, diclofop, fenoxaprop, fenoxaprop-P, fenthiaprop, fluazifop, fluazifop-P, haloxyfop, haloxyfop-P, isoxapyrifop, metamifop, propaquizafop, quizalofop, quizalofop-P and trifop; phenylenediamine herbicides such as dinitramine and prodiamine; pyrazolyl herbicides such as benzofenap, pyrazolynate, pyrasulfotole, pyrazoxyfen, pyroxasulfone and topramezone; pyrazolylphenyl herbicides such as fluazolate and pyraflufen; pyridazine herbicides such as credazine, pyridafol and pyridate; pyridazinone herbicides such as brompyrazon, chloridazon, dimidazon, flufenpyr, metflurazon, norflurazon, oxapyrazon and pydanon; pyridine herbicides such as cliodinate, dithiopyr, fluoroxypyr, haloxydine, picolinafen, pyriclor, thiazopyr and triclopyr; pyrimidinediamine herbicides such as iprymidam and tioclorim; quaternary ammonium herbicides such as cyperquat, diethamquat, difenzoquat, diquat, morfamquat and paraquat; thiocarbamate herbicides such as butylate, cycloate, di-allate, EPTC, esprocarb, ethiolate, isopolinate, methiobencarb, molinate, orbencarb, pebulate, prosulfocarb, pyributicarb, sulfallate, thiobencarb, tiocarbazil, tri-allate and vernolate; thiocarbonate herbicides such as dimexano, EXD and proxan; thiourea herbicides such as methiuron; triazine herbicides such as dipropetryn, triaziflam and trihydroxytriazine; chlorotriazine herbicides such as atrazine, chlorazine, cyanazine, cyprazine, eglinazine, ipazine, mesoprazine, procyazine, proglinazine, propazine, sebuthylazine, simazine, terbuthylazine and trietazine; methoxytriazine herbicides such as atraton, methometon, prometon, secbumeton, simeton and terbumeton; methylthiotriazine herbicides such as ametryn, aziprotryne, cyanatryn, desmetryn, dimethametryn, methoprotryne, prometryn, simetryn and terbutryn; triazinone herbicides such as ametridione, amibuzin, hexazinone, isomethiozin, metamitron and metribuzin; triazole herbicides such as amitrole, cafenstrole, epronaz and flupoxam; triazolone herbicides such as amicarbazone, bencarbazone, carfentrazone, flucarbazone, propoxycarbazone, sulfentrazone and thiencarbazone-methyl; triazolopyrimidine herbicides such as cloransulam, diclosulam, florasulam, flumetsulam, metosulam, penoxsulam and pyroxsulam; uracil herbicides such as butafenacil, bromacil, flupropacil, isocil, lenacil and terbacil; 3-phenyluracils; urea herbicides such as benzthiazuron, cumyluron, cycluron, dichloralurea, diflufenzopyr, isonoruron, isouron, methabenzthiazuron, monisouron and noruron; phenylurea herbicides such as anisuron, buturon, chlorbromuron, chloreturon, chlorotoluron, chloroxuron, daimuron, difenoxuron, dimefuron, diuron, fenuron, fluometuron, fluothiuron, isoproturon, linuron, methiuron, methyldymron, metobenzuron, metobromuron, metoxuron, monolinuron, monuron, neburon, parafluoron, phenobenzuron, siduron, tetrafluoron and thidiazuron; pyrimidinylsulfonylurea herbicides such as amidosulfuron, azimsulfuron, bensulfuron, chlorimuron, cyclosulfamuron, ethoxysulfuron, flazasulfuron, flucetosulfuron, flupyrsulfuron, foramsulfuron, halosulfuron, imazosulfuron, mesosulfuron, nicosulfuron, orthosulfamuron, oxasulfuron, primisulfuron, pyrazosulfuron, rimsulfuron, sulfometuron, sulfosulfuron and trifloxysulfuron; triazinylsulfonylurea herbicides such as chlorsulfuron, cinosulfuron, ethametsulfuron, iodosulfuron, metsulfuron, prosulfuron, thifensulfuron, triasulfuron, tribenuron, triflusulfuron and tritosulfuron; thiadiazolylurea herbicides such as buthiuron, ethidimuron, tebuthiuron, thiazafluoron and thidiazuron; and unclassified herbicides such as acrolein, allyl alcohol, aminocyclopyrachlor, azafenidin, benazolin, bentazone, benzobicyclon, buthidazole, calcium cyanamide, cambendichlor, chlorfenac, chlorfenprop, chlorflurazole, chlorflurenol, cinmethylin, clomazone, CPMF, cresol, ortho-dichlorobenzene, dimepiperate, endothal, fluoromidine, fluridone, fluorochloridone, flurtamone, fluthiacet, indanofan, methazole, methyl isothiocyanate, nipyraclofen, OCH, oxadiargyl, oxadiazon, oxaziclomefone, pentachlorophenol, pentoxazone, phenylmercury acetate, pinoxaden, prosulfalin, pyribenzoxim, pyriftalid, quinoclamine, rhodethanil, sulglycapin, thidiazimin, tridiphane, trimeturon, tripropindan and tritac.
[0024] The synergistic composition of the present invention is particularly useful when used on glyphosate-tolerant, glufosinate-tolerant, 2,4-D-tolerant, dicamba-tolerant or imiazolinone-tolerant crops. It is generally preferred to use the synergistic composition of the present invention in combination with herbicides that are selective for the crop being treated and which complement the spectrum of weeds controlled by these compounds at the application rate employed. It is further generally preferred to apply the synergistic composition of the present invention and other complementary herbicides at the same time, either as a combination formulation or as a tank mix.
[0025] The synergistic composition of the present invention can generally be employed in combination with known herbicide safeners, such as benoxacor, benthiocarb, brassinolide, cloquintocet (mexyl), cyometrinil, daimuron, dichlormid, dicyclonon, dimepiperate, disulfoton, fenchlorazole-ethyl, fenclorim, flurazole, fluxofenim, furilazole, isoxadifen-ethyl, mefenpyr-diethyl, MG 191, MON 4660, naphthalic anhydride (NA), oxabetrinil, R29148 and -phenyl-sulfonylbenzoic acid amides, to enhance their selectivity.
[0026] In practice, it is preferable to use the synergistic composition of the present invention in mixtures containing an herbicidally effective amount of the herbicidal components along with at least one agriculturally acceptable adjuvant or carrier. Suitable adjuvants or carriers should not be phytotoxic to valuable crops, particularly at the concentrations employed in applying the compositions for selective weed control in the presence of crops, and should not react chemically with herbicidal components or other composition ingredients. Such mixtures can be designed for application directly to weeds or their locus or can be concentrates or formulations that are normally diluted with additional carriers and adjuvants before application. They can be solids, such as, for example, dusts, granules, water dispersible granules, or wettable powders, or liquids, such as, for example, emulsifiable concentrates, solutions, emulsions or suspensions.
[0027] Suitable agricultural adjuvants and carriers that are useful in preparing the herbicidal mixtures of the invention are well known to those skilled in the art.
[0028] Liquid carriers that can be employed include water, toluene, xylene, petroleum naphtha, crop oil, acetone, methyl ethyl ketone, cyclohexanone, trichloroethylene, perchloroethylene, ethyl acetate, amyl acetate, butyl acetate, propylene glycol monomethyl ether and diethylene glycol monomethyl ether, methanol, ethanol, isopropanol, amyl alcohol, ethylene glycol, propylene glycol, glycerine, N-methylpyrrolidinone, N—N-dimethylalkylamides, dimethyl sulfoxide and the like. Water is generally the carrier of choice for the dilution of concentrates.
[0029] Suitable solid carriers include talc, pyrophyllite clay, silica, attapulgus clay, kaolin clay, kieselguhr, chalk, diatomaceous earth, lime, calcium carbonate, bentonite clay, Fuller's earth, cotton seed hulls, wheat flour, soybean flour, pumice, wood flour, walnut shell flour, lignin, and the like.
[0030] It is usually desirable to incorporate one or more surface-active agents into the compositions of the present invention. Such surface-active agents are advantageously employed in both solid and liquid compositions, especially those designed to be diluted with carrier before application. The surface-active agents can be anionic, cationic or nonionic in character and can be employed as emulsifying agents, wetting agents, suspending agents, or for other purposes. Typical surface-active agents include salts of alkyl sulfates, such as diethanol-ammonium lauryl sulfate; alkylarylsulfonate salts, such as calcium dodecyl-benzenesulfonate; alkylphenol-alkylene oxide addition products, such as nonylphenol-C 18 ethoxylate; alcohol-alkylene oxide addition products, such as tridecyl alcohol-C 16 ethoxylate; soaps, such as sodium stearate; alkylnaphthalene-sulfonate salts, such as sodium dibutylnaphthalenesulfonate; dialkyl esters of sulfosuccinate salts, such as sodium di(2-ethylhexyl) sulfosuccinate; sorbitol esters, such as sorbitol oleate; quaternary amines, such as lauryl trimethyl-ammonium chloride; polyethylene glycol esters of fatty acids, such as poly-ethylene glycol stearate; block copolymers of ethylene oxide and propylene oxide; and salts of mono and dialkyl phosphate esters.
[0031] Other adjuvants commonly used in agricultural compositions include compatibilizing agents, antifoam agents, sequestering agents, neutralizing agents and buffers, corrosion inhibitors, dyes, odorants, spreading agents, penetration aids, sticking agents, dispersing agents, thickening agents, freezing point depressants, antimicrobial agents, and the like. The compositions may also contain other compatible components, for example, other herbicides, plant growth regulants, fungicides, insecticides, and the like and can be formulated with liquid fertilizers or solid, particulate fertilizer carriers such as ammonium nitrate, urea and the like.
[0032] The concentration of the active ingredients in the synergistic composition of the present invention is generally from 0.001 to 98 percent by weight. Concentrations from 0.01 to 90 percent by weight are often employed. In compositions designed to be employed as concentrates, the active ingredients are generally present in a concentration from 5 to 98 weight percent, preferably 10 to 90 weight percent. Such compositions are typically diluted with an inert carrier, such as water, before application. The diluted compositions usually applied to weeds or the locus of weeds generally contain 0.0001 to 1 weight percent active ingredient and preferably contain 0.001 to 0.05 weight percent.
[0033] The present compositions can be applied to weeds or their locus by the use of conventional ground or aerial dusters, sprayers, and granule applicators, by addition to irrigation water, and by other conventional means known to those skilled in the art.
[0034] The following examples illustrate the present invention.
EXAMPLES
[0035] 2,4-D (dimethylamine salt), dichlorprop (potassium salt) and Glyphomax XRT® herbicide (isopropylamine salt) alone and in combinations were applied to the foliage of rapidly growing plant material utilizing a track sprayer calibrated to deliver an application volume of 187 L/ha. Treated plant material was maintained in a greenhouse that provided a 16-hr photoperiod, supplemented with metal halide-generated light, set to provide a minimum of 500 μmolm −2 s −1 . The greenhouse was maintained at a temperature of 26 to 28° C. and a relative humidity of 50 to 70%. Assessment of herbicidal activity was performed visually 14 to 21 days after application.
[0036] The expected growth reduction of plant species from the combination of herbicides was calculated utilizing the Colby equation:
[0000] Expected growth reduction ( E )= X+Y −( X*Y/ 100)
[0000] where X is % of growth reduction of a weed at a given concentration of a herbicide (or herbicide formulation) and Y is the % growth reduction of the same species and size weed at a given concentration of an independent herbicide (or herbicide formulation).
[0037] Tables I, II, III and IV contain the data for expected and actual herbicidal growth reduction caused by relevant individual herbicides and combinations of these herbicides on agronomically important weeds.
[0000]
TABLE I
Herbicidal effects of Glyphomax XRT ®, 2,4-D and combinations
of the two herbicides on select broadleaf weeds.
Expected
Actual
Glyphomax
Injury*
Injury
XRT Rate
2,4-D Rate
(% growth
(% growth
Species
(g ae/ha)
(g ae/ha)
reduction)
reduction)
IPOHE
210
0
—
43
0
70
—
17
210
70
53
93
CIRAR
210
0
—
25
0
280
—
38
210
280
54
95
SIDSP
420
0
—
33
0
140
—
17
420
140
44
72
ABUTH
210
0
—
17
0
280
—
28
210
280
40
60
AMBEL
105
0
—
12
0
140
—
61
105
140
66
96
COMBE
560
0
—
38
0
140
—
48
560
140
68
95
SEBEX
210
0
—
13
0
280
—
37
210
280
45
93
POLCO
420
0
—
18
0
280
—
32
420
280
44
83
AMATA
210
0
—
8
0
280
—
53
210
280
57
99
*Expected injury values were calculated using Colby's equation.
[0000]
TABLE II
Herbicidal effects of Glyphomax XRT ®, 2,4-D and combinations of
the two herbicides on glyphosate-susceptible and
glyphosate-resistant Conyza canadensis (ERICA).
Expected
Actual
Glyphomax
Injury*
Injury
XRT Rate
2,4-D Rate
(% growth
(% growth
Species
(g ae/ha)
(g ae/ha)
reduction)
reduction)
ERICA
420
0
—
50
Glyphosate
0
35
—
47
Susceptible
420
35
74
86
ERICA
420
0
—
12
Glyphosate
0
70
—
38
Resistant
420
70
45
99
*Expected injury values were calculated using Colby's equation.
[0000]
TABLE III
Herbicidal effects of Glyphomax XRT ®, dichlorprop and
combinations of the two herbicides on glyphosate-susceptible
and glyphosate-resistant Conyza canadensis (ERICA).
Expected
Actual
Glyphomax
Dichlorprop
Injury*
Injury
XRT Rate
Rate
(% growth
(% growth
Species
(g ae/ha)
(g ae/ha)
reduction)
reduction)
ERICA
420
0
—
50
Glyphosate
0
210
—
43
Susceptible
420
210
72
92
ERICA
420
0
—
12
Glyphosate
0
210
—
43
Resistant
420
210
50
93
*Expected injury values were calculated using Colby's equation.
[0000]
TABLE IV
Herbicidal effects of Glyphomax XRT ®, dichlorprop and
combinations of the two herbicides on select broadleaf weeds.
Expected
Actual
Glyphomax
Dichlorprop
Injury*
Injury
XRT Rate
Rate
(% growth
(% growth
Species
(g ae/ha)
(g ae/ha)
reduction)
reduction)
IPOHE
105
0
—
12
0
70
—
68
105
70
72
92
CIRAR
210
0
—
25
0
70
—
48
210
70
61
85
ABUTH
210
0
—
17
0
70
—
33
210
70
44
58
AMBEL
105
0
—
12
0
280
—
58
105
280
63
82
COMBE
560
0
—
38
0
70
—
80
560
70
88
96
SEBEX
210
0
—
13
0
140
—
38
210
140
46
75
POLCO
420
0
—
18
0
140
—
38
420
140
49
87
AMATA
210
0
—
8
0
280
—
48
210
280
52
98
*Expected injury values were calculated using Colby's equation.
[0038] A field study was conducted at Church Hill, Md. where glyphosate-resistant horseweed (ERICA, Conyza canadensis ) had been observed for 2-3 years prior to the start of this study. The study design was a split-plot with 4 replications per treatment and each plot was 3.048 M wide and 9.144 M long. The environmental conditions at the time of application were as follows: air temperature, 22° C.; wind speed, 6 kph; wind direction, south; releative humidity, 85%; cloud cover, 80%; target foliage moisture, none; soil moisture, moist; soil temperature at 5 cm depth, 21° C. The treatments were applied using a backpack CO 2 sprayer, with six XR8003 flat fan nozzles spaced 46 cm apart (boom length: 2.76 M) and held 40 cm above the plant canopy. The sprayer was operated at 103 kPa and 4.8 kilometers per hour to deliver 187 L of water per hectare. At the time of applications the glyphosate-resistant horseweed were 30-38 cm tall and there were between 10 and 20 plants per square meter (m 2 ). The percent visual control of glyphosate-resistant horseweed was rated over the entire plot (27.87 m 2 ) 29 days after application. In each plot between 278 and 557 glyphosate-resistant horseweed plants were rated, collectively, for percent visual control. The results are tabulated in Table V.
[0000]
TABLE V
Herbicidal effects of Glyphomax Plus ®, 2,4-D and combinations of
the two herbicides on glyphosate-resistant Conyza canadensis (ERICA)
Expected
Actual
Glyphomax
Injury*
Injury
Plus Rate
2,4-D Rate
(% growth
(% growth
(g ae/ha)
(g ae/ha)
reduction)
reduction)
280
0
—
2.5
0
280
—
12.5
280
280
14.7
35.0
280
0
—
2.5
0
560
—
23.0
280
560
24.9
43.8
280
0
—
2.5
0
1120
—
36.3
280
1120
37.9
57.5
560
0
—
8.8
0
280
—
12.5
560
280
20.2
61.3
560
0
—
8.8
0
560
—
23.0
560
560
29.8
68.8
560
0
—
8.8
0
1120
—
36.3
560
1120
41.9
86.8
840
0
—
13.8
0
280
—
12.5
840
280
24.6
60.0
840
0
—
13.8
0
560
—
23.0
840
560
33.6
87.5
840
0
—
13.8
0
1120
—
36.3
840
1120
45.1
74.5
*Expected injury values were calculated using Colby's equation.
[0039] Although the invention has been described with reference to preferred embodiments and examples thereof, the scope of the present invention is not limited only to those described embodiments. As will be apparent to persons skilled in the art, modifications and adaptations to the above-described invention can be made without departing from the spirit and scope of the invention, which is defined and circumscribed by the appended claims. | 1a
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BACKGROUND OF THE INVENTION
The present invention relates generally to apparatus and methods for securing bags and, more particularly, to a bag including a lockable handle.
People use several types of bags, handheld bags, handbags or containers for carrying different personal items with them to a store, the beach, the pool and other locations. For example, women use purses to carry cosmetics, wallets, checkbooks and other personal and valuable items with them. Similarly, students use backpacks to carry books, homework and other items to and from school. Travelers carry clothes, passports and other similar items with them when they travel. These bags or containers contain valuable items that the person does not want to lose or have stolen. Therefore, to ensure that the items are not being removed or stolen from the person's bags, the persons must keep the bags with them at all times. In some situations, carrying the bags at all times becomes burdensome and makes some activities almost impossible.
For example, if a person is at a relatively open area such as a pool or beach and the person has a bag such as a beach bag or purse, the person cannot leave their spot at the pool or beach without taking the bag with them for fear that the bag will be stolen or that one or more items from the bag will be stolen or removed by thieves or the like. The person must therefore carry the bag or purse with them to get food, go to the bathroom or to perform other activities such as playing volleyball. In addition, if the person wants to go in the water to swim, the person must have another person such as a spouse watch their bag while they are in the water. Otherwise, the person must place the bag as close to the water as possible to keep an eye on the bag. The additional burdens of watching the bag and carrying the bag makes carrying other items such as food trays or performing functions such as going to the bathroom more difficult.
Thieves operate quickly and discretely. Therefore, a bag that is secured and locked to an object or at least secured and locked in a closed position is a less desirable target for a thief because the thief will have to spend too much time and effort to attempt to remove the bag or to remove the items from the bag. A thief is less likely to want to draw attention to themselves by trying to cut, pry or break into a secured and locked bag to remove the bag or remove the contents of the bag.
Accordingly, it is desirable to have a container such as a handbag or bag which includes a handle that is securable and lockable to the body of the bag to simultaneously enable the bag to be secured and locked to another item or object such as a beach chair and also enable the container or bag to be secured closed so that personal items and valuable items cannot be removed from the bag. This enables the bag owners to temporarily leave the bag in a particular location without allowing thieves to easily take the bag or remove contents from the bag while the bag owner is away. The bag owner can then feel assured that the bag is safe while they perform other functions and activities.
It is therefore desirable to provide a bag or container that enables a user to secure the bag to another item.
It is also desirable to provide a bag having a handle that is securable to an object such as a chair to prevent the bag from being easily removed or stolen.
Furthermore, it is desirable to provide a bag including a handle that enables the bag to be secured and locked in a closed position to prevent unauthorized persons from opening the bag and removing personal items and valuable items from inside the bag.
It is also desirable to provide a bag having a lockable handle that includes several different types of locks.
SUMMARY OF THE INVENTION
The present invention provides a securable container such as a bag and method for securing containers such as bags, handbags, purses, luggage, beach bags, duffel bags, back packs and the like. The teachings of the present invention, however, are not dependent upon the handbags or bags being any particular type of bag, container or any other item which is used to carry personal items from one location to another location. The bags described herein are configured to securely hold one or more personal items while preventing the bag and any of the personal and valuable items contained inside the bag from being removed when the bag is secured to an object in a designated location.
In an embodiment, the a bag of the present invention is provided where the bag includes a body defining an interior space and an opening. A closing member is connected to the body, where the closing member is movable to a first position to allow access to the interior space through the opening and to a second position to prevent access to the interior space through the opening. The bag also includes a handle connected to the body, where the handle has a least one removable end. The bag includes a securing member connected to the removable end of the handle and a lockable member connected to the body. The securing member engages the closing member and the lockable member to simultaneously lock the closing member and the securing member to the body when the closing member is in the second position.
In an embodiment, the lockable member defines an opening, where the opening is sized to receive a key which locks and unlocks the lockable member.
In another embodiment, the body includes a front wall, a rear wall side walls and a bottom wall which are connected together.
In an embodiment, at least one cover is attached to at least one of the walls.
In another embodiment, the lockable member includes a suitable combination lock.
In an embodiment, the removable end of the handle includes a plurality of securing members each adapted to be received by the lockable member, where at least one of the securing members is insertable through the closing member to secure and lock the closing member and the removable end of the handle to the lockable member.
In another embodiment, the closing member includes a zipper having a plurality of opposing mating dividers connected to the body and a zipper pull movably connected to each of the plurality of dividers, the zipper pull including a tab, wherein the tab enables the zipper pull to be moved between the first position and the second position.
In an embodiment, at least a portion of at least one of the body and the handle includes a reinforcer.
In another embodiment, at least a portion of the reinforcer includes a metal.
In an embodiment, at least a portion of the reinforcer includes a fabric material.
In an embodiment, a suitable pad lock is attachable to the closing member, removable end and the body.
In an embodiment, the lockable member further includes a removable lock that is attachable to the handle, the closing member and the body.
A bag of another embodiment of the present invention is provided where the bag includes a body defining an interior space and a cover connected to the body. The cover is movable between an open position and a closed position. The open position allows access to the interior space of the body, and the closed position prevents access to the interior space of the body. The bag also includes a handle having at least one removable end and a securing member connected to the removable end of the handle. The bag includes a lock integrally connected to the body, where the securing member is secured to the cover and the lock to simultaneously secure and lock the cover in the closed position.
In an embodiment, the lock defines a keyhole adapted to receive a key.
In another embodiment, the lock includes a suitable combination lock.
In an embodiment, a suitable pad lock is attachable to the closing member, removable end and the body.
In an embodiment, at least a portion of at least one of the cover and the body includes a reinforcer.
In another embodiment, at least a portion of the reinforcer includes a metal.
In an embodiment, at least a portion of the reinforcer includes a fabric material.
In an embodiment, the lock further includes a removable lock that is attachable to the handle, the closing member and the body.
A method of securing and locking a bag is provided where the method includes the steps of providing a body defining an interior space and an opening, where the body includes a handle having two ends and a lockable member. At least one of the ends is removable from the body and the lockable member is adapted to receive the removable end of the handle. The next step includes moving a closing member from an open position to a closed position to prevent access to the interior space through the opening, where the closing member is adapted to receive at least a portion of the removable end of the handle. The next step includes locking the closing member and the removable end of the handle to the lockable member.
In an embodiment, the method includes positioning the removable end of the handle about an object before locking the securing member and the removable end of the handle to the lockable member.
In another embodiment, the method includes attaching a reinforcer to at least a portion of at least one of the handle and the body.
In an embodiment, the method includes locking and unlocking the closing member and the removable end of the handle to and from the lockable member using a key insertable into the lockable member.
In another embodiment, the method includes locking and unlocking the closing member and the removable end of the handle to and from the lockable member using a combination settable on the lockable member.
In a further embodiment, the method includes locking and unlocking the closing member and the removable end of the handle to and from the lockable member using a padlock.
Another embodiment of a method of securing and locking a bag according to the present invention is provided where the method includes the steps of comprising providing a body defining an interior space, where the body includes a handle with at least one removable end and a zipper including a pull which is movable between an open position and a closed position. The pull includes a tab defining an opening adapted to receive the removable end of the handle, where the open position allows access the interior space of the body, and the closed position prevents access the interior space of the body. The next steps include moving the pull to the closed position and inserting a securing member connected to the removable end of the handle through the opening of the tab and into a lockable member attached to the body. The next step includes locking the pull and the securing member to the lockable member.
In an embodiment, the method includes the step of locking the removable end of the handle to the lockable member includes inserting a key into the lockable member and moving the key to and from a designated position to lock and unlock the removable end of the handle to the lockable member.
In another embodiment, the method includes locking the removable end of the handle to the lockable member includes adjusting at least one dial having indicia to a designated position on the lockable member to lock and unlock the removable end of the handle to and from the lockable member.
It is therefore an advantage of the present invention to provide a container such as a bag which is securable and lockable so that the bag cannot be opened to remove items from the bag.
It is another advantage of the present invention to provide a bag which is securable and lockable to another object to prevent the bag from being stolen and to prevent items contained in the bag from being stolen.
It is a further advantage of the present invention to provide a bag that is simultaneously securable and lockable in a closed position and to an object so that owner of the bag can temporarily leave the bag without items in the bag or the bag itself being stolen.
Additional features and advantages of the present invention are described in, and will be apparent from, the following Detailed Description of the Invention and the figures.
BRIEF DESCRIPTION OF THE FIGURES
FIG. 1 illustrates a front perspective view of one embodiment of the bag of the present invention.
FIG. 2 illustrates a front perspective view of the embodiment of FIG. 1 where the strap is secured through the zipper to the body of the bag.
FIG. 3 illustrates a front perspective view of the embodiment of FIG. 1 where the end of the strap is locked to the body of the bag.
FIG. 4 illustrates a front perspective view of another embodiment of the bag of the present invention.
FIG. 5 illustrates a front perspective view of a further embodiment of the bag of the present invention.
FIG. 6 illustrates a front perspective view of another embodiment of the bag of the present invention where the bag includes a suitable combination lock.
FIG. 7 illustrates a front perspective view of a further embodiment of the bag of the present invention where the bag includes a plurality of securing members.
FIG. 8 illustrates a front perspective view of another embodiment of the bag of the present invention where the bag includes a securable cover.
FIG. 9 illustrates a front perspective view of a further embodiment of the bag of the present invention where the bag includes a integral handle which moves upward and downward in the body of the bag to secure and lock the handle to the body.
FIG. 10 illustrates a front perspective view of another embodiment of the bag of the present invention where a suitable padlock is attached to the removable end of the handle, the closing member and the body of the bag.
FIG. 11A illustrates a front perspective view of a further embodiment of the bag of the present invention including a combination lock and a padlock where the handle is not secured to the body of the bag.
FIG. 11B illustrates a front perspective view of a further embodiment of the bag of the present invention including a combination lock and a padlock where the handle is secured to the body of the bag.
FIG. 12 illustrates a front perspective view of another embodiment of the bag of the present invention including a body having a combination lock which secures the handle to the body of the bag.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an apparatus and method for securing different types of containers such as handbags or bags and specifically for securing the handles and/or zippers of such bags. The present invention may be employed to secure a strap, handle or other carrying device of a bag to the body of the bag to prevent the strap or handle from being removed from the bag or to prevent the bag from being opened and/or removed or stolen from a particular location. For example, the strap or handle can be secured to the body of the bag through the zipper or other closing member to prevent the zipper from being opened to gain access to the contents of the bag. It should be appreciated that the present invention may be used to secure any type of handheld bag or other type of bag such as purses, beach bags, tool bags, backpacks, luggage and the like.
The handle or strap may also be attached around and secured and locked to a relatively stationary object such as the arm of a chair or a fence, and then through the zipper pull or tab of a zipper to secure the bag to the chair or fence and also secure the pull in a closed position. This enables the bag's owner to temporarily secure the bag and specifically, the contents of the bag so that the bag owner can temporarily leave the bag at that location. For example, a bag owner may secure the bag to the arm of a beach chair and to leave the beach to go swimming, go to the bathroom, get food or perform some other activity. In another example, the bag can be secured to the handle of a stroller when in a crowded area to prevent thieves from snatching the bag or taking items out of the bag such as the bag owner's wallet or checkbook when the owner is not looking. The present invention therefore enables users to secure their bags to a relatively immovable object such as a chair at a particular location or to movable objects such as strollers or shopping carts so that the user does not have to constantly keep an eye on the bag and so the user can leave the bag temporarily to perform other activities without having the burden of carrying their bag with them at all times.
Referring now to FIGS. 1 to 3 , one embodiment of a securable and lockable container of the present invention is generally illustrated by handbag or bag 20 . Bag 20 includes a body 22 and a strap or handle 24 having two ends 25 a and 25 b . In an embodiment, the end 25 a of the handle 24 is connected to the body 22 . The end 25 a may be integrally formed with the body 22 or connected using any suitable attachment method. It should appreciated that either end 25 a or 25 b may be secured or attached to the body 22 . In this embodiment, end 25 b is removably secured to the body 22 as described in more detail below. Bag 20 also includes a closing member such as a zipper 26 having a zipper pull 28 . A tab 30 is connected to the pull 28 as shown in FIG. 1 and enables a user to grab and hold the tab to pull the tab and the zipper pull 28 along the zipper 26 to open and close the bag.
The end 25 b of the handle 24 includes a securing member such as post 34 having a slot 36 which is connected to or integrally formed with end 25 b . The slot 36 engages a corresponding surface in a receptacle 37 described below. The post 34 may be any suitable post such as a metal post or a post made out of any other suitable material. Preferably, the post 34 is made of a material which cannot be easily cut, severed, broken or removed from the handle 24 . In an embodiment, the post 34 is sized to fit through an opening 32 defined by the handle or tab 30 of the zipper pull 28 . Specifically, the zipper pull is pulled along the zipper 26 until the tab 30 is at one end of the bag which is adjacent to where the end 25 b of the handle or strap 24 is secured to the body 22 . A lockable member or lock 38 is attached to a surface of the body 22 of the bag 20 and includes a receptacle or other opening for receiving the post 34 . The post 34 is inserted through the opening 32 of tab 30 and into the receptacle 37 or other opening of the lock 38 to simultaneously secure and lock the tab 30 and the post 34 (which is attached to the removable end of the handle) to the body 22 . In an embodiment shown in FIG. 1 , a combination lock including dials 39 a , 39 b and 39 c is used to secure and lock the post 34 to the body 22 . It should be appreciated that any suitable lockable member or lock may be used to secure and lock the end 25 b of the handle 24 and the closing member to the body 22 . A release tab or lever 40 is movably connected to the body of the bag. The release tab 40 is moved upward or downward to release the post 34 from the receptacle 37 . The release tab 40 causes the receptacle to hold or secure the post 34 to the body and thereby the handle 24 to the body 22 when the lockable member 37 is in the locked or unlocked position. It should be appreciated that the release tab 40 may be any suitable tab or lever and may move in any suitable direction to release the post 34 from the receptacle 37 .
As shown in FIG. 2 , the post 34 is inserted into and through the opening 32 of tab 30 of the zipper pull. The post 34 is inserted through the opening 32 until the post cannot be inserted any further into the receptacle 37 associated with the lock 38 . In an embodiment, each of the dials 39 a , 39 b and 39 c of the lockable member of combination lock 38 include indicia such as symbols or numbers. In this embodiment, when each of the dials are set to 0-0-0, as shown in FIG. 1 , the post 34 is not locked to the body 22 . When the numbers on the dials 39 a , 39 b and 39 c are set to any other combination such as 2-5-8 shown in FIG. 3 (which is not a designated unlocking combination), the post 34 is locked to the body 22 . It should be appreciated that any suitable combination of indicia or symbols may be used to release or lock the post 34 to the body 22 . Thus, in this embodiment, a user moves or rotates the dials 39 a , 39 b and 39 c to scramble or otherwise hide the designated unlocking or release combination and thereby lock the post 34 to the body 22 after the post 34 is inserted into the receptacle 37 of the body 22 . To release the post 36 from the body 22 , the user moves or rotates the dials 39 a , 39 b and 39 c to the designated unlocking combination (i.e., a combination including three numbers which the user will remember) to unlock the post 34 from the body 22 . The user then presses or pushes the release lever or tab 40 to release the handle from the body. It should be appreciated that the dials 39 a , 39 b and 39 c of the combination lock 38 may include any suitable symbols, indicia, letters, numbers or any other suitable symbols.
In an alternative embodiment, the lockable member is connected to the removable end 25 b of the handle. The lockable member automatically locks the closing member and post to the body of the bag when the lockable member the post is inserted into a receptacle or similar opening defined by the body of the bag. The removable end of the handle and the closing member are unlocked from the body by unlocking the lockable member as described above. It should be appreciated that the lockable member may be connected to any suitable portion of the body of the bag or the handle or other part of the bag which enables the removable end of the handle and the closing member to be secured and locked to the body.
In one embodiment, the post 34 and closing member are automatically locked to the lockable member or lock when the post is inserted into the lock. In this embodiment, the post and closing member are unlocked using one of the methods described above. By automatically locking the post and closing member to the body when the post is inserted into and secured to the lock, the present invention enables a user to always securely lock their bag before they leave it at a location. This embodiment prevents a user from accidentally or inadvertently forgetting to lock the bag.
In one example, a user takes their bag to a beach. The user wants to go swimming but does not want to leave the bag unattended. Instead of searching for a locker, which could be far away, or worrying about the bag, the user removes the end 25 b of the handle 24 from the body of the bag and loops the end 25 b around the arm of their beach chair so that ends 25 a and 25 b are on opposite sides of the arm of the chair. The end 25 b is then simultaneously secured and locked to the closing member and the lock connected to the body 22 of the bag the manner described above. This method therefore secures and locks the bag 20 to the chair and also secures the bag in a closed position to prevent the bag from being opened while the bag is secured to the chair. It also prevents the bag from being easily stolen. The user can now leave the bag locked to the chair to go swimming without having to carry the entire bag with them to the water or without having to constantly watch the bag and worry about whether the bag or the contents of the bag will be stolen.
Referring to FIG. 4 , other types of closing members or closing devices may be employed by the present invention. For example, a round post 44 may be attached to the end 25 b of the handle 24 and inserted through a corresponding round receptacle or opening 32 of the tab 30 and to the combination lock 38 having settable dials 39 a , 39 b and 39 c to secure the handle 24 to the body 22 of the bag. The release tab 40 is moved to release the post 44 from the body 22 . It should be appreciated that any suitable post, closing member (i.e., zipper), or other suitable closing devices or methods may be employed by the present invention.
Referring now to FIG. 5 , another embodiment of the present invention is illustrated as bag 50 where the bag includes a reinforcing mechanism, reinforcing member or reinforcer 72 such as a metal wire or the like that adds to the security of the bag. In FIG. 5 , the bag 50 includes a body 52 and a handle or strap 54 which has two ends 55 a and 55 b . The end 55 a is connected to the body 52 using any suitable attachment method. The end 55 b of the handle 54 is removably secured to the body 52 to enable a user to secure and lock the bag to another object or item such as a chair as describe above. In this embodiment, the end 55 b of the handle 54 includes a securing member or post 64 which is inserted through an opening 62 of the zipper pull 58 to secure the end 55 b and the zipper pull 58 in place. In particular, the post 64 is inserted through the opening 62 and into the lockable member or combination lock 66 having settable dials 67 a , 67 b and 67 c . A release lever or tab 68 secures and releases the post 64 from the body 52 . The post 64 (i.e., the removable end 55 b ) and the zipper pull 58 are simultaneously secured to the lock 66 . The dials 67 a , 67 b and 67 c of the combination lock are moved to lock post 64 in place. Alternatively, the post and zipper pull are simultaneously and automatically locked to the combination lock 66 . This secures the handle 54 in place as well as prevents the zipper pull 58 from being moved to open zipper 56 and thereby gain access to the contents in the bag 50 .
In the illustrated embodiment, the bag 50 also includes a reinforcing member or reinforcer such as wire 72 which is positioned within or otherwise connected or attached to at least a portion of the handle 54 and at least a portion of the body 52 . The wire 72 is preferably made of a suitable material such as a suitable metal or a strong fiber or fabric material which is difficult to cut, rip, sever or break. This prevents the bag and specifically the secured handle 54 from being cut, broken or severed in any way to remove the bag 50 from the object that it is secured to. The reinforcer 72 thereby makes cutting or otherwise removing the bag away from the object it is secured and locked to much more difficult. This embodiment further prevents a thief from quickly and easily taking the bag or from removing the contents of the bag. It should be appreciated that the reinforcer may include any suitable wire, fabric, or other lining device or material. The reinforcer 72 may be positioned in, manufactured or otherwise connected to a portion or all of the surfaces of the body 52 of bag 50 . For example, the reinforcer 72 may be sewn into or otherwise connected to all of the sides or surfaces of the body 52 to prevent the body 52 from being severed or otherwise cut to remove the bag from an object or to gain access to the contents in the bag 50 . In another embodiment, a substantial portion of the walls of the body 52 are lined with a suitable reinforcing material to further prevent unauthorized access into the bag. It should be appreciated that any suitable portion of the body 52 or the handle 54 may include the reinforcing member 72 or a reinforcing material.
Referring to FIG. 6 , another embodiment of the bag of the present invention is generally illustrated as bag 100 . Bag 100 includes a body 102 and a handle 104 including ends 105 a and 105 b . One end of the handle 104 such as end 105 a is secured to the body 102 as described above. The end 105 b includes a post 114 which is secured through opening 112 defined by tab 110 of zipper pull 108 to secure the zipper pull 108 in place. This secures zipper 106 in a closed position. In this embodiment, the lockable member or lock 118 is a suitable combination lock which enables a user to set a designated combination to release the post 114 from the lock. In an embodiment, the combination lock includes four rotatable devices or dials 120 a , 120 b , 120 c and 120 d . Each of the dials 120 a , 120 b , 120 c and 120 d include different indicia or symbols such as letters or numbers which combine to form the combination. The user sets the combination using the dials 120 a , 120 b , 120 c and 120 d then rotates or moves the dials to scramble or hide the designated unlocking combination and lock the post 114 to the lock mechanism or combination lock 118 . When the user desires to release the post 114 from the lock 118 , the user turns or moves at least one of the dials 120 a , 120 b , 120 c and 120 d to indicate the designated unlocking combination. It should be appreciated that any suitable number of dials and/or combinations of indicia may be employed. Release tab 117 is moved to release the post 114 from the body 102 when the post 114 is unlocked.
Referring now to FIG. 7 , another embodiment of the bag of the present invention is generally illustrated as bag 200 . The bag 200 includes the body 202 and a handle 204 . The handle 204 includes a three securing members or posts 206 . Specifically, the securing members 206 include prongs or extenders 208 a , 208 b and 208 c . The securing members and specifically, the prongs are made of any suitable material such as metal. The body 202 includes a number of receptacles such as receptacles 214 a , 214 b and 214 c which correspond in size and shape to extenders or prongs 208 a , 208 b and 208 c to receive the prongs. In an embodiment the prongs 208 a , 208 b and 208 c are positioned above and adjacent to the receptacles 214 a , 214 b and 214 c and are inserted into the receptacles. At least one of the prongs such as prong 208 b is inserted through the opening 213 defined by tab 212 of zipper pull 210 to secure the zipper pull in place. The prongs 208 a , 208 b and 208 c are snap-fit or otherwise positioned in receptacles 214 a , 214 b and 214 c and secured in the receptacles using any type of securing mechanism or lock. A release lever 218 is movably connected to the body 202 and is pressed or otherwise activated to release the prongs 208 a , 208 b and 208 c from the receptacles 214 a , 214 b and 214 c . When the prongs 208 a , 208 b and 208 c are inserted into the receptacles 214 a , 214 b and 214 c , the dials 217 a , 217 b and 217 c are moved to hide the designated combination and lock the prongs to the body 202 . The three prong securing member 206 provides another apparatus and method for securing the handle 204 to the body 202 and thereby enhances the security of the bag.
Referring now to FIG. 8 , in another embodiment, a bag 300 includes a flap or cover 302 which covers the opening 304 of the bag and is secured adjacent to the removable end 308 of the handle 306 and the lock 310 . The end of the handle can then be inserted through a corresponding opening defined by the end of the flap 302 to secure the end 308 of the handle and the flap 302 to the lock 310 . It should be appreciated that the flap or cover may be any suitable type of flap or cover used to cover the opening of the bag to prevent the contents of the bag from being stolen.
In a further embodiment, the lockable member includes a key-type lock 310 which defines an opening or keyhole 312 . The opening or keyhole 312 is formed into a suitable size and shape to receive a key 314 . In this embodiment, the handle 306 is secured to the body of the bag by inserting the post into the receptacle. In one aspect of this embodiment, the post is automatically locked to the body when the post is fully inserted into the receptacle. In another aspect of this embodiment, the post is inserted into the receptacle and then the key is turned a designated distance to lock the post to the body of the bag. To release the post from the body, the key 314 is inserted into the opening 312 and turned in one direction or the other. Then, the release tab or lever 316 is moved to release the post from the receptacle defined by the body of the bag.
Referring now to FIG. 9 , in a further embodiment, a bag 400 includes a handle 402 which is a generally u-shaped handle. The handle is a single solid part or component such as a metal handle which moves or slides upward and downward within the body 404 of the bag as shown. To secure and lock the handle 402 to the body 404 of the bag, a user pushes down on the handle 402 to insert the securing member 406 through the zipper pull 408 and to the lock 410 . To release the handle 402 , the user unlocks the securing member 406 from the combination lock 410 by moving dials 411 a , 411 b and 411 c to the designated combination. The user then moves the release tab 412 to release the post from the body of the bag. Then, the user lifts or pushes upward on the handle 402 to move the handle away from the body. The handle 402 can then be re-engaged or moved downward to re-engage the lock to secure the handle in place to carry the bag. It should be appreciated that handle can be manufactured and made of any material such as a suitable metal or the like.
Referring now to FIG. 10 , another embodiment of the present invention is illustrated which includes a bag 500 having a body 501 and a handle 502 connected to the body. The handle 502 includes a first end 505 a and a second end 505 b . Securing members or securing rings 508 a and 508 b are connected to each end of the handle 512 . In this embodiment, one end 508 b is removable from the body 501 to enable the end 505 b to be secured about another item such as a chair. Specifically, the closing member or zipper 504 is pulled or moved until the tab 506 is positioned adjacent to the securing ring 508 b at one end of the body 501 . A lock ring 510 is connected to the body 501 . The securing ring 508 b , the tab 506 and the lock ring 510 are all positioned adjacent to each other so that a detachable lock such as the combination lock 514 may be used to secure the securing ring 508 b , the tab 506 and the lock ring 510 together so that the bag may not be opened or the contents in the bag may not be removed. In particular, the U-shaped member 511 of the lock 514 is inserted through the securing ring 508 b , the tab 506 and the lock ring 510 to hold these devices in place. The combination lock 514 is locked. To release these devices, the user sets or indicates the designated combination on the combination lock 514 which opens the lock and releases the securing ring 508 b , the tab 506 and the lock ring 510 . The securing ring 508 b is then suitably secured or attached to the body 501 of the bag by attaching the securing ring 508 b to the lock ring 510 or to any other suitable portion of the body 501 . It should be appreciated that any suitable attachable lock such as a padlock may be used to secure the securing ring 508 b , the tab 506 and the lock ring 510 together to lock and/or unlock the end 505 b of the handle 502 to the body 501 .
Referring now to FIGS. 11A and 11B , a further embodiment of the present invention which includes a bag 600 having a body 601 and a handle 602 connected to the body where the handle 602 is securable to the body using locking device or locking mechanism 614 and/or a suitable padlock 620 . Specifically, the handle 602 includes a first end 605 a and a second end 605 b . Securing members or securing rings 608 a and 608 b are connected to each end of the handle 602 . It should be appreciated that the bag 600 may include one or a plurality of securing rings. In this embodiment, one end 605 b is removable from the body 601 to enable the end 605 b to be secured about another item as described above. The closing member or zipper 604 is pulled or moved until the tab 606 is positioned adjacent to receptacle 612 defined by the body 601 as shown in FIG. 11A . A post 609 , which is connected to the end 605 b of the handle 602 , is inserted through an opening defined by pull tab 606 of zipper 604 and into the receptacle 612 to secure the handle 602 and zipper in place as shown in FIG. 11B . A lever or tab 611 is moved or pressed to release the post 609 from the receptacle 612 .
Once the post 609 is secured in the receptacle 612 , the handle can be locked in place by using lock mechanism 614 and/or padlock 620 . The lock mechanism 614 is a combination lock including three dials 618 a , 618 b and 618 c . As described above, the dials each include indicia which are set to a designated release or unlocking combination to unlock the post 609 . The designated combination may be any suitable combination. Alternatively, the handle 602 can be locked in place by using a suitable detachable lock such as padlock 620 as shown in FIG. 11B . Once securing ring 608 b , tab 606 and lock ring 610 are all positioned adjacent to each other, combination lock 614 is inserted through each of these components as shown in FIG. 11B to secure the securing ring 608 b , the tab 606 and the lock ring 610 together. As a result the handle 602 is locked in place. It should be appreciated that handle 602 and zipper 604 may be secured and locked in place using lock mechanism 614 , padlock 620 or both the lock mechanism 614 and padlock 620 .
Referring now to FIG. 12 , another embodiment of the present invention is directed to a bag 700 having a body 701 and a handle 702 connected to the body where the handle 702 is securable to the body using a padlock type lock 709 connected to the body 701 . In this embodiment, the lock 709 includes a dial 710 having a plurality of indicia, where the dial is rotatably connected a side of the body 701 . The lock also includes a curved securing member 712 movably connected to the top side or surface of the body. The handle 702 includes at least one ring 708 where the ring is connected to a removable end of the handle.
To secure and lock the handle to the body, the ring 708 is placed around the securing member 712 . The securing member is then pushed or pressed downward through opening 707 defined in tab 706 of zipper 704 and into a receptacle (not shown) defined in the top side of the body and the zipper to secure the securing member, closing member or zipper and handle to the body. An indicator 714 indicates one or more of the indicia on the dial to manually set a combination associated with the lock to unlock and release the securing member 712 from the body 701 . Therefore, to unlock the securing member, closing member and handle, a user turns or rotates the dial 710 to indicate the designated combination with indicator 714 . Once the designated combination is indicated, the securing member is unlocked and the user pushes or presses release tab 716 to release the securing member, closing member and the handle from the body. It should be appreciated that any suitable combination lock may be used to secure and lock the closing member and the handle to the body of the bag.
It should be understood that various changes and modifications to the presently preferred embodiments described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the present invention and without diminishing its intended advantages. It is therefore intended that such changes and modifications be covered by the appended claims. | 1a
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CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a continuation-in-part of application Ser. No. 10/230,671, filed on Aug. 29, 2002, which claims the benefit of Provisional Patent Application No. 60/316,287, filed on Aug. 31, 2001. This application claims the benefit of Provisional Patent Application No. 61/359,202 filed on Jun. 28, 2010. All of the foregoing applications are incorporated by reference herein.
BACKGROUND
1. Field of the Invention
This invention relates to the treatment of sleep-related breathing disorders such as snoring and obstructive sleep apnea.
2. Related Art
Snoring is a condition that affects people of all ages, but is more common in men once they reach middle-age and in overweight women (Schmidt-Nowara et al., 1995). It is frequently associated with the more serious, and sometimes life-threatening, obstructive sleep apnea (OSA). OSA is a condition where breathing is temporarily interrupted during sleep by obstruction of the airway resulting in episodes of hypoxia. Less serious effects of OSA include sleepiness and lethargy, but if left untreated, it can lead to more serious respiratory and cardiovascular complications (Guilleminault et al., 1976). Although not all snorers suffer from OSA, excessively loud snoring is one of the symptoms of the condition. A second form of sleep apnea, central sleep apnea (CSA) is distinguished from OSA because its underlying cause is neurological and not physical.
Snoring poses not only an inconvenience with regard to the disruption of the sleep-cycle of the sufferer's partner, but can also lead to sleep-deprivation in the sufferer due to repeated arousals from upper respiratory tract resistance even in non-apneic individuals in a condition known as upper airway resistance syndrome (Guilleminault et al., 1991). Such sleep-cycle disruption leads to daytime lethargy and drowsiness and results in a substantial decrease in the quality of life of the sufferer.
Both snoring and OSA are conditions of complex and incompletely understood etiology, but both are the result of obstructed flow due to abnormalities in the geometry of the air passages. In the case of snoring, this abnormal flow results in the vibration of soft tissues in the throat (primarily the soft palate) leading to the generation of sound. In the case of OSA, airflow is so restricted that it ceases intermittently. Some of the morphological features that can contribute to both conditions include; an enlarged tongue volume, a receding jaw that alters the geometry of the pharynx, an enlarged uvula, a lack of muscle tone in the throat leading to a more collapsible pharynx. Repeated trauma to the upper airway tissues due to snoring can damage muscle fibers and peripheral nerve fibers which further impairs muscle stabilization and increases the tendency for obstruction.
Treatments for both snoring and OSA have fallen into two broad classes (Sanders, 1990), namely, surgery and the use of various oral appliances. Surgery aims to modify the geometry of various parts of the respiratory tract, thereby facilitating the smoother passage of air. Procedures include reconstruction of the facial skeleton, tracheostomy, and surgery of the soft palate and/or the pharynx (e.g. uvulopalatopharyngoplasty). Oral appliances are worn during sleep and generally divided into two classes (Lowe, 1994). Mandibular advancing devices are custom-molded to fit the dental profile of the patient and designed to alter the geometry of the throat by pushing forward the lower jaw, thereby widening the air passage. Tongue retaining devices are designed to maintain the tongue in an anterior position to minimize its effect in restricting air flow. In the case of OSA, a third class of device has been developed to provide continuous positive air pressure (CPAP) to the patient. By increasing the pressure of the air breathed in by the patient, CPAP devices help to counter the narrowing of the air passage that leads to OSA.
All of the devices described above can be either inconvenient or uncomfortable to use, and while they all provide some level of efficacy (Schmidt-Nowara et al., 1995), patient compliance can be an issue. In addition, the surgical procedures outlined above range from being moderately to highly invasive and inconvenient.
More recently, three less invasive surgical procedures have been or are being developed for the treatment of snoring.
1. Radiofrequency ablation depends on the use of electromagnetic radiation to heat regions of the soft palate to a temperature of 77-85° C., resulting in vaporization of tissue plus shrinkage of at least some of the remaining tissue and relief of airway obstruction (Fischer et al., 2000). In addition, the damage caused by heating results in the formation of scar tissue that stiffens the palate and reduces its propensity to vibrate in response to the passage of air. This technique has also been reported to have some efficacy in cases of mild to moderate OSA (Blumen et al., 2002). It would be expected, due to the heat denaturation of the remaining target tissue, that the remaining tissue will have inferior mechanical properties, inferior molecular and micro-structural geometry, and eventual loss of some initial treatment-related benefits.
2. Injection of sclerosants such as sodium tetradecyl sulfate into the soft palate results in fibrosis and the formation of scar tissue in a procedure known as Snoreplasty (Brietzke and Mair, 2004; Brietzke and Mair, 2003; Brietzke and Mair, 2001). As in RF ablation, this scar tissue stiffens the palate and helps to prevent vibration. But also, as in RF ablation, this procedure would be associated with a decline in mechanical properties as well as molecular and microstructural structural integrity leading to an eventual loss of some initial treatment-related benefits.
3. The Pillar procedure seeks to relieve snoring by stiffening via the implantation of small fibrous strips into the soft palate using a relatively simple in-patient procedure (Catalano et al., 2007; Romanow and Catalano, 2006; Friedman et al., 2006). The strips themselves serve to physically stiffen the soft palate, but also induce subsequent scar formation that further enhances the stiffening of the tissue. To the extent that this procedure induces scar stiffening, it would be associated with contributing to the decline in mechanical properties of arguably overloaded and already degraded tissues leading to an eventual loss of some initial treatment-related benefits. In addition one would expect that the tissue-material interface could potentially be the site for micro-motion, wear, particle-release, inflammatory or cellular response, and/or tissue damage.
The underlying principal of these three procedures is the stiffening of the soft palate to increase its damping ratio and thereby ameliorate its vibration as air passes over it. While this approach may be generally effective in ameliorating or eliminating snoring, albeit with the numerous long-term concerns noted above, its success in treating OSA is more varied due to the accompanying long-term tissue degradation and the more diverse nature of the etiology of OSA. Nevertheless, some of these treatments have been demonstrated to exhibit some efficacy in some OSA patients (Blumen et al., 2002; Friedman et al., 2006).
SUMMARY
In accordance herein, treatment is achieved by chemical crosslinking of various soft tissues of the respiratory tract. This crosslinking can alter the mechanical properties of the tissues and thereby render them less susceptible to vibration or collapse during sleep, and less susceptible to mechanical degradation or fatigue.
Thus, in one aspect, a treatment for snoring and/or OSA is provided which includes the crosslinking of soft palate using protein crosslinking reagents, with no associated heating, contraction, inducing fibrosis or denaturation of the tissue in some embodiments. The treatment modifies the mechanical properties of the tissue in order to increase its damping ratio, reduce its oscillation magnitudes and vibration, or increase tissue strength, resilience (energy required to create a non-recoverable deformation), toughness (energy required to fail the tissue), and/or fatigue resistance (durability), or any combination thereof.
In another aspect, crosslinking of the outer fibrous layer of the pharynx is provided in order to stabilize, strengthen, or increase, or any combination thereof, the fatigue resistance of the tissue and help prevent or reduce its collapse in sufferers of OSA.
In a further aspect, a method of treating snoring and/or OSA in a subject in need of such treatment is provided. The method includes augmenting the crosslinking of proteins of the subject's soft palate tissue or pharynx tissue. In some embodiments, the crosslinking comprises contacting the soft palate or pharynx tissue with a crosslinking reagent. In any embodiment, crosslinking can occur without heating, contracting inducing fibrosis, or denaturing of the tissue, or any combination thereof. Also, in any embodiment, the crosslinker can be delivered to the tissue via injection, spaying, a patch, a strip-type delivery device, or any combination thereof. In addition, an aerosol delivery device, a patch, or a strip-type delivery device comprising a crosslinking reagent is also provided, where the aerosol device, patch or strip-type delivery device is adapted for use with soft palate or pharynx tissue. The term “treating” means promoting or enhancing the well being of the subject with respect to snoring and/or OSA, including reducing the severity of one or more symptoms associated with snoring and/or OSA.
Use of crosslinking agents will provide a novel method that can modify the viscoelastic and elastic-plastic and durability properties of the tissue of the soft palate and other involved tissues and so ameliorate snoring and some cases of OSA. The method does not simply stiffen the tissue per se, but can also increase the damping coefficient and/or the damping ratio of the tissue in order to minimize oscillations. At the same time, the method can increase the strength, toughness, or fatigue resistance (resistance to degradation from repeated mechanical loading) of the tissue, or any combination thereof. Protein crosslinking can provide the added benefit of being less intrusive than the Pillar Procedure, and less harsh than the induction of scar tissue formation using both Snoreplasty and radiofrequency ablation. Protein crosslinking can also avoid damaging the molecular and/or micro-structural characteristics, and can prevent the detrimental long-term mechanical effects associated with these other procedures.
BRIEF DESCRIPTION OF THE DRAWINGS
For a more complete understanding of the present invention, reference is now made to the following descriptions taken in conjunction with the accompanying drawings, in which:
FIG. 1 is a schematic drawing showing use of a crosslinker-containing patch; and
FIG. 2 is a schematic drawing showing use of a crosslinker-containing strip.
DETAILED DESCRIPTION
Protein crosslinking has been used to modulate both the mechanical properties and chemical stability of collagenous tissues (Charulatha and Rajaram, 2003; Chuang et al., 2007; Han et al., 2003; Slusarewicz et al., 2010b; Sung et al., 2001; Tang et al., 2008; Vasudev and Chandy, 1997; Zhai et al., 2006). Historically, crosslinking has been conducted ex vivo to modulate the strength and resistance to enzymatic degradation of tissue implants, and has been considered with respect to producing allografts for meniscal implant (Hunter et al., 2005), although approaches aimed at injection of crosslinkers in vivo are also being developed (Slusarewicz et al., 2010c).
An ideal crosslinker would be non-toxic and rapidly reactive, although more toxic and slower reacting crosslinkers could be considered provided that they were sufficiently safe and effective. Possible crosslinking reagents that could be used for the purposes of this invention include, but are not limited to: D- or L-Threose (Verzijl et al., 2002), genipin (Sung et al., 1999a; Sung et al., 1999b; Hedman et al., 2006; Sung et al., 1999b; Yerramalli et al., 2007), Methylglyoxal (Wagner et al., 2006), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) (Gratzer and Lee, 2001), proanthocyanidin (Han et al., 2003) and glutaraldehyde (Wu et al., 2007; Yang et al., 2005; Hoffmann et al., 2009). In addition, different crosslinkers can exert different mechanical effects (Slusarewicz et al., 2010c). Thus, combinations of crosslinkers may also be incorporated into embodiments in order to modulate the final mechanical properties of the soft palate and/or pharynx tissue. Thus the solutions, sprays, patches and strips described herein may contain a mixture of two or more crosslinking agents.
In the various aspects of this invention, crosslinker treatment can be used either alone or as an adjunct to surgery. Crosslinker can be applied in the various forms described either before or during the surgical procedure or afterwards.
In one aspect, a solution of the crosslinking reagent, in a suitable carrier solution, is injected into the soft palate in a manner analogous to Snoreplasty, with no associated heating or fibrosis induction, or denaturation of the tissue in some embodiments. As the protein crosslinking reagent reacts with the tissue, it can induce the formation of crosslinks that modify the elastic-plastic and viscoelastic mechanical properties of the tissue including increasing the damping ratio and decreasing the oscillation magnitudes and vibration and undesired deformation of the palate. The crosslink augmentation can also increase the tissue's resistance to mechanical degradation. The reagent may be injected in one location in the palate or in a number of locations in order to facilitate its diffusion to the final desired distribution. The carrier solution may be aqueous or non-aqueous and may contain other non-crosslinking components that may help to facilitate crosslinking Such components include, but are not limited to, buffers (in order to provide and maintain a pH that is most optimal for the particular crosslinker being used), surfactants (in order to enhance the diffusion of the crosslinker within the tissue, and co-factors (that enhance the reactivity of the crosslinking reagent). The crosslinker may be administered to the patient only once or over a series of treatments. In the latter case, sequential administrations may be desirable in order to provide the individual patient only with the minimal amount of palate elastic-plastic and viscoelastic property modification (including increase in damping ratio) required to relieve their symptoms. The crosslinker can be selected from several known minimally toxic crosslinking agents such as genipin at a level of up to about 1200 micromoles and concentration of at least 5 mM (preferably about 20-100 mM) and the buffer can be about 25-250 mM EPPS 4-(2-Hydroxyethyl)-1-piperazinepropanesulfonic acid (EPPS) (preferably approximately 50 mM) at a pH of about 7-10 (preferably about 8) and optionally contain about 25-250 mM of a phosphate salt (preferably about 50 mM) to facilitate the crosslinking reaction and also optionally contain a co-solvent such as dimethyl sulfoxide (at about 1-50%, preferably about 10-20%) to increase the solubility of the crosslinker.
In some embodiments, the crosslinker can be genipin or methylglyoxal at a concentration of about 10 to 60 mM in about 50 mM 4-(2-Hydroxyethyl)-1-piperazinepropanesulfonic acid (EPPS) buffer, at about pH 9, with about 50 mM phosphate ions.
In another aspect, the crosslinking solution described above is administered to the patient in the form of an aerosol spray at crosslinker concentrations and in a buffered carrier similar to that described above. The crosslinker can then diffuse into the tissue of the palate in order to increase the damping coefficient and damping ratio and mechanically stabilize the tissue. The crosslinker can be delivered from a pump that is pressurized with a suitable gaseous or liquid propellant or one that is actuated using a hand pump. An advantage of this delivery system is that the crosslinker can be delivered without the need to create an incision in the tissue. In addition, the formulation may contain both thickening agents and bio-compatible adhesives that coat the surface of the palate to maintain contact of the crosslinker with the tissue over a prolonged period of time in order to facilitate its diffusion into the tissue. Suitable thickening agents might include, but are not limited to, natural polysaccharides such as gellan gum, alginates, agar, carrageenan and pectin, proteins such as gelatin and artificial molecules such as Carbomer (polyacrylic acid), polyethylene glycol. Non-limiting examples of suitable adhesives would be poly(glycerol-co-sebacate acrylate) (Mandavi et al., 2008), oleic methyl esters (K lapperich et al., 2009) or alkyl ester cyanoacrylates (Jonn et al., 2000).
In a further aspect, the crosslinking reagent is delivered via a patch that is placed on the surface of the soft palate. The crosslinker can be impregnated into the patch or incorporated into a delivery vehicle that coats the surface of the patch that is in contact with the tissue. The patch may also be coated with a bio-compatible adhesive such as those described above in order to maintain its attachment to the tissue. The patch may also be attached to the select tissue by biodegradable or semi-permanent sutures or by a tack or staple like device. The delivery vehicle could be either a suitable solvent, or solution containing appropriate excipients described with or without suitable thickening agents. The formulation may also optionally contain penetration enhancing reagents such as dimethyl sulfoxide in order to facilitate the entry of the crosslinker into the tissue. Alternatively the solution could be impregnated into the patch. The impregnated crosslinker could also be in a solid form which would dissolve slowly over time once in contact with bodily fluids, thereby providing a sustained release of crosslinker over time. In the case of non-degradable polymers the material of the patch would be porous and the patch would be removed by a clinician once its function has been completed. In some embodiments, the crosslinker is adhered to one side of the patch as part of a semi-solid formulation. The patch could be constructed of a bio-degradable material such as polylactic or polyglycolic acid which would then slowly dissolve with time and not have to be removed by a clinician. The crosslinker would then be slowly released from the patch as it dissolved. In the case of non-degradable polymer patches the patch could also be coated with a layer or multiple layers of bio-degradable polymer containing crosslinking reagent in order to provide a pool of slowly releasing crosslinker. Different concentrations of crosslinker can be used in these different layers of degradable polymer in order to control the release rates of the crosslinker over time. In all cases the patch could also be designed to allow airflow if the patch were inadvertently dislodged. To accommodate this function the patch could include a pattern of perforations and/or intersecting cut-lines that would enable portions (flaps) of the patch to deform if not in direct contact with tissue, facilitating airflow through the flap region. Alternately the patch could contain holes to facilitate airflow, or a combination of flaps and holes.
Solid or liquid crosslinker could be incorporated into the patch by addition to the molten polymer prior to casting, molding or spinning. Alternatively the crosslinker could be co-solubilized with the polymer in a suitable solvent (for example, acetone) and then incorporated into the device by removal of the solvent by evaporation or by precipitation (for example, by the addition of ethanol) of the polymer as described previously (Athanasiou et al., 1995; Singhal et al., 1996). The crosslinker and polymer could also be solubilized separately and mixed prior to precipitation in either the same solvent or different (miscible) solvents. Also, the solid crosslinker could also be mixed into the polymer gum formed by precipitation of solubilised polymer and prior to molding. The rate of crosslinker release can be controlled by varying the amount or concentration of the crosslinker incorporated into the device as well as by selecting polymers or other materials with differing in vivo degradation rates.
Degradation of bio-degradable polymers is also associated with a decrease of pH due to the production of acidic monomers. It has been shown that many protein crosslinkers act less efficiently at acidic pH (Slusarewicz et al., 2010a), and that this acidification process can be ameliorated by the incorporation of basic salts into the polymer matrix (Agrawal and Athanasiou, 1997). The biodegradable patches described above (and the strips described below) can also incorporate such basic salts in order to maximise the reactivity of the crosslinkers. Such salts could be inorganic (for example, but not limited to, calcium carbonate, calcium hydroxyapatite or sodium bicarbonate) or organic (for example, but not limited to, 2-Amino-2-hydroxymethyl-propane-1,3-diol (Tris) or 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES). These basic salts can be incorporated at a level of about 5-50% by weight of the polymer (preferably about 15-30%).
The crosslinker can be selected from any of several known minimally toxic crosslinking agents such as genipin at a level of about 1-250 mg per patch (preferably about 5-50 mg). Additionally the patch can also optionally contain an alkaline salt such as calcium carbonate to maintain an elevated pH as the device degrades at a level of about 5-50% by weight of the polymer (preferably about 5-30%).
The crosslinker embedded into the patch may also be incorporated into a formulation that is designed to optimize its activity by the suitable adjustment or addition of, but not exclusively, pH, ionic strength, cations, anions, phosphate ions, and/or surfactants.
In addition to being applied to the soft palate, the patches described above could also be applied to the surfaces of the pharynx in order to crosslink, strengthen, increase resilience and toughness (energy required to create a non-recoverable deformation and to fail the tissue respectively), increase the mechanical fatigue resistance or resistance to repetitive mechanical loading, and otherwise mechanically modify the outer fibrous layer and thus help prevent the pharangeal collapse that occurs in many sufferers of OSA.
In another aspect, the crosslinker is incorporated into a non-degradable strip-type delivery device such as those used in a Pillar procedure of the soft palate. The crosslinker may be incorporated in any of the ways described above. Following implantation the crosslinker can diffuse into and can crosslink the tissue of the palate, and thus can serve to further assist in modifying the mechanical properties of the tissue including increasing the damping ratio, strength, toughness and/or fatigue resistance. The crosslinker can counteract the mechanical degradation of the tissue caused by the implant itself and the scarring that it induces. In this case the crosslinker provides a third mode of action for the device in order to improve its efficacy.
In addition the polymer of the strip could be constructed using a bio-degradable polymer, which can allow for the sustained release of crosslinker over time as well as the induction of biological scar tissue before complete dissolution of the strips themselves. The crosslinker can be any of several known minimally toxic crosslinking agents such as genipin or methylglyoxal at a level of about 1-20 mg per strip, though more can also be incorporated. Additionally the fixation device can also optionally contain an alkaline salt such as calcium hydroxyapatite to maintain an elevated pH as the device degrades at a level of about 5-50% by weight of the polymer (preferably about 15-30%).
The crosslinker embedded into the strips may also be incorporated into a formulation that is designed to optimize its activity by the suitable adjustment or addition of, but not exclusively, pH, ionic strength, cations, anions, phosphate ions, and/or surfactants.
In other aspects of this invention, crosslinker treatment in the form of injections, sprays or patches is combined with either the Pillar procedure or Snoreplasty in order to further enhance their effects. Crosslinker may be administered before, during or after the Pillar or Snoreplasty procedure.
The crosslinker delivery vehicles described herein are single-phase systems consisting of a solution of crosslinking reagent in either a solvent or a solvent containing various excipients and/or thickening agents. In another aspect, the carrier vehicle is comprised of a two-phase system such as an oil-in-water or a water-in-oil emulsion or micro-emulsion. Depending of the emulsion and the polarity of the crosslinker, the crosslinker may be incorporated into either the continuous or dispersed phases. The components of the emulsion may also be designed to enhance the penetration of the crosslinking into the tissue. The emulsion may also contain three or more phases, such as a water-in-oil-in-water (WOW) emulsion with the crosslinker incorporated into one or more than one of the phases as required. The formulations described here are not limited to simple emulsion systems and can also include more complex systems such as liposomal formulations and multi-vesicular emulsions.
In another aspect of the invention, the crosslinker is encapsulated into micro- or nano-spheres made from a polymeric material and which are suspended in either a single or multi-phase carrier vehicle. The beads serve as a reservoir for the sustained and controlled release of the crosslinking material into the tissue. The polymeric material is ideally bio-degradable but could alternatively be non-degradable.
FIG. 1 shows an embodiment in which a patch 2 of crosslinker embedded biodegradable material can be placed onto the surface of the soft palate 4 or pharynx 6 of a subject or patient with the aid of a suitable bio-compatible adhesive or a suture or a tack type device. Crosslinker is eluted from the patch over time to facilitate tissue stiffening and reduction in vibration or airway obstruction. Cross-shaped slits 8 are cut into the patch, which can then form flaps and openings to facilitate breathing should the patch become dislodged and enter the trachea. Alternatively the patch may be fabricated with holes to perform the same function, or a combination of holes and slits.
In another embodiment shown in FIG. 2 , crosslinker-impregnated strips 10 of biodegradable polymer are inserted into the soft palate as viewed through the open mouth 12 of a subject or patient. Crosslinker is eluted from the strips over time to facilitate tissue stiffening, strengthening and reduction in palate vibration or airway obstruction
The present invention may be better understood by referring to the accompanying examples, which are intended for illustration purposes only and should not in any sense be construed as limiting the scope of the invention.
EXAMPLE 1
One can treat a patient who suffers from excessive snoring or from OSA where airway blockage caused by the soft palate is a contributing factor by injecting a solution of 40 mM genipin in an alkaline solution such as 100 mM EPPS/100 mM sodium phosphate buffer at pH 9, or a higher concentration of genipin in a similar buffer further supplemented with dimethyl sulfoxide or a solution of 100 mM methylglyoxal in a similar buffer. This injection can be performed with a large volume at a single location in the palate or in multiple locations using smaller volumes to obtain sufficient coverage of the tissue.
EXAMPLE 2
One can treat patients suffering from snoring or from OSA where airway constriction is a contributing factor, by applying a solution of crosslinker as described in Example 1 to either the soft palate or the surface of the pharynx in the form of an aerosolized spray. The spray could be delivered from either a self-contained pressurized container, an actuated pump or from a device where the pressurized propellant is supplied from a separate vessel to that in which the crosslinker is contained.
EXAMPLE 3
One can treat patients suffering from snoring or from OSA where airway constriction is a contributing factor, by applying a patch composed of the biodegradable polymer, polylactic acid to either the soft palate of the surface of the pharynx respectfully. The patch is constructed by dispersing solid genipin crosslinker to the liquid polymer during manufacture at a ratio of 10 mg of genipin to 1 g of poly lactic acid. Following application, crosslinker is released as the patch is dissolved and can then penetrate into the tissue to which the patch has been applied.
EXAMPLE 4
One can treat a patient who suffers from excessive snoring or from OSA where airway blockage caused by the soft palate is a contributing factor by implanting non-degradable fibrous strips, for example such as the polystyrene strips used in the Pillar Procedure into the soft palate, coated with a layer of degradable polymer impregnated with crosslinking agent. These strips are coated by either immersing them in a molten polymer containing a dispersed crosslinking agent such as genipin at a concentration of 10 mg per gram of polymer, or by sequential immersions in a solution of containing 50 mM genipin and a saturating concentration of the biodegradable polymer solubilized in a suitable solvent such as ethyl acetate and subsequent evaporation of the solvent.
EXAMPLE 5
One can treat a patient who suffers from excessive snoring or from OSA where airway blockage caused by the soft palate is a contributing factor by conducting the Pillar Procedure immediately followed by injecting a solution of 40 mM genipin in an alkaline solution such as 100 mM EPPS/100 mM sodium phosphate buffer at pH 9 into the soft palate.
EXAMPLE 6
A patient suffering from OSA can be surgically treated by uvulopalatopharyngoplasty and then further treated by; (a) affixing a patch as described in Example 3 to the surface of the pharynx or soft palate, (b) injecting a solution as described in Example 1 into the soft palate, (c) applying a spray as described in Example 2 to the soft palate or pharynx or (d) by implanting crosslinker impregnated strips such as those described in Example 4 into the soft palate.
EXAMPLE 7
One can treat a patient who suffers from excessive snoring or from OSA where airway blockage caused by the soft palate is a contributing factor by co-injecting into the soft palate a solution of 40 mM genipin in an alkaline solution such as 100 mM EPPS/100 mM sodium phosphate buffer at pH 9 with a sclerosant such as sodium tetradecyl sulfate.
EXAMPLE 8
The improvement in soft palate mechanical properties including increase in the damping ratio due to the present methods and devices can be measured using human or bovine cadaveric soft palate explants and in vitro experimental methods briefly summarized here. An appropriate number of tissue specimens are included in the study according to previously documented variances in mechanical properties of the selected tissue type. The specimens are randomly divided into a crosslinking treatment group and a buffer only sham treatment group. The crosslinked specimens each receive a 0.5 ml injection of 40 mM genipin in 100 mM EPPS/100 mM sodium phosphate buffer at pH 9 using a small, greater than 20 gauge, or insulin-sized needle. The sham group receives 0.5 ml injections of buffer only. The anterior bony portion of the palate is potted or clamped and mounted in a simple variable flow wind tunnel to simulate physiologic airflow at various velocities across the soft palate. Specimen displacements can be measured in a variety of ways. Preferably the measurements are made with a non-contact laser caliper with data collection rate of at least 10 Hz. Oscillation magnitudes and frequencies of the tip of the soft palate are calculated. The data is normalized using the specimen's cross-sectional area measured with a rotating laser micrometer. Comparisons between treatment groups can be made using a Mann-Whitney non-parametric comparison of means. Additionally, before and after crosslinking treatment measurements can also be made using the sham treatment group by subjecting it to buffered genipin injection subsequent to initial testing (post-sham injection). Post-crosslinking-treatment test data can then be compared to pre-treatment data using a paired statistical analysis such as the Wilcoxon non-parametric paired analysis. The effect of the crosslinking treatment is evidenced by a statistically significant and greater than 20%: a) increase in damping coefficient or damping ratio, or b) decrease in peak displacement.
The following publications are incorporated by reference herein in their entirety.
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Zumbuehl, S. Hong, J. Borenstein, J. Vacanti, R. Langer, and J. M. Karp. 2008. A biodegradable and biocompatible gecko-inspired tissue adhesive. Proc. Natl. Acad. Sci. U.S.A 105:2307-2312. 23. Romanow, J. H. and P. J. Catalano. 2006. Initial U.S. pilot study: palatal implants for the treatment of snoring. Otolaryngol. Head Neck Surg. 134:551-557. 24. Sanders, M. H. 1990. The management of sleep-disordered breathing. In Cardiorespiratory disorders during sleep. R. J. Martin, editor. Futura, Mount Kisco, N.Y. 141-187. 25. Schmidt-Nowara, W., A. Lowe, L. Wiegand, R. Cartwright, F. Perez-Guerra, and S. Menn. 1995. Oral appliances for the treatment of snoring and obstructive sleep apnea: a review. Sleep 18:501-510. 26. Singhal, A. R., C. M. Agrawal, and K. A. Athanasiou. 1996. Salient Degradation Features of a 50:50 PLA/PGA Scaffold for Tissue Engineering. Tissue Eng 2:197-207. 27. Slusarewicz, P., K. Zhu, and T. Hedman. 2010a. Kinetic characterization and comparison of various protein crosslinking reagents for matrix modification. J. Mater. Sci. Mater. Med. 21:1175-1181. 28. Slusarewicz, P., K. Zhu, and T. P. Hedman. 2010b. Kinetic Characterization and Comparison of Various Protein Crosslinking Reagents for Matrix Modification. J. Mater. Sci. Mater. Med . DOI: 10.1007/s10856-010-3986-8. 29. Slusarewicz, P., K. Zhu, B. Kirking, J. Toungate, and T. Hedman. 2010c. Optimization of Protein Crosslinking Formulations for the Treatment of Degenerative Disc Disease. Spine In Press. 30. Sung, H. W., Y. Chang, C. T. Chiu, C. N. Chen, and H. C. Liang. 1999a. Crosslinking characteristics and mechanical properties of a bovine pericardium fixed with a naturally occurring crosslinking agent. J. Biomed. Mater. Res. 47:116-126. 31. Sung, H. W., Y. Chang, C. T. Chiu, C. N. Chen, and H. C. Liang. 1999b. Mechanical properties of a porcine aortic valve fixed with a naturally occurring crosslinking agent. Biomaterials 20:1759-1772. 32. Sung, H. W., I. L. Liang, C. N. Chen, R. N. Huang, and H. F. Liang. 2001. Stability of a biological tissue fixed with a naturally occurring crosslinking agent (genipin). J. Biomed. Mater. Res. 55:538-546. 33. Tang, S. Y., A. D. Sharan, and D. Vashishth. 2008. Effects of collagen crosslinking on tissue fragility. Clin. Biomech . ( Bristol., Avon .) 23:122-123. 34. Vasudev, S. C. and T. Chandy. 1997. Effect of alternative crosslinking techniques on the enzymatic degradation of bovine pericardia and their calcification. J. Biomed. Mater. Res. 35:357-369. 35. Verzijl, N., J. De Groot, Z. C. Ben, O. Brau-Benjamin, A. Maroudas, R. A. Bank, J. Mizrahi, C. G. Schalkwijk, S. R. Thorpe, J. W. Baynes, J. W. Bijlsma, F. P. Lafeber, and J. M.te Koppele. 2002. Crosslinking by advanced glycation end products increases the stiffness of the collagen network in human articular cartilage: a possible mechanism through which age is a risk factor for osteoarthritis. 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Although the present invention has been described in connection with the preferred embodiments, it is to be understood that modifications and variations may be utilized without departing from the principles and scope of the invention, as those skilled in the art will readily understand. Accordingly, such modifications may be practiced within the scope of the invention and the following claims. | 1a
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CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation of co-pending U.S. patent application Ser. No. 09/892,141, filed on Jun. 25, 2001, which is a continuation-in-part application of U.S. patent application Ser. No. 09/753,264, filed on Dec. 29, 2000, now U.S. Pat. No. 6,402,634, which is a continuation application of U.S. patent application Ser. No. 09/310,835, filed on May 12, 1999, now U.S. Pat. No. 6,224,493, which is hereby incorporated by reference in its entirety.
FEDERAL RESEARCH STATEMENT
[0002] [Not Applicable]
BACKGROUND OF INVENTION
[0003] 1. Field of the Invention
[0004] The present invention relates to golf equipment and, more specifically, to a diagnostic golf club having the ability to make quantitative measurements of specific mechanical or physical properties of the golf club during a golf swing. Strain gauges are provided on the exterior of the shaft of the golf club and a memory device is provided within the interior containing data descriptive of the measured properties.
[0005] 2. Description of the Related Art
[0006] Various data measuring and collecting devices and methods are used for analyzing a golf club during a golf swing. In a similar manner, the effectiveness of a golf ball impact with the golf club during the golf swing can be measured in terms of initial launch conditions. Such launch conditions include the initial velocity, launch angle, spin rate and spin axis of the golf ball. These launch conditions are determined principally by the velocity of a club head at impact and the loft and angle of a club face relative to the intended trajectory of the golf ball's flight. There are two general methods for analyzing the golf club during a golf swing: visual analysis and quantitative variable analysis.
[0007] The method of analyzing a golf club during a golf swing using visual analysis typically is conducted by a golf instructor capable of visually discerning golf swing variables, and suggesting corrections in the golfer's swing to provide improvement. However, not every golfer has ready access to professional golf instruction. The golfer also can diagnose certain swing faults using visual analysis methodology employing one or more cameras to record the golfer's swing and comparing it to a model swing. Using various camera angles and slow motion play back, the actual swing motion can be reviewed and altered in subsequent swings.
[0008] On the other hand, quantitative variable analysis employs sensors to directly measure various mechanical or physical properties of the golf club during the swing motion. Sensors, such as strain gauges or accelerometers, typically are attached to the shaft or the golf club head. Data collected from these strain gauges then may be transferred to a signal processor via wires or radio waves, and can be presented in various graphical formats, including graphical and tabular charts. A significant drawback associated with the use of wires in an instrumented golf club is that the wires can be very cumbersome, and can become obtrusive to the golfer when the golfer attempts to swing the golf club. Several different approaches to analyzing a golf club or baseball bat during a baseball or golf swing using quantitative variable analysis are discussed in the patents listed below.
[0009] For example, in U.S. Pat. No. 4,759,219, issued to Cobb et al., the specification discloses a baseball bat with a self-contained measuring device and display. A spring potentiometer is used to measure centrifugal force, and an LED or LCD displays the measured force. However, this bat does not contain any data storage capability.
[0010] U.S. Pat. No. 5,233,544, issued to Kobayashi, discloses a golf club having multiple sensors, and a cable for transmitting data to a computer for data processing. This arrangement can accommodate up to 5 sensors in a cartridge located in the handle region of the golf club.
[0011] U.S. Pat. No. 3,182,508, issued to Varju, discloses the use of a strain gauge in the bottom of a golf club, and a wire for connecting the sensor to a data processing means located separate from the golf club.
[0012] U.S. Pat. No. 5,694,340, issued to Kim, discloses the use of multiple sensors for measuring the acceleration of a golf club, and uses either a cable or radio transmissions to transfer data from the sensors to an external data processing means.
[0013] U.S. Pat. No. 4,991,850, issued to Wilhelm, discloses the use of a sensor for measuring the applied force of a golf swing. The sensor data can be displayed on a wrist-mounted arrangement or be downloaded to a computer via cable or radio transmission.
[0014] U.S. Pat. No. 3,792,863, issued to Evans, discloses the use of multiple sensors, including an accelerometer and strain gauges, to measure torque and flex. Data is transferred from the golf club to a data analysis station via FM radio signals, with each sensor having its own data transfer frequency.
[0015] Thus, data transfer to an external memory device is a significant drawback. The cumbersome nature of data transfer via cables or wires affects the motion and feel of a golfer's actual golf swing. In addition, while the use of radio transmissions is preferable to the use of wires or cables emanating from the golf club for transferring data, a transmitter adds excessive weight. The effective range of these wireless instrumented golf clubs is limited by the low power used in such embodiments, and the accuracy of the radio transmitted data is subject to interference or noise from other sources of nearby radio transmissions.
[0016] Furthermore, in conventional systems, the receiving equipment typically must be located in close proximity to the radio transmitter disposed in the golf club thereby restricting the flexibility and portability of using such systems. Thus, it is desirable to provide an instrumented golf club that approximates the weight, balance and feel of a golfer's own golf club, in order to ensure that the data collected from the instrumented golf club is applicable to the golfer's actual golf swing. It also may be desirable to provide additional sensors for measuring certain parameters of a golf swing that have previously not been available in instrumented golf clubs. It further may be desirable to provide an efficient means of memory storage within the instrumented golf club to enable internal data capture and storage until the user is ready to download the data for further processing. It further may be desirable to provide data from the instrumented golf club for golf club design.
SUMMARY OF INVENTION
[0017] The diagnostic golf club of the present invention comprises an internally powered and instrumented golf club with multiple sensors to measure, store, and provide an external display of quantitative variables of a golf club during a golf swing. A distinctive feature of the diagnostic golf club of the present invention is the use of a data storage memory device located within the shaft of the golf club, which is capable of receiving and storing data received from the plurality of sensors located on the club. The use of an internal memory device eliminates the need to use radio transmission hardware, data cables or wires to transfer data to an external data processing means. This also allows a golfer to swing the instrumented golf club without getting entangled in cables or wires, thus better allowing the golfer to replicate his or her natural golf swing.
[0018] In a preferred embodiment, swing data in the form of digitized signals are stored in a non-volatile flash buffer memory. The use of non-volatile memory insures that data is not lost if the system is turned off or in the event the battery fails. Because a ring buffer memory is used, it is still possible to replace older data with new data during successive cycles. The use of a ring buffer memory device provides for the creation of an instrumented golf club that is lightweight and free of cables or radio transmitters. Using a linear data capture approach, as taught by the prior art, would require extensive amounts of memory, and would make it very difficult to provide such memory requirements completely internal to an instrumented golf club. It is through the use of the ring buffer memory that one is able to efficiently capture the desired swing data of interest, such as impact with a golf ball, and eliminate the need to provide internal memory to capture data unrelated to a golfer's swings.
[0019] Furthermore, since the ring buffer memory captures only the desired swing data of interest, data for multiple swings can be stored in the memory device of the instrumented golf club of the present invention until the user decides to upload the information to a computer unit for processing. Uploads can be effected via an interface mechanism located within the shaft. The interface provides for the electronic communication of data between the golf club and a computer unit. This provides increased flexibility and mobility to the user since the user is not required to stay within close physical proximity to the external data processing means.
[0020] In addition to the internal memory device, electronic circuitry consisting of a circuit board comprising a power control circuit, a signal conditioning circuit for the plurality of sensors and a serial communication circuit are located within the hollow interior of the shaft. Having these features incorporated into the circuit board allows downloading of high-level digital signals as well significantly reducing noise corruption and enables data to be stored indefinitely on the club. Locating the circuit board and components within the shaft also increases protection from shock loadings typically experienced upon ball impact when the circuitry is placed upon the golf club head.
[0021] In addition, incorporation of an internal power source for the instrumented golf club of the present invention is preferred for providing the benefits of flexibility and mobility. The internal power source can also be used to provide a proper weight balance, or swing weight, for the instrumented golf club, thereby closely approximating the golfer's own golf club. Although the internal power source can be placed in various locations within the instrumented golf club, in a preferred embodiment, a battery tube and one or more batteries are located within the shaft.
[0022] A preferred embodiment of the instrumented golf club system of the present invention comprises a first plurality of strain gauges located at an exterior tip end of the golf club shaft. A second plurality of strain gauges are located at an exterior butt end of the golf club shaft. In a preferred embodiment the plurality of strain gauges comprise two sets of three rosettes. Each rosette group containing gauges having a central bend gauge and two crossing shear gauges. The rosette groups are arranged such that they form six individual Wheatsone bridges. Additionally, while it is preferable to locate individual rosette groups 120° from each other rosette group, those skilled in the pertinent art will recognize that distribution locations of the strain gauge rosette groups around the exterior perimeter of the golf club shaft is not critical and that distribution may be adjusted to achieve a desired placement distribution without departing from the scope and spirit of the present invention.
[0023] The system further comprises a circuit board positioned within the interior of the shaft comprising a memory circuit for storing the strain measurements, a power control circuit, a first signaling conditioning unit for the first plurality of strain gauges, a second signaling conditioning circuit for the second plurality of strain gauges, and a serial communication unit. The circuit board is connected via a first plurality of wires to the first plurality of strain gauges and via a second plurality of wires to the second plurality of strain gauges. A power source as previously described is positioned within the interior of the shaft for providing power to the circuit board the first plurality of strain gauges and the second plurality of strain gauges.
[0024] Once the swing data has been obtained by the strain gauges and stored in the memory, a processor may retrieve the stored memory from the instrumented golf club via an interface mechanism used to permit communication from the instrumented golf club to the processing unit. The retrieved data can then be used to provide a shaft flex profile for a golfer.
[0025] Furthermore, the strain and bend measurements stored by the instrumented golf club system of the present invention may be converted to a variety of measurements including axial force, transverse shear forces, bending moments, and torsion of the club during the swing. These measurements can also be used to generate a shaft flex profile for a golfer.
[0026] Through the use of an external data means, the instrumented golf club system enables quantitative swing data to be captured, transferred to the processing means, and then presented in any number of graphical, tabular or other visual formats to provide a golfer with meaningful feedback regarding the dynamics of a golf swing.
[0027] In addition, the instrumented golf club system of the present invention can be used as a design tool for golf clubs including investigation of such variables as club head geometry, shaft dynamics, structural material behavior and type and location of weighting materials. As an example, the effect of different club head weighting locations can be measured for a wide range of golf swings to provide improved performance within this range of swings.
[0028] Accordingly, it is an object of the present invention to provide an instrumented golf club capable of measuring and storing data within the instrumented golf club without the use of an intermediate conduit such as external data transfer cables, wires or radio transmissions, thereby allowing greater flexibility and mobility to a user of the instrumented golf club.
[0029] It is a further object of the present invention to provide an instrumented golf club with non-volatile memory so that the memory is not lost if the club is turned off or the battery is removed.
[0030] It is a further object of the present invention to provide an instrumented golf club capable of converting a series of strain measurements to a series of force and bending moments in order to generate a shaft flex profile for a golfer.
[0031] Having briefly described the present invention, the above and further objects, features and advantages thereof will be recognized by those skilled in the pertinent art from the following detailed description of the invention when taken in conjunction with the accompanying drawings.
BRIEF DESCRIPTION OF DRAWINGS
[0032] [0032]FIG. 1 is a perspective view of an instrumented golf club system in accordance with an embodiment of the present invention comprising an instrumented golf club, an associated interface mechanism and an external computing means.
[0033] [0033]FIG. 2 is a top perspective view of an instrumented golf club head in accordance with an embodiment of the present invention illustrating a predetermined XYZ coordinate system.
[0034] [0034]FIG. 2A is an illustration of shaft bending planes of the instrumented golf club in accordance with an embodiment of the present invention.
[0035] [0035]FIG. 3 is a perspective view of the shaft of the instrumented golf club in accordance with an embodiment of the present invention.
[0036] [0036]FIG. 4 is a view of a segment of the instrumented golf club shaft as defined by the area IV-IV in FIG. 1, and shows two strain gauge of the rosette group on a front surface and a strain gauge of the rosette group in phantom on a back surface.
[0037] [0037]FIG. 5 is a view of the triplet strain gauge elements as arranged about the exterior circumference of the shaft of the instrumented golf club in tip and butt ends.
[0038] [0038]FIG. 6 is an illustration of the forces acting upon a typical strain gauge element in the instrumented golf club of the present invention.
[0039] [0039]FIG. 7 is a chart illustrating the relationship between the strain, stiffness and force/moments for the data collected from the strain gauges in accordance with an embodiment of the present invention.
[0040] [0040]FIG. 8 ( 8 A, and 8 B) shows a flow chart illustrating the operational steps of the instrumented golf club system in accordance with an embodiment of the present invention.
[0041] [0041]FIG. 9 displays sample initial values for all strain gauges.
[0042] [0042]FIG. 10 is a graphical presentation of data recorded by the strain gauges located at the butt end of the shaft of the instrumented golf club during a typical golf swing.
[0043] [0043]FIG. 11 is a graphical presentation of data recorded by the strain gauges located at the tip end of the shaft of the instrumented golf club during a typical golf swing.
DETAILED DESCRIPTION
[0044] [0044]FIG. 1 illustrates an instrumented golf club system 2 comprising an instrumented golf club 10 , an interface mechanism 18 and a computing or data processing means 28 . The instrumented golf club 10 comprises a grip 12 , a shaft 14 , a club head 16 , a first plurality of strain gauges 20 located on the exterior 25 portion of the shaft 14 proximate the butt end 27 , and a second plurality of strain gauges 21 located on the exterior 25 portion of the shaft 14 proximate the tip end 26 , as further described below. Data measured by the first plurality of strain gauges 20 and second plurality of strain gauges 21 is transferred from the instrumented golf club 10 to the computing means 28 via the interface mechanism 18 . The interface mechanism 18 comprises a connection plug 18 a and a serial interface device 18 b . The connection plug 18 a has a plurality of pins 19 for connection to a plurality of receptors (not shown) within the shaft for electronically communicating data from the instrumented golf club 10 to the data processing means 28 .
[0045] When connected, the interface mechanism 18 provides external power to the instrumented golf club 10 . The data that is collected by the instrumented golf club 10 is transferred to the computer means via the interface mechanism 18 .
[0046] The golf club head 16 may be any type of conventional club head since the strain gauges 20 and 21 are located on the shaft 14 . In a preferred embodiment, the club head 16 is composed of composite material such as disclosed in U.S. Pat. No. 6,248,025, filed on Dec. 29, 1999, entitled Composite Golf Club Head And Method Of Manufacturing, and which pertinent parts are hereby incorporated by reference. However, those skilled in the pertinent art will recognize that other materials, such as titanium, titanium alloys, stainless steel, amorphous metals, persimmon and the like, may be used for the club head without departing from the scope and spirit of the present invention. Regardless of the material chosen for the club head, the golf club 10 , when combined with the circuitry and electronic elements, should approximate the weight of a standard golf club.
[0047] The club head 16 is preferably a driver. However, the club head may be a fairway wood, an iron (1-iron through 9-iron), a wedge (lob, sand, pitching and approach) or a putter.
[0048] The shaft 14 may be anywhere from 35 inches for a wedge to 50 inches for a driver, and is preferably composed of a graphite material. However, the shaft may also be composed of steel titanium, or a bi-material. The shaft 14 has a wall 22 that defines a hollow interior 23 . The shaft 14 has an interior surface 24 and an exterior surface 25 . The shaft 14 has a tip end 26 in proximity to the club head 16 and a butt end 27 , opposite the tip end 26 . The shaft 14 also having an opening 31 to the hollow interior 24 located at the butt end 27 . The shaft 14 generally tapers in its diameter from the butt end 27 to the tip end 26 .
[0049] [0049]FIG. 2 is a top perspective view of the club head 16 , comprising a top 30 , a heel region 32 , a face 34 , a toe region 36 , a rear region 38 and a ribbon 40 . A right-hand coordinate system is used, and is illustrated by the designation of the X, Y and Z axes in FIG. 2. The X axis is oriented vertically (at address position) from a soleplate 54 (as shown in FIG. 3) to the top 30 of the club head 16 . The Y axis is oriented horizontally (at address position) from the toe region 36 to the heel region 32 . The Z axis is oriented horizontally (at address position) from the face 34 to the rear region 38 .
[0050] [0050]FIG. 2A is an illustration showing a first bending plane 49 , and a second bending plane 51 , wherein, the central axis of the shaft 14 (not shown) defines the intersection line of the first bending plane 49 , and the second bending plane 51 . The first bending plane 49 is aligned with the face 34 of the club head 16 , and the second bending plane 51 is at a 90° angle, or orthogonal, to the first bending plane 49 .
[0051] [0051]FIG. 3 illustrates the golf club shaft 14 of the instrumented golf club system 2 comprising a first plurality of strain gauges 20 consisting of a set of three rosette groups 20 a , 20 b , 20 c (in phantom) located on an exterior 25 butt end 27 of the shaft 14 for providing axial and strain measurements during a golf swing. Additionally, a second plurality of strain gauges 21 consisting of a set of three rosette groups 21 a , 21 b and 21 c (not shown) are shown located on the tip end 26 of the shaft 14 for providing axial and strain measurements during a golf swing.
[0052] A circuit board 46 is located within the hollow interior 24 of the shaft and is comprised of a memory circuit 48 for storing strain measurements, a power control circuit 50 , a first signal conditioning circuit 52 for the first plurality of strain gauges 20 , a second signal conditioning circuit 54 for the second plurality of strain gauges 21 , and a serial communication circuit 56 . In a preferred embodiment, the circuit board 46 is located approximately 10″ down the shaft. However, one skilled in the art would understand that the location of the circuit board 46 is not critical and that placement could be varied to accommodate weight adjustments in different club types. Locating the electronics within the shaft helps to further protect the instrumentation from shock loadings that electronics mounted on the club head typically experience upon impact of the golf club with a golf ball.
[0053] An internal power source 58 is also positioned within the shaft to provide power supply to the circuit board 46 as well as to the first and second plurality of strain gauges 20 and 21 respectively.
[0054] An LED 60 is located on the exterior 25 of the shaft 14 to notify the user that the instrumented golf club system 2 is powered up and to signal upon each successive hit that a triggering event has occurred.
[0055] [0055]FIG. 4 is a view of a segment of the instrumented golf club system 2 , as defined by the area IV-IV in FIG. 1, and shows a first plurality of strain gauges 20 . This first plurality of strain gauges are located on the exterior circumference of the shaft at a position proximate the butt end and comprising a set of three rosette groups. The first strain gauge group 20 a , the second strain gauge group 20 b , and the third strain gauge group 20 c (in phantom). Individual strain gauges are comprised of a triple element having a central axial gauge and right and left crossing shear gauges such that when grouped the nine strain gauges from six Wheatstone bridges.
[0056] A first plurality of wires 62 is used to connect the first plurality of strain gauges 20 to the circuit board 46 . At a triggering event, such as the golfer”s swing, each strain gauge input receives a signal referred to by a channel numbered (0-11). Each channel number references a recorded variable, such as butt bend, butt shear, tip bend and tip shear for each strain gauge.
[0057] The first plurality of wires 62 connect the individual strain gauge groups 20 a , 20 b and 20 c to the circuit board 46 by first connecting to the circuit board 46 and then running along the interior portion 24 of the golf club shaft 14 , exiting the shaft 14 via an exit hole 100 located below the butt end 26 of the shaft 14 and connecting with the individual sets of strain gauge groups 20 a , 20 b and 20 c located on the exterior 25 butt end 27 of the shaft 14 .
[0058] The shaft 14 has an opening 64 at the butt end 27 . The shaft 14 has a hollow compartment for placement of a power supply therein, electronic circuitry, sensors, and necessary wiring. A cap 76 is used to cover the hollow compartment of the shaft 14 . In a preferred embodiment, the power supply is a battery tube 78 containing at least a first battery 80 . The battery 80 provides internal power for the instrumented golf club 10 . Preferably, a protective casing is located within the shaft 14 for placement of the battery 80 .
[0059] The shaft electronic circuitry board 46 , which may be one or two boards, includes the internal memory device 134 , a non-volatile buffer memory, a main microprocessor 136 , power control circuitry 120 , signal conditioning circuitry 121 for the strain gauges in the butt end 27 of the shaft 14 , signal conditioning circuitry 122 for the strain gauges in the tip end 26 of the shaft 14 , serial communication circuitry 124 , filter circuitry 126 for the strain gauges, and an analog to digital converter circuitry 128 . The shaft electronic circuitry board 46 is a typical power circuitry board.
[0060] The placement of all of the electronics in the shaft 14 , as opposed to the club head 16 , allows for the use of multiple club heads 16 in order to analyze a golfer's swing for different clubs. Further, the components in the shaft 14 are modular, and thus are easily replaceable if damaged. Such replacement is performed via the opening.
[0061] A second plurality of strain gauges is also located at the tip end 26 of the golf club shaft 14 . This second plurality of strain gauges 21 are located on the exterior circumference of the tip end of the shaft comprised of a set of three rosette groups being a mirror image of the strain gauges located at the butt end of the shaft. The first strain gauge group 21 a , the second strain gauge group 21 b and the third strain gauge group 21 c . The individual strain gauges are comprised of a triple element having a central axial gauge and right and left crossing shear gauges such that the rosette groups from six Wheatstone bridges.
[0062] A second plurality of wires 63 is used to connect this second plurality of strain gauges 21 to the circuit board 46 . At a triggering event, such as a golfer's swing, individual strain gauge inputs receive a signal referred to by a channel numbered (0-11). Each channel number references a recorded variable, such as butt bend, butt shear, tip bend and tip shear for each strain gauge pair.
[0063] A second plurality of wires 63 connects the strain gauge groups 21 a , 21 b and 21 c to the circuit board 46 by first connecting to the circuit board 46 and then running along the interior 24 portion of the golf club shaft 14 , exiting the interior 24 of the shaft 14 via a second exit hole (not shown) located below the butt end 26 of the shaft 14 and running along the length of the exterior 25 of the shaft 14 to connect with the second plurality of strain gauge sets 21 a , 21 b and 21 c located on the tip end 26 of the shaft. This second plurality of wires 63 connecting the second plurality of strain gauges 21 from the tip end 26 of the golf club shaft 14 are preferably glued to the exterior of the golf club shaft 14 , however, the second plurality of wires 63 may also be affixed to the shaft 14 by any other means including mechanical, that are commonly used in the art.
DETAILED DESCRIPTION OF A PREFERRED OPERATION
[0064] [0064]FIG. 5 is a view of an individual strain gauge group 20 a as arranged about the circumference of the exterior of the shaft 14 of the instrumented golf club 10 of the present invention. Six independent strain gauge elements are needed to make essential measurements in order to calculate the six independent forces and moments. These six individual elements are axial force (Px), transverse shear forces (Vy) and (Vz), bending moments (My) and (Mz) and torsion (Tx). FIG. 6 is a view of these forces acting upon a typical strain gauge of the present invention.
[0065] Data obtained from the independent forces and moments acting on the shaft at the tip end 26 and butt end 27 are computed from the strain data received via the sets of strain gauges and from the information obtained relative to the shaft stiffness matrix at each location. These stiffness matrices are obtained using experimental or analytical techniques well known in the art. Once obtained, the values are entered into the computer program and the data is converted from strains and bends to loads and moments. The relationship between the strain, stiffness and force/moment is illustrated in FIG. 7.
[0066] [0066]FIG. 8 is a flow chart illustrating the steps of operation of the instrumented golf club (as shown in FIG. 1) of the present invention. The entire flow chart is shown in two sections, FIGS. 8A and 8B. Prior to initial use it is necessary to load the programming software into the instrumented golf club. First, at step 202 , the computer program is activated at the computer. The club is then connected to the computer via a probe and at step 204 inquiry of the club status is displayed. In the event, as in step 206 , the display indicates that communication between the club and the computer is off-line, the user should verify the connection of the interface mechanism between club and computer. When the status indicates as in step 208 that the communication is on-line, the user should select load round from the club.
[0067] At step 210 , data is then transferred from the club through the interface to the computer processor. Once the data is transferred, at step 212 the engineering menu may be enabled by typing CTR-ALT-E.
[0068] The user will then be asked at step 214 to set the triggering protocol for the club. At step 216 verification of the real time clock is performed and at step 218 , the probe is removed from the club and installation of the battery pack is performed.
[0069] In FIG. 8B once the probe has been removed and the battery pack installed, at step 220 an LED located on the shaft 14 indicates that the swing analysis program has been activated and that the club has been powered up for use. At step 222 , the LED indicates that the program is ready for a triggering.
[0070] At step 224 , the golfer swings the club. The swinging of the club indicates to the strain gauges that a triggering event has occurred, and at step 226 the LED will display the occurrence of this triggering event.
[0071] At step 228 , the data received by the strain gauges with respect to the bending and shear moments will be stored in a non-volatile ROM memory.
[0072] At step 230 , the user may reconnect the interface mechanism between the instrumented golf club and the computer in order to facilitate the download of information from the club to the computer for processing. At step 232 , data from both the first plurality of strain gauges 20 and the second plurality of strain gauges 21 is downloaded to the processing unit.
[0073] The processor at step 234 then calculates the six independent forces and moments from the strain gauge measurements. The forces and moments are then used to determine an appropriate shaft flex profile for an individual golfer at step 236 .
[0074] [0074]FIG. 9 comprises sample initial data values when the instrumented golf club 10 is in a ready state, before the triggering event of the golf swing and impact with the golf ball has occurred. The top of FIG. 9 indicates the values of the calibration constants at various locations along the shaft used in calculating the values for the data obtained during the collection of the sample data. The first twelve columns indicate the values of the twelve strain gauge channels received from the pairs of strain gauges located either on the tip end or the butt end of the club. The next six columns indicate the calculated values of the six independent forces and moments for the strain gauges located on the butt end of the shaft and the last six columns indicate the calculated values of the six independent forces and moments for the strain gauges located on the tip end of the shaft.
[0075] [0075]FIG. 10 and FIG. 11 illustrate sample displays of data collected from a portion of a typical golf swing of the instrumented golf club 10 illustrating the calculated forces and moments both before impact and after impact on the butt end 27 of the shaft 14 (FIG. 10) and tip end 26 of the shaft 14 (FIG. 11). The data is collected from the channels and then converted to values in terms of forces and moments. These forces and moments are displayed in graphical representation and identified as axial force (Px), bending moments (Mz) and (My), transverse shear forces (Vy) and (Vz) and torsion (Tx).
[0076] Once the raw data is collected, the information can be used to generate information to allow the proper shaft flex to be determined for an individual golfer.
[0077] It is understood that a person of ordinary skill in the art of computer programming can create a program that will take the raw data, and manipulate the data such that the characteristics of the golf club during the golfer's swing can be pictorially displayed in a more useful, informative and user friendly manner. This will provide the golfer with useful feedback beyond just the physically measured numerical data.
[0078] A similar procedure can be used in golf club design, for example, to improve the club head geometry, select materials for the club head or shaft, or help locate weighting material within the club head. Furthermore, various tabular, graphical, or other visual formats can be used to display this raw data, including synchronization of the data with a camera for highlighting the golfer's swing area of maximum club head acceleration, hand rotation and shaft bending stress.
[0079] In addition, data from an individual golf swing or golf club design can be plotted against golf ball launch data associated with that golf swing or design, so that changes can be suggested to improve distance and accuracy.
[0080] Further, the data may be used to design a golf club that is appropriate for a specific type of golfer, or even for an individual golfer. Various shafts may be utilized in the testing to determine which type of shaft may be appropriate for a specific type of golfer. The shafts may vary in length, thickness, flexibility, and the like. One example would have a golfer swing each type of shaft to determine which one was appropriate for that specific type of golfer.
[0081] Various club heads also may be utilized in the testing to determine which type of club head may be appropriate for a specific type of golfer. The club heads may vary in material composition, mass, weight placement (e.g. center of gravity purposes), and the like. As above, one example would have a golfer swing each type of club head to determine which one was appropriate for that specific type of golfer. Alternatively, the data may be used to determine an appropriate club head for a specific type of golfer.
[0082] From the foregoing it is believed that those skilled in the pertinent art will recognize the meritorious advancement of this invention and will readily understand that while the present invention has been described in association with a preferred embodiment thereof, and other embodiments illustrated in the accompanying drawings, numerous changes, modifications and substitutions of equivalents may be made therein without departing from the spirit and scope of this invention which is intended to be unlimited by the foregoing except as may appear in the following appended claims. Therefore, the embodiments of the invention in which an exclusive property or privilege is claimed are defined in the following appended claims. | 1a
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FIELD OF THE INVENTION
[0001] The present invention relates in general to the connector portion of a medical device. More particularly, embodiments of the disclosed invention are directed to the surface finish of a luer slip fitting having a conical tip. Methods of manufacturing a male luer slip fitting device with a roughened surface are also disclosed.
BACKGROUND OF THE INVENTION
[0002] Medical devices having male luer slip fittings, for example, male luer syringes, are often assembled with female tube adapters or tube extensions. As described in International Standard ISO 594-1, published by the International Organization for Standardization, such devices include a male conical fitting. Female luer fittings are assembled to the male conical tip by applying axial force to the female luer fitting until the female fitting is sufficiently tight.
[0003] Luer slip connections may become loose due to the presence of lubricious materials, such as glycerol monostearate (GMS). GMS is an additive in polypropylene that acts as an antistatic agent. The GMS migrates to the surface over time and causes the coefficient of friction (COF) to drop. GMS is an example of a lubricious material that migrates to the surface, other materials such as a slip agent or other lubricious materials that migrate or are present on the surface of the syringe tip can cause a drop in the COF. Such loose connections could result in leakage of potentially harmful drugs during various medical procedures and result in user dissatisfaction and other complications. Therefore, there exists a need in the art for a luer syringe or fitting that resists or minimizes the drop in COF resulting from lubricious materials without leaking.
SUMMARY OF THE INVENTION
[0004] One or more embodiments of the invention pertain to medical devices comprising a male luer slip fitting connectable to a female luer portion of a second medical device by application of an engagement force to provide a contact surface between the male luer slip fitting and female luer portion and separable by application of a disengagement force that does not require substantial twisting motion. The male luer slip fitting comprises a material incorporating a lubricious agent such that the disengagement force of a dry connection is less than the engagement force when the contact surface does not include a roughened surface, and the male luer slip fitting has contact surface that is roughened such that the disengagement force required to separate the male luer slip fitting from the female luer portion of the second medical device when in a wet connection is greater than the force required to disengage the male luer fitting from the female luer portion of the second medical device when the contact surface of the male luer fitting is not roughened.
[0005] Another aspect of the invention pertains to methods of making a medical device comprising manufacturing a male luer fitting with a conical tip having an outside surface that mates with a female luer fitting of a second medical device. The male luer fitting being manufactured from a material containing a lubricious agent such that the force required to disassemble a non-roughened male conical tip from a female luer fitting is less than the force required to assemble the non-roughened male luer fitting from the female luer fitting. The outside surface of the male conical tip is roughened such that upon assembly of the male luer fitting with the female luer fitting, with liquid present between the male conical tip and female luer fitting, the removal force is less than about the assembly force.
BRIEF DESCRIPTION OF THE DRAWING
[0006] So that the manner in which the above recited features of the present invention can be understood in detail, a more particular description of the invention, briefly summarized above, may be had by reference to embodiments.
[0007] FIG. 1 . shows a syringe with a luer slip and a luer connector;
[0008] FIG. 2 shows the hub pull force at various assembly forces for luer fittings made of different materials;
[0009] FIG. 3 shows the hub pull force for various materials and surface finishes when assembled at known forces; and
[0010] FIG. 4 shows the hub pull force in materials having a lubricious agent when assembled at various forces with various surface finishes.
DETAILED DESCRIPTION
[0011] Before describing several exemplary embodiments of the invention, it is to be understood that the invention is not limited to the details of construction or process steps set forth in the following description. The invention is capable of other embodiments and of being practiced or being carried out in various ways.
[0012] As used herein, “luer slip” or “luer fitting” used in conjunction with luer connectors and other luer fittings means a connector that is disassembled primarily by the application of axial force as described in ISO 594-1, as distinguished from luer lock fittings that are disassembled primarily by the application of torque, as described in ISO 594-2.
[0013] It has been determined that when a male luer fitting with a conical tip and a female luer fitting are assembled in the presence of a lubricious material under wet conditions, the force required to disassemble the fitting decreases, potentially resulting in leakage. This is especially problematic because plastic formulations often have additives, like glycerol monostearate, designed to reduce friction or the static properties of the material. Without being bound by any particular theory, it is believed that these additives may migrate to the surface of the material resulting in lubricious material being present at the surface. This can cause a decrease in the coefficient of friction of the material resulting in a lower pull force required to disengage a luer connection. It has been found that adjusting the surface finish on at least the male conical tip of a luer connection of a medical device results in an increase in the force required to disengage the fitting.
[0014] This is a surprising result as it has long been known that increasing the surface roughness of a luer fitting increases the tendency for leakage during injection. Therefore, it was unexpected to find that increasing the surface roughness could, instead, result in a connection with high pull forces with little or no leakage.
[0015] With reference to FIG. 1 , one or more embodiments of the invention are directed to medical devices 10 comprising a male luer slip fitting 12 . The male luer slip fitting 12 being connectable to a female luer portion 14 of a second medical device 16 by application of an engagement force to provide a contact surface between the male luer slip fitting 12 and female luer portion 14 , and separable by application of a disengagement force that does not require substantial twisting motion, meaning that in normal use, the male luer slip fitting 12 and female luer portion 14 do not require more than 90 degrees of relative radial movement. Normally, the male luer slip fitting 12 and female luer portion 14 are assembled by simply applying an axial force in the direction of the longitudinal axis of each fitting by pressing the parts together. It will be appreciated that during normal assembly some small amount of relative twisting between the male luer slip fitting 12 and female luer portion 14 may be utilized by the practitioner to assembly the fittings. The male luer slip fitting 12 comprises a material incorporating a lubricious agent such that the disengagement force of a dry connection is less than the engagement force when the contact surface does not include a roughened surface. The male luer slip fitting 12 has a contact surface that is roughened 18 such that the disengagement force required to separate the male luer slip fitting 12 from the female luer portion 14 of the second medical device 16 , when in a wet connection, is greater than the force required to disengage the male luer fitting 12 from the female luer portion 14 of the second medical device 16 when the contact surface of the male luer fitting 12 is not roughened.
[0016] Another aspect of the invention pertains to methods of making a medical device. The methods comprise manufacturing a male luer fitting with a conical tip having an outside surface that mates with a female luer fitting of a second medical device. The male luer fitting is manufactured from a material which contains a lubricious agent such that the force required to disassemble a non-roughened male conical tip from a female luer fitting is less than the force required to assemble the non-roughened male luer fitting from the female luer fitting. The outside surface of the male conical tip is roughened such that upon assembly of the male luer fitting with the female luer fitting, with liquid present between the male conical tip and female luer fitting, the removal force is less than about the assembly force.
[0017] In other embodiments, the force required to disengage the male luer fitting from the female luer portion increases with increasing engagement force. In specific embodiments, the force required to disengage the male luer fitting from the female luer portion is less than about 80% of the engagement force. In more specific embodiments, the force required to disengage the male luer fitting from the female luer portion is less than about 75%, 70% or 65% of the engagement force.
[0018] The surface of the male luer in various embodiments is roughened using a mold to form the tip. The mold has been roughened using a technique selected from Electrodischarge Machining (EDM), vapor honing, cross hatching, polishing and combinations thereof. The external surface of the male luer fitting of some embodiments is roughened to between about 0.3 μm to about 1.2 μm. In specific embodiments, the external surface of the male luer fitting is roughened to between about 0.4 μm to about 0.8 μm. In other specific embodiments, the surface is roughened to have an average roughness of about 0.3 μm or about 0.4 μm or about 0.7 μm or about 1.2 μm. In further specific embodiments, the roughened surface is prepared by electrodischarge machining. The roughened surface of detailed embodiments has a surface with a random patterned finish, i.e., there is not obviously repeatable pattern to the finish. The surface of other detailed embodiments has a repeatable pattern.
[0019] In one or more embodiments of the invention, the medical device is made of a material that includes an additive that enhances the lubricious property of the material. The additive of detailed embodiments is glycerol monostearate. In other detailed embodiments, the additive is a slip agent. In still further detailed embodiments, the slip agent is a fatty acid amide.
[0020] The invention will be further described with reference to examples.
EXAMPLES A-E
[0021] Luer slip syringes made from a resin which lacked glycerol monostearate, or other lubricious agents, were assembled with a needle tip luer fitting. Assembly occurred under controlled axial forces at 3, 6, 8, 10 and 12 lb. The hub pull force required to disassemble the syringe from the luer fitting was measured.
EXAMPLES F-J
[0022] Luer slip syringes made from a resin which included a lubricious agent, specifically 2500 ppm glycerol monostearate, were assembled with a needle tip luer fitting. Assembly occurred at controlled axial forces of 3, 6, 8, 10 and 12 lb. (Although a resin having 2500 ppm was used for these samples, the same phenomenon has been observed in syringes made from resins with lower amount of GMS, for example, 1200 ppm and 600 ppm.) The hub pull force required to disassemble the syringe from the luer fitting was measured.
[0023] FIG. 2 shows a graph of the pull force required to disassemble a connected hub for Examples A-J under wet conditions. There were between 25 and 30 measurements taken at each data point. The data shows that the pull forces increased with increasing assembly force for materials without GMS. On the other hand, the pull forces for syringes with GMS remained fairly constant, with increasing spring back, regardless of the assembly force. Spring back is a phenomenon where the assembly force, on a luer slip syringe assembled to a female luer device, when removed, the syringes shows a sudden movement away from the female device. The number of samples exhibiting spring back is listed above each column of data points in FIG. 2 .
EXAMPLES K-O
[0024] Luer slip syringes made from a resin without glycerol monostearate or other lubricious agents were prepared with a variety of surface finishes. The surface finishes were prepared by Electro-Discharge Machining (EDM) or using a sandblasted tip insert. The average roughness of the EDM finished surfaces were 0.3, 0.4, 0.7 and 1.2 μm. The syringes were assembled with a luer hub using an assembly axial force of 10 lbs. The force required to disassemble the syringe from the hub was measured.
EXAMPLES P-T
[0025] Luer slip syringes made from a resin containing a lubricous agent, specifically glycerol monostearate, were prepared with a variety of surface finishes. The surface finishes were prepared by Electro-Discharge Machining (EDM) or a sandblasted insert. The average roughness of the EDM finished surfaces were 0.3, 0.4, 0.7 and 1.2 μm. The syringes were assembled with a luer hub using an assembly axial force of 10 lbs. The force required to disassemble the syringe from the hub was measured.
COMPARATIVE EXAMPLE CA
[0026] For comparison purposes only, syringes from Terumo Medical Corporation were assembled with a luer hub using an assembly force of 10 lbs. The force required to disassemble the syringe from the hub was measured.
[0027] FIG. 3 shows a graph of the hub axial pull force (lbs) required to disassemble the syringes of Examples K-T and Comparative Example CA under wet conditions. The average surface roughness for the EDM prepared samples is listed below the chart. The surface roughness for the samples containing the sandblasted insert is not listed. FIG. 3 shows that the syringes which have glycerol monostearate and a surface finish (Examples P-T) show equivalent pull forces to the modified surface finished syringes that do not have GMS. The data also shows that after modifying the surface with EDM or adding a sandblasted tip insert, the pull forces are equivalent to the pull forced exhibited by a Terumo® syringe.
EXAMPLES U-Z
[0028] Luer slip syringes made from a resin containing a lubricious agent, specifically glycerol monostearate, were prepared with the surface finishes shown in Table 1. The syringes were assembled with a luer hub at assembly axial forces of 8, 10 and 12 lbs. The force required to disassemble the syringe from the hub was measured.
[0000]
TABLE 1
Sample
Surface Finish
U
Unmodified
V
Sandblasted tip insert
W
EDM, Average Roughness = 0.3 μm
X
EDM, Average Roughness = 0.4 μm
Y
EDM, Average Roughness = 0.7 μm
Z
EDM, Average Roughness = 1.2 μm
[0029] FIG. 4 . Shows a graph of the hub pull forces for Samples U-Z under wet conditions. The data shows that the syringes with GMS and a surface finish (Samples V-Z) have a pull of force which increases with the assembly force, like the samples without a lubricious agent. (See Samples A-E in FIG. 2 .) Whereas the group of samples that have GMS but no surface finish (Sample U) have relatively equivalent pull off forces regardless of the assembly force, as was previously shown in Samples F-J. (See FIG. 2 .)
[0030] Reference throughout this specification to “one embodiment,” “certain embodiments,” “one or more embodiments” or “an embodiment” means that a particular feature, structure, material, or characteristic described in connection with the embodiment is included in at least one embodiment of the invention. Thus, the appearances of the phrases such as “in one or more embodiments,” “in certain embodiments,” “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily referring to the same embodiment of the invention. Furthermore, the particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments.
[0031] Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and applications of the present invention. It will be apparent to those skilled in the art that various modifications and variations can be made to the method and apparatus of the present invention without departing from the spirit and scope of the invention. Thus, it is intended that the present invention include modifications and variations that are within the scope of the appended claims and their equivalents. | 1a
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BACKGROUND
[0001] The present invention relates to inhibiting mold growth and more particularly the invention is directed to a coating that protects buildings from mold.
[0002] The growth of fungi and mold on and in structures has become of major concern to builders, owners and their respective insurers. For instance U.S. Pat. No. 6,894,136 entitled Mold Inhibitor Integrated within a Matrix and Method of Making Same , teaches a composition for the prevention or remediation of mold growth in a man made structures. The composition contains an extruded milo matrix incorporating terpenes, phytoalexins, calcium propionate or combinations of these chemicals having anti-fungal activity. Methods of making and using the described compositions are also disclosed.
[0003] While methods have been developed to protect structures from a host of environmental elements and conditions, the successful treatment of structures against the growth of mold has continued to prove troublesome. The solutions proposed to date are costly to implement, often involve the use of toxic chemicals or substances that present additional risks to the environment, the user or both or that require repeated application.
[0004] There remains a need for an effective, long term, simple, safe and inexpensive means of inhibiting the growth of fungus and mold on building materials incorporated into structures and in finished building constructions. Therefore, one objective of the present invention is to provide a mold inhibitor that is relatively low in cost to produce and to apply. Another objective of the present invention is to provide a method for applying the mold inhibitor.
SUMMARY
[0005] The present invention is directed to a mold inhibiting mixture including hydrated lime, (CaH 2 O 2 ), also referred to as calcium hydroxide, mixed with a viscosity enhancing agent, lemongrass oil and an emulsifying agent. In a preferred embodiment, the viscosity enhancing agent includes a base oil. In a preferred embodiment, the mold inhibiting mixture also includes a spray tracer. A mold inhibiting emulsion is formulated by mixing water with the mold inhibiting mixture. A method of protecting a building construction material with a mold inhibiting emulsion includes the steps of applying the mold inhibiting emulsion onto at least one surface of the construction material. Preferably, the method includes application of the spraying the mold inhibiting emulsion onto the outer surfaces of all framed component parts of a framed construction and observing that there has been complete coverage as indicated by the spray trace.
[0006] These and other features of the invention will be apparent from the following description of the preferred embodiments thereof, and from the claims.
DETAILED DESCRIPTION
[0007] A mold inhibiting mixture according to the present invention includes calcium hydroxide, (CaH 2 O 2 ), (hydrated lime), mixed with a viscosity enhancing agent, lemongrass oil and an emulsifying agent.
[0008] In a preferred embodiment of the invention, the viscosity enhancing agent includes a base oil. The base oil may be any of a variety of light mineral or vegetable oils. Horticultural oils are the preferred as they are the least toxic on the market. Horticultural oils are characterized as having a viscosity in the range of approximately 50 to 200. In one preferred embodiment, a paraffin-based horticultural oil is used as the base oil. One such paraffin-based horticultural oil is produced by Bonide Products, Inc., of Oriskany, N.Y. and marketed as Bonide All-Seasons Horticultural Spray Oil or Sunspray Ultra-Fine. In an alternate embodiment, a food-grade canola or cottonseed horticultural oil is employed as the base oil. One such food-grade horticultural oil is marketed as Concern Pesticide Oil, Oil-Away by Gardens Alive, Inc., 5100 Schenley Place, Lawrenceburg, Indiana. Alternately, neem seed-oil extract may be used as the base oil. Neem seed-oil is an extract from the seeds of the neem tree, ( Azadirachta indica ). In another alternate embodiment, a modified biodegradable petroleum oil may be used as the base oil.
[0009] In an alternate embodiment of the invention, the viscosity enhancing agent includes a spreader-sticker agent. A spreader-sticker agent is a biodegradable, combination spreading, sticking and penetrating agent for providing improved distribution and adhesion of the sprayed mold inhibiting emulsion. The spreader-sticker agent is substituted for the base oil and aides the active ingredient chemicals by increasing adhesion to a sprayed surface and providing enhanced flow characteristics allowing the mixture to spread out evenly on the sprayed surface maximizing effectiveness. By providing better distribution and adhesion of the active ingredient chemicals a greater effectiveness is achieved from the mixture reducing waste and cost of application. In one embodiment, the spreader-sticker agent is mixed with ten parts water to make an additive that is then mixed with the hydrated lime, lemongrass oil and the emulsifying agent. In one embodiment a spreader-sticker agent includes ethane, 1,1,1-Trichloroethane, (C 2 H 3 Cl 3 ), mixed at a rate of 20-25% with 75-80% phthalic/glycerol alkyl resin. In one embodiment a spreader-sticker agent manufactured by Bonide Products, Inc., of Oriskany, N.Y. and marketed as Turbo spreader-sticker agent is mixed with the active ingredients to provide a mold inhibiting mixture having desirable spreading, sticking and penetrating characteristics.
[0010] Lemongrass oil is an extract of one of the grasses of the family Poaceae (Gramineae), species Cymbopogon , i.e., Cymbopogon afronardus, Cymbopogon ambiguus, Cymbopogon citratus , ( Andropogon citratus ), Cymbopogon citriodora, Cymbopogon flexuosus, Cymbopogon jwarancusa, Cymbopogon jwarancusa, Cymbopogon nardus, Cymbopogon martini, Cymbopogon nardus, Cymbopogon refractus, Cymbopogon schoenanthus, Cymbopogon tortilis, Cymbopogon validus and Cymbopogon winterianus . Lemongrass is a perennial herb widely cultivated in the tropics and subtropics, characterized broadly as East Indian lemongrass and West Indian lemongrass. The qualities of any particular lemongrass oil are determined by the content of citral, terpineol, myrcene, citronellol, methyl heptenone, dipentene, geraniol, limonene, nerol, and farnesol. West Indian lemongrass oil is characterized by a slightly lower citral content than East Indian lemongrass oil.
[0011] In a preferred embodiment, the mold inhibiting mixture also includes an emulsifying agent. In the preferred embodiment of the invention, the emulsifying agent is formulated as a 9-Octadecanoic acid (9z)-, monoester with 1, 2, 3 propanetriol. In an alternate preferred embodiment, the emulsifying agent comprises glyceryl monooleate, (C 21 H 40 O 4 ).
[0012] In a preferred embodiment, the mold inhibiting mixture also includes a spray tracer mixed with the emulsifying agent so that those areas to which the mixture or an emulsion containing the mixture have been applied are readily discernable from those areas that have not been treated.
[0013] A mold inhibiting mixture according to the preferred embodiment of the invention includes hydrated lime, lemongrass oil, a base oil and a spray tracing agent mixed with an emulsifier as follows: Approximately 90.7 kilograms, (two-hundred pounds) of hydrated lime, (CaH 2 O 2 ), 17.24 kilograms, (thirty-eight pounds), of horticultural base oil, 0.45 kilograms, (one pound), of lemon grass oil are mixed with 0.68 kilograms, (one and half pounds), of an emulsifying agent.
[0014] In a preferred embodiment, a mold inhibiting emulsion includes a mold inhibiting mixture of hydrated lime, a base oil, lemongrass oil and an emulsifying agent mixed with water at a rate in the range of 2%-50% of the mold inhibiting mixture and 50-98% water. More preferably, a mold inhibiting emulsion includes the mold inhibiting mixture of hydrated lime, lemongrass oil, a horticultural base oil and an emulsifying agent mixed with water at a rate in the range 2%-50% of the mold inhibiting mixture and 50-98% water.
EXAMPLES
[0015] The test procedure for testing resistance to growth of fungi on a treated surface included the inoculating a malt extract agar applied to plates treated with the mold inhibiting emulsion of the present invention. Various mold inhibiting emulsions were formulated and tested. The various mold inhibiting emulsions were prepared by mixing a mold inhibiting mixture according to the preferred embodiment of the invention with water at various concentrations. Two certified strains of fungi, Aspergillus niger and Stachybotrys chartarum , were employed in the testing. The treated and inoculated plates were incubated at 25° C. for a period of 7 days. Colony size as measured by diameter was recorded at the end of the incubation period and compared with the colony size of the same organisms cultured on untreated plates.
[0016] According to the test procedure, a mold inhibiting mixture according to the present invention including hydrated lime, lemongrass oil, base oil, emulsifying agent and spray tracer agent was mixed initially. For the purpose of these tests, the mold inhibiting mixture included the following constituents by percentage weight:
[0017] Composition—Mold Inhibiting Mixture, (by weight):
[0000]
Hydrated Lime
82.8%
Base Oil
15.8%
Emulsifying Agent
0.6%
Lemongrass oil
0.4%
Spray Tracer Agent
0.4%
Total
100.0%
[0018] TESTED FORMULATIONS: According to the test procedure, a mold inhibiting emulsion according to the present invention was prepared by mixing the mold inhibiting mixture with water to the percent by volume concentrations shown below.
[0000]
TABLE 1
Mold Inhibiting Emulsion:
Sample # 1
Sample # 2
Sample # 3
Mold Inhibiting Mixture
5.0%
10.0%
25.0%
Water
95.0%
90.0%
75.0%
Total
100.0%
100.0%
100.0%
[0019] According to a preferred embodiment of the invention, a mold inhibiting emulsion is formulated by combining the mixture according to the present invention including hydrated lime, lemongrass oil, base oil, emulsifying agent and spray tracer agent with water. For the purpose of these tests, the mold inhibiting mixture included the following constituents by percentage weight:
[0000]
TABLE 2
Mold Inhibiting Emulsion:
Sample # 1
Sample # 2
Sample # 3
Hydrated Lime
4.14%
8.28%
20.70%
Lemongrass oil
0.02%
0.04%
0.10%
Base Oil
0.79%
1.58%
3.95%
Emulsifying Agent
0.03%
0.06%
0.15%
Spray Tracer Agent
0.02%
0.04%
0.10%
Water
95.00%
90.00%
75.00%
Total
100.00%
100.00%
100.00%
[0020] Test results.
[0000]
TABLE 3
Test # 1
Colony size/mm
Negative control 1
No Growth
Negative control 2
No Growth
Positive control Aspergillus niger 1
95
Positive control Aspergillus niger 2
95
Positive control Stachybotrys chartarum 1
10
Positive control Stachybotrys chartarum 2
12
Sample # 1 Aspergillus niger 1
No growth
Sample # 1 Stachybotrys chartarum 1
No growth
Sample # 1 Aspergillus niger 2
No growth
Sample # 1 Stachybotrys chartarum 2
No growth
Sample # 2 Aspergillus niger 1
No growth
Sample # 2 Stachybotrys chartarum 1
No growth
Sample # 2 Aspergillus niger 2
No growth
Sample # 2 Stachybotrys chartarum 2
No growth
Sample # 3 Aspergillus niger 1
No growth
Sample # 3 Stachybotrys chartarum 1
No growth
Sample # 3 duct Aspergillus niger 2
No growth
Sample # 3 Stachybotrys chartarum 2
No growth
[0000]
TABLE 4
Test # 2
Colony size/mm
Negative control 1
No Growth
Negative control 2
No Growth
Positive control Aspergillus niger 1
100
Positive control Aspergillus niger 2
95
Positive control Stachybotrys chartarum 1
13
Positive control Stachybotrys chartarum 2
13
Sample # 1 Aspergillus niger 1
No growth
Sample # 1 Stachybotrys chartarum 1
No growth
Sample # 1 Aspergillus niger 2
No growth
Sample # 1 Stachybotrys chartarum 2
No growth
Sample # 2 Aspergillus niger 1
No growth
Sample # 2 Stachybotrys chartarum 1
No growth
Sample # 2 Aspergillus niger 2
No growth
Sample # 2 Stachybotrys chartarum 2
No growth
Sample # 3 Aspergillus niger 1
No growth
Sample # 3 Stachybotrys chartarum 1
No growth
Sample # 3 duct Aspergillus niger 2
No growth
Sample # 3 Stachybotrys chartarum 2
No growth
[0021] In the preferred embodiment of the invention, the base oil, the emulsifying agent, the lemongrass oil and spray tracer agent are shipped as a “concentrate.” In this case, a typical formulation for a mold inhibiting concentrate would be formulated to include a viscosity enhancing agent mixed at a concentration in the range of 80% -95%, an emulsifying agent mixed at a concentration in the range of 1.0%-10.0% and lemongrass oil mixed at a concentration in the range of 1.0%-10.0%. A spray tracer agent may also be included in the mold inhibiting concentrate mixed at a concentration in the range of 1.0%-10.0% In a preferred embodiment, a mold inhibiting concentrate is formulated as follows:
[0022] Composition—Mold Inhibiting Concentrate, (by weight):
[0000]
Base Oil
91.9%
Emulsifying Agent
3.5%
Lemongrass oil
2.3%
Spray Tracer Agent
2.3%
Total
100.0%
[0023] A mold inhibiting concentrate is mixed first with hydrated lime to prepare the mold inhibiting mixture described herein above. This mixing is typically performed at the location of application for reasons associated with ease of shipping and handling. Water is then added to the mold inhibiting mixture in the concentrations noted herein above to prepare the mold inhibiting emulsion. The mold inhibiting emulsion is then applied according to the methods of the present invention.
[0024] It will be evident that there are additional embodiments and applications that are not disclosed in the detailed description but which clearly fall within the scope of the present invention. The specification is, therefore, intended not to be limiting, and the scope of the invention is to be limited only by the following claims. | 1a
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CROSS REFERENCE TO RELATED APPLICATION
This application claims the benefit of provisional U.S. Patent Application Serial No. 60/192,469, filed Mar. 27, 2000.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to point of sale packaging for image-grade printing paper which can be additionally used for display and storage of images printed upon the paper.
2. Background of the Invention
Digital imaging including artwork, photography, or even text, now enjoys wide-spread popularity for personal use. Digital printers such as ink jet, laser jet and dye sublimation printers are becoming popular means for the average consumer to print a variety of images for personal display and in some instances, limited distribution.
High grade papers especially adapted for accepting digital images have been developed for use with these digital printers. Such high grade papers, some grades of which may sometimes be called “photo-finishing papers”, will hereinafter be referred to as “image-grade papers,” to distinguish them from standard paper used largely for the printing of text and from standard light sensitive photographic papers. Image-grade papers may be adapted for receiving water based inks, used with ink-jet printers which, for example, are currently popular for home use. These papers are adapted to handle the higher water content concomitant with the higher amount of water-based ink used in printing an image as compared to a text based document. These papers may consist of four layers including a receiver layer, a barrier layer, a base layer and a backing layer enabling the paper to set the ink, handle the water and protect the paper from saturation which may lead to paper wrinkling, smearing, and image degradation. Gloss level, fade resistance and wear resistance may also be carefully controlled attributes of these image-grade papers. The paper may become quite expensive to the consumer as its ability to accept and display high resolution printed images becomes more refined.
Currently these image-grade papers are provided to the general public largely in letter size 8.5×11 inch format, packaged in some combination of cardboard and shrink-wrap outer covers. Neither the size of the paper nor its container is particularly suitable for personal printing and display of standard sized images. For example, a typical photograph, or print, may be in 3×5 inch or 5×7 inch format, both of which are accepted by most people as standard and reasonable sizes. Also, for these sizes of prints, or images, a great deal of display hardware, such as various frames, in already extant.
To trim such a printed image from a single sheet of image-grade paper may result in much waste of expensive paper and will require concerted effort by the individual wishing to display the print. If a person prints an image to utilize as much of the 8.5×11 inch paper as possible, then display of the image with ubiquitous frames becomes problematic. Also the 8.5×11 inch format will be recognized as a text format and may be psychologically less pleasing for display. Further, storage of the odd sized prints may be problematic.
Therefore what is needed is a packaging which supplies image-grade paper in traditional image display sizes and formats in order to prevent waste and promote convenience of digital image printing and display for the user. It is further desirable that such packaging be useful for the convenient display or storage, or both, of the images printed thereon.
SUMMARY OF THE INVENTION
The present invention solves the above needs in the art by providing pre-cut image-grade paper sheets for typical image sizes and formats in a sturdy, easily-stored container which may be further used as a display stand for the printed images.
The image-grade papers provided may be adapted for receiving water based inks, used with ink-jet printers which, for example, are currently popular for home use, or the image-grade papers may be adapted for use with other printers which may dispense variously formulated image printing compounds onto the paper.
The container is preferably a rigid plastic case which is lightweight and easily mass produced such as by injection molding. The container preferably has at least one clear, or translucent, or both, surface for facilitating display of a pre-cut sheet upon which an image has been printed by the purchaser. The closed container will provide close fitting halves to protect the expensive image grade paper and may further provide protection for the printed image by affording display in the closed position.
In one embodiment, a specially-adapted stand is provided for the closed paper container whereby display and protection of the printed images, as well as any unused blank sheets, is provided. The stand may alternatively be used inside the container as a means to bias the paper towards the display surface of the container. The stand is preferably constructed and arranged to fit within the container before purchase and has two halves connected by a living hinge to facilitate the proper shape for use as a display stand or provide the bias means as stated above.
The container is preferably provided as a two part box incorporating a closely fitted base and hinged cover allowing the cover to swing through about a 315° arc. According to one such embodiment of the present invention, the cover section can then serve as an upright display easel supported by the base section in an abutting relationship without the need for elaborate hinge or stop mechanisms. The container preferably has at least one internal shelf constructed and arranged to hold the blank paper within the container and to place a printed sheet in a display position.
Through use of the present invention, small scale printing of individualized announcements, artistic portfolios, or other commercial or aesthetic images may be created and conveniently conveyed. Simple image printing and display for personal use is, of course, contemplated.
By correctly sizing the container, ubiquitous storage means such as those available for compact disc storage, may be used to facilitate the storage of the containers when they are used for storing printed images.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 depicts a laid open position of one embodiment of the container and paper according to one aspect of the present invention;
FIG. 2 depicts the embodiment of FIG. 1 in a closed position;
FIG. 3 depicts the embodiment of FIGS. 1 and 2 in a display position;
FIG. 4 depicts a laid flat position of one embodiment of a multipurpose stand according to one aspect of the present invention.
FIG. 5 depicts a side view of the stand of FIG. 4 and the container arranged in an alternative display position.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Referencing FIG. 1, one embodiment of a point of purchase image-quality paper packaging, storage and display container 11 is shown in the open state. The container generally comprises a rigid box structure having a first section 13 serving as a cover or base portion as further explained below, and a second section 15 serving as the paper retaining portion. The first section 13 and second section 15 are hingedly connected by a simple pin-in-hole arrangement 17 on opposing sides 19 , 21 of the container 11 . The general structure of the container 11 is akin to a common compact disc case and may be congruently sized therewith to utilize compact disc storage racks. The hinged portions of the first and second sections 13 , 15 are constructed to allow the sections to rotate freely through about 315° until the major surface 23 of the second section 15 abuts an edge 25 of the major surface of the first section 13 , as shown in FIG. 3 .
The container is suitably formed by injection molding crystal polystyrene, K-resin, or a combination thereof, although other materials may be found suitable. The entire container may be translucent and clear although only the second section major surface 23 needs to be clear in an embodiment such as FIG. 5 where the container 11 is closed and yet utilized as a display. Alternatively as seen in FIG. 3, the container 11 may be utilized in an open position as a display, leaving the image exposed to the air and thus requiring no clear surfaces on the container 11 . Certain embodiments of the present invention may utilize ultraviolet (UV) light inhibitors or colors in the material of the container if desired.
The second section 15 is shown with a single shelf 29 , provided with a lip 31 extending parallel to the major surface 23 from a side wall 33 of the second section. The shelf 29 is provided as a simple means for releasably holding blank paper sheets 35 within the second section 15 . The lip 31 may be sized at 2.9×0.46 inches in an embodiment sized congruently with a standard compact disc case, sometimes also called a jewel box or case. The ordinarily skilled artisan will appreciate that various constructions may be utilized for the paper-holding function without departing from the scope of the present invention.
The paper 35 is sized to fit closely within the confines of the container 11 . The paper 35 and the container 11 are preferably provided in sizes close to standard image printing formats such as three by five (3×5) inch, four by six (4×6) inch, or five by seven (5×7) inch, all of which may utilize to some degree storage containers mass produced for the storage of compact disc containers. A standard compact disc container, or jewel box, has outer dimensions of 4.92 inches by 5.65 inches by 0.41 inch. The present invention may utilize the injection molds of jewel boxes with minimal modifications.
The paper is preferably a premium quality image-grade blank paper at greater than 20 pound weight and a brightness ratio of 92 or more as will be understood by those of skill in the paper arts. More preferably, the image-grade blank paper is of the highest quality for image reproduction such as coated or glossy so called “photo printing” papers. A variety of paper grades may also be provided in a single container allowing the consumer to test printing on less expensive grade paper before committing to a print on the most expensive grade of paper provided. At a depth of 0.41 inch, the container 11 will generally hold 14-20 such blank sheets of image-grade printing paper. By pre-sizing the paper to meet standard image sizes and/or formats, the present invention will result in less waste of the expensive image-grade papers, as well as less wasted packaging, and minimal effort on the part of the individual who wishes to print a stored visual image.
Referencing FIG. 2, the container 11 is shown in a closed position with the first section 13 and the second section 15 releasably engaged and containing the multiple sheets of blank image-grade printing paper 35 therein. Also indicated therein is a stand 47 , as further explained below. Sales, branding, or identifying indicia may be easily placed into the container 11 and remain visible when the container, or parts thereof, are constructed from translucent materials. A wrapping may also be placed over the container 11 to protect both the container, or a display surface thereof, and the paper 35 , if desired.
Referencing FIG. 3, the container 11 is shown in one possible display position. The first and second sections 13 , 15 have been disengaged from their closed position (FIG. 2) and rotated through about a 315° arc placing the second section at about a 45° angle when the first section 13 is placed on the horizontal to act as a base for supporting the upright second section 15 . A single paper sheet 37 having an image 39 printed thereon, has been placed in the shelf 29 with the image facing away from the second section major surface 23 for display. Cutaways 41 may be provided in opposing side walls 43 of the second section 15 to provide for ease of paper handling. The second section major surface 23 abuts the first section major surface 27 at an edge 25 thereof. A cutaway 45 in the second section major surface 23 behind the shelf 29 may be provided for ease of molding.
Referencing FIGS. 4, the stand 47 is shown in a laid flat position. The stand 47 is preferably a bilaterally symmetrical one piece apparatus molded from a resilient plastic polymer. The line of symmetry is a thinned area serving as a living hinge 49 . Also referencing FIG. 5, the living hinge 49 allows the halves of the stand 47 to be folded downward whereby inside portions 53 of support hooks 51 integral to each half of the stand 47 may support the container 11 . Outside portions 55 of support hooks 51 are configured to contact a horizontal surface. Contiguous with each support hook 51 is an angled front edge 57 serving as further support for the container 11 in the display position (FIG. 5 ). Rearward of the angled edge 57 , the body 59 of the stand 47 forms the remainder of the support structure and provides an additional edge 61 , contiguous with outside portions 55 , for each stand half for contacting the horizontal surface on which the stand rests. Due to the resilient nature of the living hinge 49 , once the stand 47 has been folded in half it will have a tendency to assume a partially flattened shape thereby making the hinge 49 useful as a biasing means for urging a paper sheet 37 towards a major surface, e.g., 23 , of the container 11 when the stand 49 is replaced inside the container 11 , as shown in FIG. 2 .
A magnet 61 may be glued to the outside of the major surface 27 of the first section 13 to aid in using the container 11 as a display in the closed position without the aid of the stand 47 . The magnet 61 will provide means for attachment of the container to a separate surface nonintegral with said container surfaces, such as a refrigerator door or the like. In nonpreferred embodiments, the container 11 may have additional means for aiding in display, such as holes in the container or appendages thereon, for receiving mounting means such as picture hooks or the like.
Having thus described an exemplary embodiment of the point of sale package for the sale of image-quality printing paper serving as a display means for printed images, it will be appreciated that many variants of the described embodiment may occur to person of ordinary skill in the art. The scope of the present invention is not intended to be limited by the described embodiment, but only by the appended claims. | 1a
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BACKGROUND OF THE INVENTION
[0001] The present invention pertains to medication delivery devices, and, in particular, to a piston of a pharmaceutical cartridge for a medication delivery device.
[0002] A variety of medication delivery devices, such as injector pens and infusion pumps, employ pharmaceutical cartridges that include a movable piston and contain a multi-dose quantity of liquid medication. In an injector pen, a drive member, extending from within a base of the injector pen and operably connected with typically more rearward mechanisms of the pen that control drive member motion, is movable forward to advance the piston in the cartridge in such a manner to dispense the contained medication from an outlet at the opposite cartridge end, typically through a needle that penetrates a stopper or septum at that opposite end. In disposable pens, after a pen has been utilized to exhaust the supply of medication within the cartridge, the entire pen is discarded by a user, who then begins using a new replacement pen. In reusable pens, after a pen has been utilized to exhaust the supply of medication within the cartridge, the pen is disassembled to allow replacement of the spent cartridge with a fresh cartridge, and then the pen is reassembled for its subsequent use.
[0003] While these types of medication delivery devices with cartridges offer a number of advantages to their users, such devices are not without their limitations. For example, possible compression of the cartridge piston during an injection can have a negative effect on the overall operation of the device. For an injector pen, such piston compression can result in the pen's medication drooling from the needle after an injecting force has been removed and the needle has been prematurely withdrawn from the user, and/or the pen delivering a dose that is less than anticipated.
[0004] Thus, it would be desirable to provide an apparatus that can overcome one or more of these and other shortcomings of the prior art.
BRIEF SUMMARY OF THE INVENTION
[0005] In one form thereof, the present invention provides a piston for a pharmaceutical cartridge including a tubular barrel extending in an axial direction, the piston being advanceable by a separate drive member of a medication delivery device equipped with the cartridge. The piston includes a body and a core. The body has a distal end, a proximal end and a sealing periphery, which distal end is in contact with a medication disposed within the cartridge barrel, which sealing periphery is in sealing contact with an interior surface of the barrel, and the distal end and the sealing periphery are unitarily constructed from a material having a first hardness. The core is within the body and sealed within the cartridge barrel between the distal end and the proximal end. The core is constructed from at least one material having a second hardness greater than the first hardness to limit axial compressibility of the piston.
[0006] One advantage of the present invention is that a pharmaceutical cartridge piston can be provided which resists axial compression during an injection.
[0007] Another advantage of the present invention is that a pharmaceutical cartridge piston can be provided which may enhance dose accuracy.
[0008] Still another advantage of the present invention is that a pharmaceutical cartridge piston can be provided which may reduce injection hold time.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] The above-mentioned and other advantages and objects of this invention, and the manner of attaining them, will become more apparent, and the invention itself will be better understood, by reference to the following description of embodiments of the invention taking in conjunction with the accompanying drawings, wherein:
[0010] FIG. 1 is a front perspective view of a pharmaceutical cartridge including a first embodiment of a piston of the present invention;
[0011] FIG. 2 is a longitudinal cross-sectional view of the cartridge of FIG. 1 , which cartridge is further shown loaded in one form of an abstractly shown medication delivery device;
[0012] FIG. 3 is a rear perspective view of the piston of FIG. 1 removed from the rest of the cartridge;
[0013] FIG. 4 is a front perspective view in longitudinal cross-section of the piston of FIG. 3 ;
[0014] FIG. 5 is an exploded, front perspective view of the piston of FIG. 3 ; and
[0015] FIG. 6 is a longitudinal cross-sectional view of a second embodiment of a pistoin of the present invention.
[0016] Corresponding reference characters indicate corresponding parts throughout the several views. Although the drawings represent embodiments of the present invention, the drawings are not necessarily to scale, and certain features may be exaggerated or omitted in some of the drawings in order to better illustrate and explain the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0017] Referring now to FIG. 1 , there is shown a perspective view of a pharmaceutical cartridge, generally designated 10 , including a first embodiment of a piston of the present invention, which piston is generally designated 20 . FIG. 2 shows the cartridge of FIG. 1 loaded in one type of a medication delivery device, such as an injector pen or injection pen. The present invention alternatively may be utilized in other medication delivery devices.
[0018] With additional reference to FIGS. 3-5 , cartridge piston 20 has an axially extending, generally cylindrical, main body 21 that includes a distal end face 22 and a proximal end face 24 . Along its radial periphery, body 21 is formed with a first sealing rib 26 that is immediately adjacent to the distal end face 22 , a second sealing rib 28 immediately adjacent to the proximal end face 24 , and an axially shorter rib 30 centrally disposed therebetween. Circumferential recesses 27 and 29 are disposed between ribs 26 and 30 , and ribs 30 and 28 , respectively. Sealing ribs 26 , 28 and 30 each extend continuously around the circumference of body 21 to form rings that provide a fluid tight seal with the interior surface of the cartridge tubular barrel to prevent passage of materials out from and into the medicine reservoir. A plurality of protuberances 32 project from the planer distal end face 22 and the planer proximal end face 24 to limit adhesion between multiple pistons when in, for example, a hopper during assembly line production of multiple pharmaceutical cartridges.
[0019] Main body 21 is formed of a material, such as halo butyl rubber, that is chemically and biologically compatible with the not shown medication contained within cartridge 10 . A silicone emulsion coating may be provided on body 21 to provide lubrication. One particularly suitable elastomeric formulation for body 21 is available from West Pharmaceutical Services of Lionville, Pa. and is known as West Formulation PH 4002/50 Red. This elastomeric formulation has a hardness, or resistance to deformation by indentation, using the Shore A Durometer scale, of between 45 and 55.
[0020] Piston 20 also includes a relatively rigid core or insert 40 that is fixedly disposed within a cylindrical hollow or bore 35 of piston body 21 . Core 40 is shown as being cylindrical in overall form, with a planer distal face 42 , a planer proximal face 44 , and an outer periphery 46 . Core 40 is axially centered within the axial or longitudinal length of body 21 , and further is radially centered within body 21 so as to be in alignment with and symmetrical with respect to the central axis of cartridge tubular barrel 55 .
[0021] Core 40 results in piston 20 being less compressible in the axial direction, while not compromising the ability of the piston via its sealing ribs 26 , 28 and 30 to seal the medicine reservoir. This lesser compressibility not only may improve dose accuracy, but also may shorten the dynamic response, and therefore the injection hold time, during which the piston's elastic properties cause the piston to return toward its original shape to account for any piston compression during injection. In one form, core 40 is a solid aluminum casting, having a hardness which is greater than the hardness of the elastomeric formulation of body 21 so as to provide a stiffening effect to the piston. Although aluminum is described as being used, one or more other relatively stiff materials, such as various plastics or other polymeric materials, may be used to form the rigid core in alternate embodiments. The hardness or resistance to deformation of these other possible core materials is greater than the hardness of the piston main body material, regardless of, for example, numerical values that are dependent on the type of hardness test, such as Brinell, Rockwell, Shore or other method, by which the hardness is measured. Furthermore, the shape of the rigid core need not be cylindrical to provide advantageous piston properties. For example, cores which have an overall shape more hour-glass in design, or cores having protruding ribs or molding features, may be used within the scope of the invention.
[0022] Core 40 can be of various axial lengths as well as various diameters, while still performing its stiffening function. For a standard piston body having an axial dimension of about 0.32 inch, and a diameter of the sealing ribs 26 , 28 and 30 of about 0.39 inch, the axial length of core 40 extending between distal face 42 and proximal face 44 is within the range of about 0.08 inch-0.24 inch, more preferably within the range of about 0.16 inch-0.24 inch, and most preferably about 0.24 inch. The diameter of the core may be of various size, such as in the range of about 0.08 inch-0.31 inch.
[0023] Plug 50 covers the proximal face of core 40 and is secured to the piston body 21 , such as via adhesives. Plug 50 is cylindrical and sized to completely fill the piston hollow 35 not filled by core 40 , and seals core 40 within body 21 . The proximal face of plug 50 is coplanar with proximal end face 24 . Plug 50 is made of the same elastomeric formulation as is piston body 21 . Consequently, core 40 is completely encapsulated within the elastomeric formulation that is chemically and biologically compatible with the medication contained within the pharmaceutical cartridge. In alternate embodiments, core 40 may be encapsulated within a one-piece piston body molded completely thereover, in that the plug/piston body combination shown separately formed in the embodiment of FIGS. 1-5 is integrally molded and formed as a single encapsulating piece.
[0024] The remainder of cartridge 10 may be of standard form, including a tubular barrel 55 , made of glass or other suitable material, which has an inner surface 52 . The inner surface 52 along the larger diameter section of the barrel is sealingly engaged by sealing ribs 26 , 28 and 30 of piston 20 . The distal end of tubular barrel 55 includes an inwardly sloping shoulder portion 56 , a reduced diameter neck 58 , and a rim 60 . Rim 60 provides a circumferential flange having a larger outer radius than that of neck 58 . The distal, outlet end of barrel 55 is sealed by septum 62 held by cap 64 that is secured to rim 60 . The medicine-filled reservoir 54 is of variable volume due to the movability of piston 20 , and is defined by septum 62 , the interior surface 52 , and the distal end face 22 of piston 20 . In alternate embodiments, the larger diameter section of the tubular barrel can have other than the cylindrically shaped interior surface shown, provided the exterior of the piston is appropriate modified so as to provide the fluid tight seal therewith.
[0025] With reference again to FIG. 2 , cartridge 10 including piston 20 is shown loaded in an abstractly shown injection pen. The injection pen is equipped with a pen-needle assembly of known design, generally designated 70 , a drive member, generally designated 80 , having an enlarged foot 81 that directly contacts piston 20 , a manually accessible input member, such as the shown plunger, generally designated 90 , and an injecting mechanism, generally designated 100 . The needle of assembly 70 punctures cartridge septum 62 during mounting of the needle assembly to the medication delivery device as is conventional to provide an outlet for the pharmaceutical within the reservoir 54 . As is conventional, injecting mechanism 100 is operatively connected with the drive member 80 and plunger 90 to produce appropriate motion of the drive member that shifts piston 20 distally within barrel 55 during plunger operation. A variety of different known injecting mechanisms are suitable to convert an input, such as a plunging force, into an advancement of a drive member to force medication from the pharmaceutical cartridge.
[0026] Referring now to FIG. 6 , there is shown an axial cross-sectional view of an alternate cartridge piston 20 ′ of the present invention. In this embodiment, rigid core 100 has a larger axial length than core 40 , so as to have its proximal face 101 coplanar with the annular proximal end face 24 ′ of the piston body 21 ′. Such a construction may facilitate molding, but may require either proper orientation of the piston during its assembly to the cartridge barrel during manufacture, or a suitable material selection for core 100 along with sufficient testing to satisfy any requirements related to the core material possibly being in contact with the medicine should the piston be inadvertently inverted during cartridge/piston assembly.
[0027] Piston 20 and 20 ′ are well suited to be axially advanced, without rotation, via an abutting contact with a foot 81 that merely translates, without rotation, during drive member 80 advancement. In alternate embodiments, piston 20 or 20 ′ c an be screwed into the cartridge barrel during piston advancement via, for example, a foot that contacts, and does not slip relative to, the piston, which foot and drive member screw distally as a unit during injecting operations. Such a screwably advancing piston may provide even better dose accuracy, but likely requires larger forces being generated to so move that piston during its advancement. Still further, the core and/or piston body can include a hollow for accommodating a portion of the drive member that inserts thereinto. In such a construction, the hollow may be keyed in the case of a torque-transmitting engagement between a screwing drive member and the screwable piston.
[0028] While this invention has been shown and described as having preferred designs, the present invention may be modified within the spirit and scope of this disclosure. This application is therefore intended to cover any variations, uses or adaptations of the invention using its general principles. Further, this application is intended to cover such departures from the present disclosure as come within known or customary practice in the art to which this invention pertains. | 1a
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a fishing rod and its method of manufacture and more particularly, to an improved fishing rod including a tubular rod and a first plurality of multiple longitudinally extending, helical weavings intertwined with a second plurality of multiple longitudinally extending, helical weavings of a tow or yarn disposed on the tubular rod, said weavings defining a crossing interlocking pattern which provides high elasticity, excellent softness and super power control properties. The present invention is also directed to the method of manufacturing the fishing rod.
2. Description of Related Art
Various types of fishing rods are well known in the art. Such conventional fishing rods are made by the following process. After a properly sized sheet of carbon prepreg such as a pre-impregnated material containing glass fibers is wound onto a steel fishing rod as a mold, a polyethylene or polypropylene tape is then wound on the rod mold. Thereafter, the rod mold is molded and processed and the steel rod mold is then separated therefrom and the tape is removed from the sheet to form the conventional fishing rod.
However, such conventional fishing rods suffer from a number of problems such as, for example, they tend to crack when the fishing rod is exposed to shock. Also, conventional fishing rods do not posses high elasticity, excellent softness and super power control, and also they are expensive to manufacture due to the complicated manufacturing steps which are required.
SUMMARY OF THE INVENTION
Accordingly, it is an object of the present invention to provide a fishing rod, which eliminates the above problems encountered with conventional fishing rods.
Another object of the present invention is to provide an improved fishing rod including a tubular rod and a first plurality of multiple longitudinally extending, helical weavings intertwined with a second plurality of multiple longitudinally extending, helical weavings of a tow or yarn disposed on the tubular rod, said weavings defining a crossing, interlocking pattern which possesses high elasticity, excellent softness and super power control properties.
A further object of the present invention is to provide a method of manufacturing a fishing rod which comprises the steps of longitudinally and helically weaving a plurality of weavings of tow or yarn onto a tubular rod, said weavings being initiated from different positions along the circumference of the tubular rod but proceeding in substantially the same direction longitudinally along the rod for intertwining and forming a crossing, interlocking pattern along the surface of the rod.
Still another object of the present invention is to provide a tubular fishing rod which is simple in structure, inexpensive to manufacture, durable in use, and refined in appearance.
Other objects and further scope of applicability of the present invention will become apparent from the detailed description given hereinafter. It should be understood, however, that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
Briefly described, the present invention is directed to a fishing rod including a tubular rod which is provided with a plurality of multiple longitudinal, helical weavings which intertwine with each other and to a method of manufacturing such a fishing rod which possesses high elasticity, excellent softness and super power control properties.
BRIEF DESCRIPTION OF THE DRAWINGS
The present invention will become more fully understood from the detailed description given hereinbelow and the accompanying drawings which are given by way of illustration only, and thus, are not limitative of the present invention, and wherein:
FIG. 1 is a perspective view of the fishing rod according to the present invention; and
FIG. 2 is an enlarged perspective view of an A portion of FIG. 1 showing how the longitudinally extending, helical weavings disposed on the fishing rod cross and interlock with each other to produce the reinforced fishing rod of the present invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Referring now in detail to the drawings for the purpose of illustrating preferred embodiments of the present invention, the tubular fishing rod and its method of manufacture as shown in FIGS. 1 and 2 comprises a tubular rod 1, a first plurality of longitudinally extending tows or yarns and a second plurality of longitudinally extending tows or yarns helically intertwined with the first plurality of longitudinally extending tows and disposed on the surface of the tubular rod 1.
The tubular rod can be made of any well known natural or synthetic resinous (plastic) material, e.g., polyethylene, polypropylene, polyvinyl chloride, various types of polyesters, and the like. Also the tubular rod can be made of graphite, reinforced graphite, graphite-boron, and fiberglass.
The first plurality of longitudinally extending tows or yarns are identified in FIGS. 1 and 2 as elements 2, 2a, 2b, 2c, and 2d. The second plurality of longitudinally extending tows or yarns are identified in FIGS. 1 and 2 as elements 3, 3a, 3b, 3c, and 3d.
As shown in FIG. 2, each longitudinally extending tow or yarn 2, 2a, 2b, 2c, and 2d, etc. is helically intertwined with each longitudinally extending tow or yarn 3, 3a, 3b, 3c, and 3d, etc. in an over-under relationship and thus are intertwined in a crossing, interlocking pattern along the surface of the rod. The weaving process is repeated until the manufacture of the fishing rod is complete. The number of weaving can be varied to establish the desired properties in the fishing rod, such as strength, elasticity and the like. Advantageously, the weavings cross each other, two at a time in defining the interlocking and crossing pattern of the fibers.
The tows or yarns 2, 2a, 2b, 2c, 2d, 3, 3a, 3b, 3c, and 3d can be made of natural or synthetic resinous materials, carbon or glass fibers, or natural or synthetic resinous material containing carbon or glass fibers. The tow or yarn 2 can be in the form of a string, a braid or a bundle and advantageously, the resinous material can be an epoxy resin, a polyamide resin, or the like.
The method of manufacturing the tubular fishing rod according to the present invention can be described as follows. First of all, as shown in FIGS. 1 and 2, the first longitudinal tow or yarn 3 is helically intertwined with the first and second longitudinal tows or yarns 2 and 2a by passing over the tows or yarns 2 and 2a, and is further helically intertwined With the third and fourth longitudinal tows or yarns 2b and 2c by passing under the tows or yarns 2b and 2c. Thereafter, the tow or yarn 3 is helically intertwined with the longitudinal tows or yarns 2d, etc. and so on (not shown) by passing over tows or yarns 2d and so on.
The second longitudinal tow or yarn 3a is helically intertwined with the same manner as discussed above but when yarn 3a is passing over two yarns 2 and 2a, yarn 3 is passing under one yarn 2 and over adjacent yarn 2a. However, in the embodiment shown in FIGS. 1 and 2, all the yarns cross each other in an over-under relationship, two at a time. Although this arrangement has been found to be particularly effective in achieving the advantageous results of the present invention, it will be obvious that many other weaving an interlocking patterns can be utilized.
The number of tows or yarns 2, 2a, 3, 3a, etc. wound around the tubular rod can be varied depending on the properties desired in the fishing rod. Obviously, the distance the tows or yarns are disposed on the rod relates to each other affect the strength, elasticity, etc. of the rod. The closer the spacing, the stronger and more rigid the rod becomes.
The tows or yarns 2, 2a, 2b, 2c, 2d, 3, 3a, 3b, 3c, and 3d can be present in numbers of about 16 to 120 for providing high elasticity and super power control properties, preferably numbers of 40 to 100, more preferably numbers of 60 to 80. These number ranges indicate the number of tows or yarn disposed around the circumferential cross section of the fishing rod.
Accordingly, the fishing rod of the present invention as shown in FIG. 1 has high elasticity, excellent softness, and super power control so that the tubular fishing rod does not break, has a long lifetime and can be mass-produced. In order to produce a thick rod with increased hardness, the weaving process is continuously repeated.
In addition, the fishing rod according to the present invention is simple in structure, inexpensive to manufacture, durable in use and refined in appearance.
The invention being thus described, it will be obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention, and all such modifications as would be obvious to one skilled in the art are intended to be included within the scope of the following claims. | 1a
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a mechanism for changing a length or position of a support surface of seats and/or couches.
2. Description of the Prior Art
Modern, mass-produced upholstery furniture pieces such as seats and/or couches have backrests with a constant height. Therefore, they do not provide an appropriate support for short persons. For tall persons, the height of the seat backrests often is too short. The leg support for tall persons is also inadequate, and a tall person cannot properly bend his/her legs because a short distance between the seat and a floor surface.
Accordingly, an object of the present invention is a mechanism for changing the position of the support surface(s), e.g., of the seating surface, in such a way that the position of at least one of associated support surfaces, which are smoothly combined with each other, can be easily arbitrary changed.
SUMMARY OF THE INVENTION
This and other objects of the present invention, which will become apparent hereinafter, are achieved by providing a mechanism for changing a position of a support surface for seats and couches and a length of which changes in a longitudinal direction, and including two horizontally spaced from each other, telescopic rods having each a bent region, two slide connection elements surrounding the two telescopic rods and carrying a deformable region of the support surface, and two telescopic sleeves in which the two telescopic rods are telescopically displaceable. The mechanism permits to arbitrary change the position of a respective support surface, which permits to accommodate it for a person with a different height.
The novel features of the present invention, which are considered as characteristic for the invention, are set forth in the appended claims. The invention itself, however both as to its construction and its mode of operation, together with additional advantages and objects thereof, will be best understood from the following detailed description of preferred embodiments, when read with reference to the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
The drawings show:
FIG. 1 a perspective view of a support surface in a retracted condition;
FIG. 1 a , a view similar to that of FIG. 1 but with sliding elements surrounding the telescopic rods;
FIG. 2 a perspective view of a support surface in a pull-out condition;
FIG. 2 a , a view similar to that of FIG. 1 but with sliding elements surrounding the telescopic rods.
FIG. 3 a perspective view of a support frame for the support surface;
FIG. 4 a perspective view of the support frame shown in FIG. 3 for relaxation of thigh muscles;
FIG. 5 a cross-sectional view of telescopic rods and the support surface;
FIG. 6 a side view of a folding mechanism;
FIG. 7 a side view of the folding mechanism shown in FIG. 6 in its extended position;
FIG. 8 a schematic view of the telescopic arrangement in its retracted position;
FIG. 9 a schematic view of the telescopic arrangement in its pull-out position;
FIG. 10 a schematic view of a bending zone of another embodiment of the displacement mechanism;
FIG. 11 a perspective view of a deformable region of the support surface;
FIG. 12 a perspective view of a telescopic leg with a portion of the retracted support surface;
FIG. 13 a perspective view of a telescopic leg with a portion of the pull-out support surface;
FIG. 14 a view showing the telescopic leg shown in FIG. 12 with a covering; and
FIG. 15 a view showing the telescopic leg shown in FIG. 13 with a covering.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
FIG. 1 shows a deformable region 22 of the support surface 3 in the retracted position of the support surface 3 . In the position shown in FIG. 1 , telescopic rods 1 of the telescopic mechanism are completely inserted in telescopic sleeves 2 provided in the frame of the telescopic mechanism. The support surface 3 is displaced into its retracted position to accommodate a short person. The displacement of the telescopic rods 1 , together with the support surface 3 secured thereto, is effected by a height controlling mechanism including tooth bars 4 which are attached to the support surface 3 , and tooth gears 5 which cooperate with respective bars 4 and which are supported on a common shaft supported in brackets 7 secured to respective sleeves 2 . The displacement of the support surface 3 is effected manually with a hand wheel 6 . The support surface 3 can be displaced in any position between the completely retracted position shown in FIG. 1 , and a completely pull-out position shown in FIG. 2 in which the deformable region is completely expanded as shown with a reference numeral 23 .
FIGS. 1 a and 2 a show, respectively, views similar to those of FIGS. 1 and 2 and showing telescopic rods of the telescopic mechanism being surrounded by sliding elements 8 which are secured to respective telescopic sleeves 2 by brackets 29 , as shown in FIG. 1 a . As further shown in FIG. 1 a, the sliding elements 8 almost completely surround the telescopic rods 1 in the retracted position of the deformable region 22 of the support surface 3 . However, the sliding elements 8 , as shown in FIG. 2 a , only partially surround the telescopic rods in the pull-out position of the deformable region 22 of the support surface 3 .
FIG. 3 shows the support frame 30 for the support surface 3 , together with the height controlling mechanism.
FIG. 4 shows the support frame 30 shown in FIG. 3 but with means for relaxation of thigh muscles. The relaxation means includes a support 12 and a resilient strip 14 mounted on the support 12 and having a smooth surface 13 .
FIG. 5 shows a cross-sectional view of the telescopic rods 1 and the support surface 3 which is attached to the slide connection elements 8 surrounding the telescopic rods 1 and secured thereto. Means 9 provides for stretching of the support surface 3 . The reference manual 9 represent a back cover which can be more elastic or less elastic. The support surface can be formed of upholstery 10 of textile or foam material which is covered by a covering 11 .
FIG. 6 shows a folding mechanism 15 which controls the position of the telescopic sleeve 2 . The telescopic sleeve 2 is retained in its predetermined position by an axle bolt 17 displaceable in a slot 16 .
FIG. 7 shows the position of the folding mechanism 15 in a maximum extended position of the sleeve 2 .
FIGS. 8 and 9 show the mechanism for displacing the telescopic rods 1 between their retracted ( FIG. 8 ) and pull-out ( FIG. 9 ) positions which correspond, respectively, to folded and extended positions of the telescopic sleeves 2 which are determined by positions of the axle bolt 17 in the slot 16 . The axle bolt 17 is displaced by displacement bars 18 which is displaced by a lever mechanism including two levers 19 . The free ends of the levers 19 are connected with the telescopic rods 1 by displacement bars 20 . Upon appropriate actuation of the lever mechanism, the telescopic sleeves 2 and the telescopic rods II are displaced from the retracted position shown in FIG. 8 to the pull-out position shown in FIG. 9 .
FIG. 10 shows an end element 21 with which a synchronized displacement of the telescopic rods 1 is achieved. The end element 21 is attached to a region 25 of the support surface 3 the length of which does not change during displacement of telescopic rods 1 between the retraced and pullout positions. With the constant length region 25 , a height-controlling mechanism for displacing the telescopic rods 1 is not necessary. The retraction and pull-out is effected by a corresponding displacement of the cover 9 in a respective direction for displacing the telescopic rods 1 in the channels 26 .
The end element 21 is connected to the bending region 25 in a predetermined spaced relationship with respect to the corresponding telescopic sleeves 2 . The angular position of the deformable end element 21 influences the position of the telescopic rods 1 . The different positions of the telescopic rods 1 correspond to different degrees of deformation of the end element 21 which is supported at its opposite ends in brackets 29 ( FIG. 11 ). The position of the telescopic rods 1 depend on the degree of stiffness of the deformed end element 21 . Thus, the changing of the angular position or the degree of deformation of the end element 21 results in a desired displacement of the telescopic rods 1 . This permits to eliminate the height controlling mechanism. Different degrees of deformation of the end element 21 are shown in FIGS. 12–15 . The reference numeral 27 and 28 show the positions of telescopic rods 1 in the retracted ( FIG. 12 ) and pull-out ( FIG. 13 ) positions. Reference numerals 27 a , 28 a designate conditions of the coverings of the telescopic rods 1 .
The present invention makes a substantial contribution to the advancement of health care. The present invention is based on an effective use of ecological resources. The present invention is based on a mechanical principle that contributes to economy of material and sets forth alternative possibilities of changing the conditions of the support surface without the use of external energy sources.
Though the present invention was shown and described with references to the preferred embodiments, such are merely illustrative of the present invention and are not to be construed as a limitation thereof and various modifications of the present invention will be apparent to those skilled in the art. It is therefore not intended that the present invention be limited to the disclosed embodiments or details thereof, and the present invention includes all variations and/or alternative embodiments within the spirit and scope of the present invention as defined by the appended claims. | 1a
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BACKGROUND
[0001] Men's dress has evolved over the years such that formal and business attire is generally staid with respect to color. Neutral tones are prevalent and bright tones nearly absent. However, despite the fact that most formal and business dress relies heavily on a neutral palette, color is still an essential component of men's dress: The addition of color to men's wardrobes is the job of the tie. As a men's dress accessory, the tie is such an essential part of men's attire that it is required in most formal and business situations. Furthermore, the tie bears part of the responsibility of making the wearer's impression upon viewers a favorable one, as it may be the most visible piece of apparel in a suit of clothes that is seen by approaching viewers. It rests in a conspicuous, forward position at nearly eye level, and even when a suitcoat is closed, the tie knot is a spot of bright color above the lapel.
[0002] While the tie has been a dress essential for years, the evolution of ultrasmall modes of electronic entertainment is relatively recent. The miniaturization of entertainment and information means has made it possible for one to bring music and other auditory modes of entertainment and information with them to the gym, to the office, on errands, etc. However, even though such miniaturized modes of entertainment are small and relatively unobtrusive, carrying them in plain view is not appropriate for every common setting, as they can still be very visible when worn with formal or business clothes, such as attached to a belt or stowed in a breast pocket. The visible presence of, for example, an ipod, on ones person, may give the subtle impression that the wearer is distracted by recreation and lacks the presence of mind and discipline for the occasion. Even hiding a device, such as an ipod, in a pocket, generally does not make the device inconspicuous because the wire to the audio piece is visible. Nevertheless, the stability afforded by such an arrangement has always been considered necessary in order to keep the device from being damaged by blows and spills.
[0003] While ties are essential, and there is a need for effective methods for concealing technological entertainment and information devices, there have been few attempts to merge ties and technology. Ties are important ornamental accessories as they greatly impact the wearer's first impression upon new acquaintances. Thus, the involvement of the tie in a more functional sense has been avoided. Creases and outlines visible on the surface of the tie are generally unacceptable in any setting, and any interference with the natural dynamics of the tie, such as that caused by weights or fasteners is just as undesirable. Furthermore, securing a section of a tie by methods known in the art does not improve its ability to be merged with technology, as adding weight to the unsecured section, such as by attaching a technological device, could cause the tie to move unnaturally as the wearer moved about, particularly when leaning forward.
[0004] In short, the tie has remained an important ornamental accessory, required in many common settings, but for such a common accessory, surprisingly, it has, not been utilized to address the need for effectively concealed technological devices.
BRIEF DESCRIPTION OF THE DRAWINGS
[0005] FIG. 1 :
[0006] A pocket in position on a necktie, bearing upper ( 10 ), and lower ( 50 ) tabs along the extended long axis of the pocket, a flap ( 20 ) and a slanted upper edge ( 30 ) in the side of the pocket which rests against the wearer ( 40 ).
[0007] FIG. 2 :
[0008] A pocket in position on a necktie, bearing a flap ( 20 ) having a depth ( 70 ); and a slanted upper edge ( 30 ) in the side of the pocket which rests against the wearer ( 40 ).
[0009] FIG. 3 :
[0010] A pocket in which corners of the upper edge of the side of the pocket which rests against the wearer terminate at points having the same distance from the upper edge of the pocket.
[0011] FIG. 4 :
[0012] A pocket ( 120 ) attached to a tie ( 90 ). The pocket has two tabs, ( 110 ) and ( 150 ), which bear insertion slots through which buttons ( 100 ) and ( 130 ), respectively, are inserted. The upper tab ( 110 ) is alternatively depicted in dashed lines as folded downward. No device is depicted in the figure.
BRIEF DESCRIPTION OF THE INVENTION
[0013] The present invention pertains to a tie which comprises a suitably placed pocket and attachment mechanism such that the tie can be used to conceal and carry devices having relatively flat profiles without causing the motion of the tie to be awkward with wearer movement. Furthermore, the article of the present invention conceals and carries such devices without causing creases or outlines on the front surface of the tie. In one embodiment, the pocket is sized such that it has the ability to snugly contain an object having approximate dimensions of 4.5×3.5×0.5 inches or less. In another embodiment the pocket is sized such that it has the ability to snugly contain an ipod. In another embodiment, the pocket is sized such that it has the ability to the snugly contain one or more items of card-thickness, such as business cards, credit cards or the like. In another embodiment, the pocket is sized such that it has the ability to fit an iphone.
DETAILED DESCRIPTION OF THE INVENTION
[0014] Unlike other designs, the present invention can port objects having a flat profile and a weight as great or greater than about 8 ounces without causing outlines or creases on the front surface of the tie. The weight is secured in a pocket secured to the shirt with at least one attachment slot attached to the pocket edge, or an attachment hole within the surface of the pocket facing away from the tie. The pocket is attached to the wide portion of the tie, and is dimensioned such that its corners do not extend beyond the edges of the tie, allowing the tie to carry the device without moving unnaturally with wearer motion. Furthermore, the tie also does not buckle when the wearer leans over. Upon stowing the appliance in the pocket, the weight of the load is supported by the attachment slots or button hole.
[0015] The necktie pocket of the present invention comprises a front and a back. The front and back may be of two different materials or of the same material. The word “material” as used here has a meaning which is not limited to textiles and woven fabrics, but encompasses sheet-like forms which are fabricated in ways other than weaving, such as, for example, forms fabricated by rolling and cutting.
[0016] While many different materials can be used, materials having a thickness of less than or about 0.8 mm are preferred, with materials having a thickness in the range of from about 0.05 to about 0.25 most preferred. Examples of suitable materials include organic fabrics such as fabrics based on cotton, flax, jute, mohair, silk, wool, hemp, tweed and the like, or other fabrics consisting of or comprising fibers or threads of organic materials such as, but not limited to the forenamed materials or other cellulose-based fibers. Suitable materials also include fabrics consisting of or comprised of synthetic threads or fibers, for example, those of nylon, rayon, polyester, spandex, acetate, acrylic, modacrylic, and olefin, or other synthetic materials. Many fabrics having a blend of organic and inorganic components are suitable. So called “non-woven fabrics, such as, for example sheets of polytetrafluoroethylene, nylon, or other synthetics formed by processes such as, for example, rolling or cutting, can be used to comprise the present invention.
[0017] It is preferred that the side of the pocket which rests against the wearer be of a material which is sheer and sleek to such as degree that the intended article slides easily into and out of the pocket with out “grabbing” or bunching of the pocket material. Furthermore, sheer materials having a degree of transparency are preferred; the device in the pocket can be adjusted without removal from the pocket, adding to the unobtrusiveness of the design. Such fabrics are also generally cooler in that they dissipate heat at a faster rate that non-sheer fabrics. One advantage to such a design is that the heat produced during the operation of the device is readily dissipated from the sheer surface and thus the pocket remains comfortable to the wearer over long periods of time. Furthermore, because the pocket does not produce elevated temperatures when worn, less sweat is produced by the wearer, and the pocket material remains dry, ensuring that the article slides freely in and out of the pocket.
[0018] In general, many different types of sheer materials can be utilized for the pocket surface which faces the wearer. Preferred are materials having some degree of transparency such as, for example, tricot, tulle, voile, organdy, organza, net, lawn, linen, chiffon, georgette and lace. Other sheer materials having less transparency can also be used, but are less preferred. Such materials are preferred for the surface of the pocket which contacts the tie, and include most types of natural or synthetic fabric. These fabrics can include fabrics used for lining, underlining, backing or mounting, including silk, china silk, batiste, bemberg, cotton net, satin, muslin, organza, taffeta or tricot. Preferred is lining fabric as it is thin and lightweight.
[0019] Non-fabric materials can also be used in the present invention. Examples include sheet synthetic materials, such as of the aforementioned synthetic materials.
[0020] In one embodiment, the side of the pocket which is against the tie is of silk, or of the material from which the tie is made. In another embodiment, both the side of the pocket against the tie and the side against the wearer are of silk or of the material from which the tie is made.
[0021] It should be noted that the necktie pocket of the present invention can be integral. By “integral,” it is meant that the pocket can be of “one-piece” construction. Examples of such construction are one-piece designs comprising a folded piece of construction material which is sewn or otherwise seamed such that it forms a pocket. Another example of a one-piece construction is a flattened tubular section, which may be preferred in the case of synthetic or sheet construction materials. Where a pocket is of one-piece construction, it is preferred that the unsewn, closed sides be creased such the pocket lies flat against the wearer. In a preferred embodiment, the pocket is of two-piece construction.
[0022] In one embodiment, the pocket comprises a flap ( FIG. 2 , 60 ). Preferably, the flap is integral with the side of the pocket which rests against the tie, although in one embodiment, the flap is sewn to the body of the pocket, and in an additional embodiment, the flap is not of the same material as the side of the pocket to which it is attached. Preferably, the flap has a depth ( FIG. 2 , 70 ) which is in the range of from about 0.5 inches to about 3.5 inches, and more preferably in the range of from about 0.5 inches to about 2.0 inches.
[0023] In one embodiment, the necktie pocket of the present invention comprises a slanted edge to the front side of the pocket ( FIG. 2 , 65 ). Preferably, the slanted edge is relatively straight and does not bear projections or edgings that interfere significantly with the insertion or extraction of the device. In one embodiment, the edge deviates from being straight in that the lower portion of the edge comprises a slightly concave section which facilitates the insertion and extraction of the device. In one embodiment, the slanted edge is finished along its length with stitching or lamination which stiffens the edge and improves the ability of the wearer to insert and extract the device. In one embodiment the uppermost corner of the slanted edge terminates at a corner of the pocket. In other embodiments, the upper corner of the edge terminates at a point below a pocket corner (See FIG. 2 ). In a further embodiment, the upper corner of the edge terminates at a point which is in the range of from about 0.25 inches to about 2.0 inches below a corner of the pocket. The lowermost corner of the edge preferably terminates at a point which is in the range of from about 0.25 to about 2.0 inches below a corner of the pocket. However, in another preferred embodiment the lowermost corner of the edge is low enough such that controls on the edge or body of a device carried within the pocket are exposed, such as button- or wheel-shaped volume, selection or other controls.
[0024] In one embodiment, the corners of the edge terminate at points which are in the range of from about 0.0 to about 2.0 inches below a corner of the pocket. In a further embodiment, the corners of the edge terminate at equal distances from the upper edge of the pocket as shown in FIG. 3 . In further embodiments, the edge is straight, or it bears one or more concave portions.
[0025] The necktie pocket of the present invention preferably comprises at least one attachment means. Said attachment means can be a clip which secures the necktie pocket against the shirt of the wearer in the tie's natural position against the shirt. Such a clip should secure the middle of the pocket to the wearer's shirt, such that when loaded, the pocket remains flat against the wearer's shirt, even when the wearer leans over. In a preferred embodiment, said at least one attachment means comprises at least one attachment slot. By “attachment slot” is meant a slot or a loop into which a button on the shirt of the wearer can be inserted, maintaining the necktie pocket in a flat position against the shirt of the wearer. If two such attachment slots are used (for example, see FIG. 1 in which an attachment slot extends from the upper and lower edge of the pocket, although the embodiment speaks to situations in which the slots are in two different positions) the necktie pocket is essentially immobilized against the shirt of the wearer.
[0026] In one embodiment, the necktie pocket itself has an attachment slot in its exposed side into which one of the shirt buttons of the wearer is inserted. In another embodiment, the pocket comprises attachment loops or attachment slots, preferably two, one of which can be located at the middle of the upper edge of the pocket and one of which can be located in the middle of the lower edge of the pocket. See, for example, FIG. 1 , 10 and 50 ). In one embodiment, the attachment slots are each able to receive a button on a standard dress shirt. In one embodiment, the slots have lengths such that the slots can simultaneously accommodate a button on dress shirts having a range of distances between buttons. Thus, the pocket can be used with nearly any dress shirt, even though the button distances for one shirt may not be exactly equal to the button distances of another shirt; the pocket can accommodate the buttons on most or all dress shirts. In yet another embodiment, the slots are comprised of a relatively sturdy material, or are reinforced such that they have a degree of resistance to bending and retain the functional aspects of their shapes, such as a rigid slot which is not bent or crimped, and which can accept a button without needing to be straightened or flattened. In another embodiment, the attachment slots are of a material such that they are flexible or floppy, and such that they may require straightening or flattening in order to accept a button. In a preferred embodiment, at least one of the slots has the shape of two parallel flat strips which are joined together for a portion of their lengths such that they form a slot. In another preferred embodiment, the slots are comprised of an elastic material such that the slot can be stretched, if necessary, to accommodate a button. In a most preferred embodiment, one slot is located essentially in the middle of the upper edge, on the back piece of the pocket, and one is located essentially in the middle of the lower edge of the pocket; each attachment slot comprises an elastic material; and the midpoints of the slots contained in each attachment slot are in the range of from about 5 inches apart to about 9 inches apart.
[0027] In another embodiment, the pocket comprises one or more tabs, each containing one or more insertion slots. In a preferred embodiment, illustrated in FIG. 1 , the pocket comprises two tabs, one tab (the “upper tab”) is located essentially in the middle of the upper edge, on the back piece of the pocket, and one tab (the “lower tab”) is located essentially in the middle of the lower edge of the pocket. At least one tab, and preferably both tabs comprise multiple insertion slots which are, in one embodiment, serially arranged on the tab in positions along the extended long axis of the pocket. In one embodiment, the tabs are comprised of an elastic material. In a preferred embodiment, and the midpoint of each slot on the upper tab is in the range of from about 4 inches to about 10 inches from the midpoint of each slot on the lower tab.
[0028] It should be noted that insertion slots and/or tabs which are oriented along the vertical axis of the pocket and tie can be folded upward (in the case of a downward pointing tab) or downward (in the case of an upward pointing tab) and accept a button through the slots thereon. Folding the tabs/insertion slots enables the inventive pocket to accommodate an even range of button spacings. Furthermore, it prevents the flap from opening, providing an extra measure of protection for the device stowed in the pocket. | 1a
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CROSS-REFERENCE TO OTHER PATENT APPLICATIONS
[0001] This application is a continuation of U.S. patent application Ser. No. 10/147,533 filed on May 16, 2002, the entire content of which is hereby incorporated by reference herein in its entirety.
TECHNICAL FIELD
[0002] The invention relates to devices for manually implanting a bone anchor into bone.
BACKGROUND OF THE INVENTION
[0003] Female Stress Urinary Incontinence (FSUI) is a disorder that can interfere with daily activity and impair the quality of life of women. In approximately 8% of the women suffering from FSUI, incontinence is caused by intrinsic sphincter deficiency (ISD), a condition in which the valves of the urinary sphincter do not properly coapt. In approximately another 8% of FSUI sufferers, incontinence is caused by hypermobility, a condition in which the muscles around the bladder relax, causing the bladder neck and proximal urethra to rotate and descend in response to increases in intraabdominal pressure. Hypermobility may be the result of pregnancy or other conditions which weaken the muscles. Urinary incontinence may also be caused by a combination of ISD and hypermobility. Other causes of urinary incontinence include birth defects, disease, injury, aging, and urinary tract infection.
[0004] Numerous approaches for treating urinary incontinence are available. For example, several procedures for stabilizing and/or slightly compressing the bladder neck or urethra to prevent the leakage of urine have been developed. The stabilizing or compressive force may be applied directly by sutures passing through the soft tissue surrounding the urethra or, alternatively, may be applied by means of a sling suspended by sutures. In some procedures bone anchors are inserted into the pubic bone or symphysis pubis in order to anchor the sutures to the bone. The suture or sling is anchored to the bone by one or more bone anchors and the support provided improves the incontinence condition.
[0005] The instruments used to insert bone anchors are designed to be inserted transvaginally and to position the bone anchor so that a retrograde or pulling force is applied for insertion of the anchor into the bone. However, the optimal configuration or position of the handle of such an instrument for insertion of the device into the vagina is not necessarily the optimal handle position for providing a retrograde force for implanting the bone anchors into the bone. For example, the fixed handle position of conventional bone anchor devices is particularly awkward when treating obese patients
SUMMARY OF THE INVENTION
[0006] The present invention relates to devices and methods for inserting anchors, such as bone anchors, into a bone or tissue.
[0007] In one aspect, a device is provided for manually implanting a bone anchor into a bone; the device includes a handle, a shaft, and a bone anchor-mount. The handle has a proximal end and a distal end. The shaft has a first end and a second end, and may be straight with a bend at its second end, or may instead be hook-shaped. The first end of the shaft is connected to the distal end of the handle. The bone anchor-mount is connected to the second end of the shaft and oriented toward the handle so that a bone anchor received within the mount may be implanted into a bone by applying a retrograde force using the handle. The handle may have at least one finger indentation at its distal end, thereby providing an ergonomic grip. For example, the handle may contain two, three, four or more finger indentations at its distal end. The handle may also be shaped to fit into a user's palm.
[0008] In another aspect, the invention provides a bone anchor implantation device with a handle that can be rotated relative to the longitudinal axis of the shaft during a bone anchor implantation procedure, to facilitate the insertion of the device into a body cavity and/or implantation of a bone anchor. For example, the device can be inserted into the vagina of a patient with the handle in one position, following which the handle can be rotated about the longitudinal axis of the device's shaft and locked into a second position, wherein the second position facilitates the application of a retrograde force or pulling action required for anchoring the bone anchor into a bone.
[0009] In a particular embodiment, the handle may be both rotatable and ergonomic.
[0010] In one version of the device, the handle may be rotatable between two angular positions and may contain a stop assembly for locking the handle in a first or a second angular position. For example, a representative stop assembly has an outer cylinder, an inner cylinder and a spring. The outer cylinder is fixed to the handle and aligned with the shaft, and includes a circumferential slit having a pair of diametrically opposed detents, for example. The inner cylinder is rotatably disposed within the outer cylinder and is also fixed to the first end of the shaft. The inner cylinder includes a drive pin extending horizontally through the inner and outer cylinders. The drive pin has a pair of ends, one or both of which are received within the outer cylinder's circumferential slit and seatable within the detent(s). The seating of the drive pin within the detent(s) prevents rotation of the outer cylinder with respect to the inner cylinder. The spring is disposed within the outer cylinder and urges the inner cylinder in a direction toward the bone anchor-mount. Compression of the spring releases the drive-pin ends from the detents, permitting rotation of the handle.
[0011] In this example, the handle is rotatable between first and second angular positions separated by about 180°, but the detents may be located to provide any desired angular displacement between stops as dictated by the application. The handle may be placed in the first angular position for insertion of the device into a cavity and rotated to the second angular position for implanting the bone anchor. The handle may also have additional angular stop positions.
[0012] The bone anchor-mount may comprise an outer cylinder, an inner cylinder, and a tapered bone anchor receptacle for releasably engaging a bone anchor. In one representative bone anchor-mount, the outer cylinder has a distal end and a proximal end. An annular shoulder is located at the proximal end of the outer cylinder. The inner cylinder is rigidly connected to the outer cylinder and extends proximally therefrom. The bone anchor receptacle is rigidly connected to the inner cylinder and extends proximally therefrom. The device may further comprise a protective sheath connected to the bone anchor-mount for isolating the bone anchor from contact with tissue prior to implantation of the bone anchor into a bone. The protective sheath may be axially movable relative to the bone anchor such that the bone anchor is exposed from the sheath as the bone anchor is pulled or pressed into a bone. In a preferred embodiment, the protective sheath is composed of a flexible material such as, for example, silicone or rubber.
[0013] In another aspect, the present invention provides a method for inserting a bone anchor releasably engaged to a bone anchor implantation device into a bone. The bone anchor implantation device is inserted, a bone anchor implantation site is located on the bone, and a retrograde force is applied to the bone anchor to implant the bone anchor into the bone. The handle may contain one or more finger indentations and may be in a first position for insertion of the device into a body cavity and rotated to a second position for implanting the bone anchor. The locating and implanting steps may be accomplished transvaginally. For procedures relating to FSUI, the bone anchor may be implanted in the posterior pubic bone or implanted lateral to the symphysis pubis and cephalad to the inferior edge of the pubic bone.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] In the drawings, like reference characters generally refer to the same parts throughout the different views. Also, the drawings are not necessarily to scale, emphasis being placed upon illustrating the principles of the invention.
[0015] FIG. 1 is a perspective view of a bone anchor implantation device having an ergonomic handle and a shaft.
[0016] FIG. 2 is a perspective view of a bone anchor implantation device having an ergonomic handle and a bent shaft.
[0017] FIG. 3A is a side view of a bone anchor implantation device having an ergonomic handle and a hooked shaft.
[0018] FIG. 3B is a perspective view of a bone anchor implantation device having an ergonomic handle and a bent shaft.
[0019] FIG. 3C is a perspective view of the handle of the device in FIG. 3B .
[0020] FIG. 3D is a top view of the handle of the device in FIG. 3B .
[0021] FIG. 3E is a side view of the handle of the device in FIG. 3B .
[0022] FIG. 3F is a rear view of the handle of the device in FIG. 3B .
[0023] FIG. 3G is a front view of the handle of the device in FIG. 3B .
[0024] FIG. 3H is a bottom view of the handle of the device in FIG. 3B .
[0025] FIG. 4 is an exploded view of the components of a rotatable bone anchor implantation device having an ergonomic handle.
[0026] FIG. 5 is a perspective view of a rotatable bone anchor implantation device with the handle in a first angular position.
[0027] FIG. 6 is a perspective view of a rotatable bone anchor implantation device with the handle in a second angular position.
[0028] FIG. 7 is an exploded view of the components of a rotatable bone anchor implantation device having an ergonomic handle.
[0029] FIG. 8 is a side view of a rotatable bone anchor implantation device with the handle in a first angular position.
[0030] FIG. 9 is a side view of a rotatable bone anchor implantation device with the handle in a second angular position.
[0031] FIG. 10 is a perspective view of the bone anchor-mount.
[0032] FIG. 11 is a cross-sectional view of the bone anchor-mount of FIG. 10 .
[0033] FIG. 12A is a perspective view of a bone anchor-mount protective sheath.
[0034] FIG. 12B is a perspective view of a protective sheath detached from a bone anchor mount.
[0035] FIG. 12C is a perspective view of a protective sheath attached to a bone anchor mount in an extended position.
[0036] FIG. 12D is a perspective view of a protective sheath attached to a bone anchor mount in a compressed position, showing a protruding bone anchor.
[0037] FIG. 12E is a perspective view of a protective sheath.
[0038] FIG. 13 is a schematic view showing the bone anchor implantation device inserted into the vagina with the proximal end of the second telescoping cylinder contacting the pubic bone.
[0039] FIG. 14 is a schematic view showing an embodiment of the bone anchor implantation device illustrated in FIG. 13 wherein the handle has been rotated after insertion into the vagina, and showing the implantation of a bone anchor into the pubic bone and the compression of the spring.
[0040] FIG. 15 is a cross sectional view of the bone anchor-mount and protective sheath when the protective sheath is contacting the pubic bone.
[0041] FIG. 16 is a cross sectional view of the bone anchor-mount and the protective sheath when the bone anchor is being implanted into the pubic bone.
DETAILED DESCRIPTION OF THE INVENTION
[0042] The present invention relates to a device for implanting a bone anchor into bone. It also relates to methods for improving or maintaining a patient's urinary continence in which bone anchors are inserted transvaginally into the posterior portion of the pubic bone or symphysis pubis.
[0043] A bone anchor implantation device in accordance with the invention may have an ergonomic handle which has at least one finger indentation in the distal end of the handle. The handle may have one, two, three or four or more finger indentations. In one version of this embodiment, the shaft may be attached to the handle between finger indentations.
[0044] A bone anchor implantation device in accordance with the invention may have a handle that can be rotated relative to the shaft of the device, facilitating bone anchor implantation by allowing a physician the flexibility of rotating the handle of the device during the procedure in order to optimize the angle of the bone anchor-mount and shaft relative to the physician's hand and the patient's body. For example, the design of the device allows it to be inserted into the vagina of a patient and to position the bone anchor on a bone and for the handle to be rotated about the longitudinal axis of the shaft of the device prior to providing the retrograde force required to implant the bone anchor into a bone. The form of the handle is not critical to its rotation, e.g., the handle does not need indentations for rotation.
[0045] The bone anchor-mount generally points toward the handle, such that the user can drive the bone anchor into the bone by simply pulling back on the handle and using the patient's body weight to provide an opposing force. Preferably, the longitudinal axis of the bone anchor-mount may be aligned with the longitudinal axis of the handle. A protective sheath may be attached to the bone anchor-mount such that the bone anchor is releasably engaged to the bone anchor-mount but enclosed within the protective sheath and isolated from tissue contact during placement of the device and prior to implantation.
[0046] Referring to the two embodiment illustrated in FIGS. 1 and 2 , the device 110 has a handle 112 , a cylinder 114 , a shaft 116 , 117 and a bone anchor-mount 118 , 119 . The cylinder 114 is connected to, or forms a part of, the handle 112 . The inner end 120 of the shaft 116 , 117 is connected to the distal end 122 of the cylinder 114 . The bone anchor-mount 118 , 119 maybe connected to the outer end 124 of the shaft 116 , 117 .
[0047] The handle 112 may be made of a variety of materials, such as plastic or metal. The shaft 116 , 117 may be made of a variety of materials, such as stainless steel, one or more engineering plastics, fiber-bearing components, or other rigid materials. Preferably, the shaft 116 , 117 is made of stainless steel.
[0048] The shaft 116 may be straight as illustrated, for example, in FIG. 1 . Alternatively, the shaft 117 may be bent, as illustrated, for example, in FIG. 2 or may be arched or hooked, as illustrated, for example, in FIG. 3A .
[0049] The handle 112 may have at least one finger indentation 126 at its distal end 128 . The physician's fingers may be seated in these indentations 126 during operation of the device. The finger indentations 126 are provided and positioned such that a physician has an improved grip for exerting a retrograde force for implanting a bone anchor. In the version illustrated in FIGS. 1 and 2 , the handle 112 has four finger indentations 126 on its distal end 128 .
[0050] The bone anchor-mount 118 , 119 is able to releasably engage a bone anchor. In one embodiment of the invention, the bone anchor-mount 118 , 119 is fixed perpendicular to the outer end 124 of the shaft 116 , 117 . The outer end 124 may be bent or otherwise angled so that the bone anchor-mount 118 , 119 is substantially parallel to the shaft 116 , 117 . For example, FIG. 1 illustrates an embodiment of the invention in which the outer end 124 is bent at an angle of about 90° relative to the longitudinal axis of the shaft 116 and the bone anchor-mount 118 is parallel to the shaft 116 . Alternatively, the outer end 124 may be angled more or less than about 90° relative to the longitudinal axis of the shaft 116 , 117 . The bone anchor-mount 118 , 119 may be fixed to the shaft 116 , 117 at an angle greater or less than 90°.
[0051] The bone anchor-mount 118 , 119 may be oriented toward the handle 112 so that a bone anchor received within the bone anchor-mount 118 , 119 may be implanted into a bone by applying a retrograde force (e.g., a pulling force) using the handle 112 .
[0052] Referring to the device 210 of FIG. 3A , a handle 212 having a different configuration is attached to the inner end 214 of the shaft 216 . The handle is also designed to ergonomically fit the fingers of a physician's hand. As illustrated, the handle contains three finger indentations 220 at its distal end 222 . Alternatively, the handle 212 may contain two, four or more finger indentations 220 at its distal end 222 . In addition, the proximal end 218 of the handle 212 is shaped to fit a physician's palm. FIGS. 3B-3H illustrate various views of a preferred embodiment of the invention in which the handle 212 has three lower finger indentations 220 and one upper finger indentation 220 .
[0053] Referring to FIG. 3A , the shaft 216 comprises an inner end 214 and an outer end 224 , a straight proximal section 226 , a first generally curved section 228 distal to the straight proximal section 226 , a second generally curved section 230 distal to the first curved section 228 , a third generally curved section 232 distal to the second curved section 230 , and a fourth generally curved section 234 distal to the third curved section 232 . The straight proximal section 226 of the shaft 216 may be from about 3 inches to about 6 inches in length, depending on the application. For FSUI procedures, the straight proximal section 226 is preferably from about 4 inches to about 5 inches in length and more preferably about 4.5 inches in length. One of skill in the art will appreciate that the shaft 216 could also comprise a series of straight segments angled relative to one another to form a hook.
[0054] The inner end 214 of the shaft 216 may be connected to the distal end 222 of the handle 212 in between finger indentations 220 . Alternatively, the straight proximal section 226 may pass through a lumen (not shown) extending through the distal end 222 of the handle 212 . The inner end 214 may have a threaded bore which may be adapted to receive a screw 236 which secures the shaft 216 to the handle 212 . If desired, a washer (not shown) may be placed between the distal end 222 of the handle 212 and the screw 236 . Those skilled in the art will appreciate that a variety of other means for securing the shaft 216 to the handle 212 may be employed. For example, a plastic handle may be formed over the shaft such that the shaft is integral with the handle. It should be stressed that the benefits of an ergonomic handle 112 , as illustrated in FIG. 1 , and an ergonomic handle 212 , as illustrated in FIG. 3 , may be utilized in devices that do not permit rotation.
[0055] With continued reference to FIG. 3A , the handle 212 defines an axis at the proximal end of the anchor implantation device 210 , and then moving distally from the handle 212 the shaft 216 first curves away from the axis of the handle and then back toward the axis of the handle 212 . The outer end 224 of the shaft 216 is preferably located in the vicinity of the axis of the handle 212 . In some preferred embodiments, the shaft 216 at the outer end 224 is generally perpendicular to the axis of the handle or can actually curve back toward the handle 212 . For FSUI applications, the distance from the distal end 222 of the handle 212 to the tip of the bone anchor-mount 238 measured along the longitudinal axis of the handle 212 is preferably about 3 and ⅜ inches; the distance from the distal end of the handle 212 to the base of the bone anchor-mount 240 is about 4 inches; and the distance of a line perpendicular to the longitudinal axis of the handle 212 extending from the bottom of the third curved section 232 is about 2 inches.
[0056] A bone anchor-mount 240 may be attached to the outer end 224 of the shaft 216 . The bone anchor-mount 240 may be oriented at an angle from about 60° to about 120° relative to the outer end 224 of the shaft 216 . For FSUI applications, the bone anchor-mount 240 is preferably oriented at an angle from about 80° to about 100°. relative to the outer end 224 of the shaft 216 , and more preferably at an angle of approximately 90°.
[0057] In another version of the invention, illustrated for example in FIGS. 4-6 , the handle of the bone anchor delivery device may be rotatable about the longitudinal axis of the shaft. The device 310 has a stop assembly 312 operable within the cylinder 314 , which is located at the base of the handle 316 . The stop assembly 312 retains the handle 316 in any of two or more angular positions.
[0058] Referring to FIG. 4 , the stop assembly 312 includes a cylinder 314 , a spring 318 , a cylindrical plug 320 , and a drive pin 322 . The cylinder 314 has a proximal end 324 , a distal end 326 , a lumen 328 , a proximal shoulder 330 , a distal shoulder 332 , a circumferential slit 334 and one or more detents 336 within the slit 334 . The plug 320 has a proximal end 338 , a distal end 340 , a drive pin aperture 344 for receiving the drive pin 322 , a proximal face 346 , and a distal face 348 . The plug 320 may have a lumen 342 . The distal end 340 of the plug 320 is fixed to the near end 350 of the shaft 352 . The drive pin 322 is received within the drive pin aperture 344 but not fully, so that it protrudes beyond the radial extent of the plug 320 . Alternatively, the aperture 344 may extend fully through the plug 320 , and the drive pin 322 may have a length greater than the diameter of the plug 320 , so that each end of the drive pin 322 protrudes beyond the radial extent of the plug 320 . Alternatively, the plug 320 may contain more than one aperture and receive more than one drive pin 322 .
[0059] The plug 320 is spring loaded into the cylinder 314 , and the drive pin 322 is introduced into the drive pin aperture 344 so that it engages with (i.e., is movable within) the circumferential slit 334 in cylinder 314 . The distal face 348 of the plug 320 is retained behind the distal shoulder 332 of the cylinder 314 , thereby preventing plug 320 from exiting the cylinder 314 , notwithstanding the force applied by spring 318 . The spring 318 is disposed between the proximal face 346 of the plug 320 and the proximal shoulder 330 of the cylinder 314 . The spring 318 urges the plug 320 in a direction toward the bone anchor-mount 354 .
[0060] The spring 318 may have a resistance of from about 5 to about 35 pounds. Preferably, the spring 318 has a resistance from about 15 to about 25 pounds, and more preferably, about 20 pounds. Those skilled in the art will appreciate that the anchor implantation device may also be adapted to include a force indicating spring in the handle.
[0061] The handle 316 may be rotatable between first and second angular positions, which are dictated by the placement of detents 336 in the cylinder 314 . When the drive pin 322 is seated within the detent 336 , no rotation is possible, and the spring 318 retains the seating of the drive pin 322 until the handle 316 is driven forward, compressing the spring 318 . When the spring 318 is compressed, the drive pin 322 is released from the detent 336 and is free to travel within the circumferential slit 334 , thereby allowing the handle 316 to be rotated about the plug 320 . The handle 316 may be rotated until the spring 318 locks or seats the drive pin 322 into one or more detents 336 , thereby preventing further rotation of the handle 316 with respect to the shaft 352 . In one version of the device, two detents 336 are diametrically opposed along the circumferential slit 334 of the cylinder 314 .
[0062] The drive pin 322 may engage one detent in the cylinder 314 if only one end of the drive pin 322 extends beyond the plug 320 . Alternatively, the drive pin 322 may engage two detents 336 in the cylinder 314 if both ends of the drive pin 322 extend beyond the plug 320 and through the circumferential slit 334 . There may be more detents 336 along the circumferential slit 334 , so that the handle 316 may be rotated among more than two angular positions. There may also be more than one drive pin 322 ; for example, a cross-shaped drive pin may be used to simultaneously be seated in four detents 336 .
[0063] As illustrated in FIG. 5 , the drive pin 322 is seatable within detent(s) 336 and the handle 316 is in a first angular position. FIG. 6 illustrates the device shown in FIG. 5 after rotation of the handle 316 to a second angular configuration, with the drive pin 322 seated within a second detent (or detents) 337 . The first and second angular positions may be, for example, about 180° apart. Of course, depending on the envisioned application, the first and second angular positions may be more or less than about 180° apart.
[0064] In a version of the invention as illustrated to FIGS. 7-9 , a rotatable handle 416 may have a different configuration, in that it may be attached to the inner end 414 of the shaft 452 . The handle may be designed to ergonomically fit the fingers of a physician's hand, as in the non-rotatable device of FIG. 3 . The device 410 is rotatable in a similar fashion as that described for the device illustrated in FIGS. 4-6 .
[0065] Referring to FIG. 7 , the handle 416 may be rotatable between first and second angular positions, which are dictated by the placement of detents 436 in the cylinder 414 . When the drive pin 422 is seated within the detent 436 , no rotation is possible, and the spring 418 retains the seating of the drive pin 422 until the handle 416 is driven forward, compressing the spring 418 . When the spring 418 is compressed, the drive pin 422 is released from the detent 436 and is free to travel within the circumferential slit 434 , thereby allowing the handle 416 to be rotated about the plug 420 . The handle 416 may be rotated until the spring 418 locks or seats the drive pin 422 into one or more detents 436 , thereby preventing further rotation of the handle 416 with respect to the shaft 452 . In one version of the device, two detents 436 , 437 are diametrically opposed on along the circumferential slit 434 of the cylinder 414 .
[0066] The drive pin 422 may engage one detent in the cylinder 414 if only one end of the drive pin 422 extends beyond the plug 420 . Alternatively, the drive pin 422 may engage two detents 436 , 437 in the cylinder 414 if both ends of the drive pin 422 extend beyond the plug 420 and through the circumferential slit 434 . There may be more detents 436 , 437 along the circumferential slit 434 , so that the handle 416 may be rotated among more than two angular positions. There may also be more than one drive pin 422 ; for example, a cross-shaped drive pin may be used to simultaneously be seated in four detents 436 .
[0067] As illustrated in FIG. 8 , the drive pin 422 is seatable within detent(s) 436 , 437 and the handle 416 is in a first angular position. FIG. 9 illustrates the device shown in FIG. 8 after rotation of the handle 416 to a second angular configuration, with the drive pin 422 seated within a second detent(s) 437 . The first and second angular positions may be, for example, about 180° apart. Of course, depending on the envisioned application, the first and second angular positions may be more or less than about 180° apart.
[0068] Referring to FIGS. 10 and 11 , the bone anchor-mount 510 may comprise an outer cylinder 512 , an inner cylinder 514 , and a tapered bone anchor receptacle 516 for releasably engaging a bone anchor 518 . The bone anchor used may be the bone anchor disclosed in the U.S. Pat. No. 5,527,342, the entire disclosure of which is incorporated herein by reference.
[0069] The bone anchor-mount 510 and the bone anchor receptacle 516 are oriented so that the bone anchor 518 may be pointed in the general direction of the handle 512 . In a particular embodiment, the axis of the bone anchor 518 may be generally aligned with the axis of the handle, with the bone anchor 518 pointed toward the handle.
[0070] The bone anchor-mount 510 may be fabricated from the same materials as the shaft 516 and may be attached to the shaft 516 by a variety of methods known to those skilled in the art, such as brazing. The distal end 520 of the outer cylinder 512 has a pair of holes 522 therein sized to accommodate a suture 524 . The outer cylinder 512 may have a diameter from about 0.18 inches to about 0.6 inches. Preferably, the outer cylinder 512 has a diameter from about 0.25 inches to about 0.5 inches. More preferably, the outer cylinder 512 has a diameter of about 0.375 inches.
[0071] As best shown in FIG. 11 , the outer cylinder 512 has a cavity 526 formed therein, creating a cup in the proximal region of the outer cylinder 512 . The proximal end 528 of the outer cylinder 512 has an annular shoulder 530 thereon. The inner cylinder 514 may be connected to the outer cylinder 512 and extends into the cavity 526 . The inner cylinder 514 may be connected to the outer cylinder 512 in a variety of ways known to those skilled in the art. For example, the inner cylinder 514 may be fused to the outer cylinder 512 . Inner cylinder 514 may have grooves 532 therein adapted to accommodate a suture 524 .
[0072] A tapered bone anchor receptacle 516 extends from the proximal end 534 of the inner cylinder 514 . The tapered bone anchor receptacle 516 may extend from the proximal end 534 of the inner cylinder 514 by a distance of from about 0.3 inches to about 0.7 inches. Preferably, the tapered bone anchor receptacle 516 extends from the proximal end 534 of the inner cylinder 514 by a distance of from about 0.4 inches to about 0.6 inches. More preferably, the tapered bone anchor receptacle 516 extends from the proximal end 534 of the inner cylinder 514 by a distance of about 0.5 inches.
[0073] The proximal end 540 of the tapered bone anchor receptacle 516 preferably has a width smaller than that of the proximal end 534 of the inner cylinder 514 . This configuration produces a shoulder 538 which may serve as a depth stop to ensure that the bone anchor 518 may be driven into the bone to the desired depth.
[0074] The proximal end 540 of the tapered bone anchor receptacle 516 may be from about 0.08 inches to about 0.12 inches in width. Preferably, the proximal end 540 of the tapered bone anchor receptacle 516 is from about 0.09 inches to about 0.110 inches in width. More preferably, the proximal end 540 of the tapered bone anchor receptacle 516 is 0.1 inches in width.
[0075] The distal end 536 of the tapered bone anchor receptacle 516 may be from about 0.110 inches to about 0.15 inches in width. Preferably, the distal end 536 of the tapered bone anchor receptacle 518 is from about 0.12 inches to about 0.14 inches in width. More preferably, the distal end 536 of the tapered bone anchor receptacle 516 is 0.13 inches in width. The distal end 536 of the tapered bone anchor receptacle 516 may have a variety of cross sectional shapes adapted to releasably engage the bone anchor 518 . For example, the distal end 536 of the tapered bone anchor receptacle 516 may be square, rectangular, pentagonal, triangular or hexagonal in cross section.
[0076] The tapered bone anchor receptacle 516 may have a notch 542 therein in which the bone anchor 518 may be releasably seated. Alternatively, the outer cylinder, inner cylinder, and tapered bone anchor receptacle may be a single integral component.
[0077] The bone anchor implantation device may have a protective sheath 544 connected to the bone anchor-mount 510 which protects the point of the bone anchor from tissue contact during placement of the device and also protects the bone anchor from contacting potentially infectious microorganisms. The protective sheath 544 comprises a first telescoping cylinder 546 and a second telescoping cylinder 548 . A spring 550 biases the first telescoping cylinder 546 and the second telescoping cylinder 548 to a position in which they extend from the outer cylinder 512 and cover the bone anchor 518 . The first and second telescoping cylinders 546 , 548 may be made of a variety of materials such as stainless steel or plastic. Preferably, the first and second telescoping cylinders 546 , 548 are made of stainless steel.
[0078] The first telescoping cylinder 546 has a lumen 552 extending therethrough. The first telescoping 546 cylinder has a first shoulder 554 which engages shoulder 530 on the outer cylinder 512 and a second shoulder 556 which engages a first shoulder 558 on the second telescoping cylinder 548 . The second telescoping cylinder 548 has a first shoulder 558 which engages the second shoulder 556 on the first telescoping cylinder 546 as described above. A second shoulder 560 may be located at the proximal end of the second telescoping cylinder 548 and engages the spring 550 . The second telescoping cylinder 548 also has a lumen 562 extending there through which may be in fluid communication with the lumen 552 of the first telescoping cylinder 546 and the cavity 526 in the outer cylinder 512 .
[0079] In the embodiments of the invention illustrated in FIGS. 12A-12E , the outer end 570 , 670 of the shaft 572 , 672 and the bone anchor-mount 574 , 674 are covered by a flexible hood 576 , 676 . Referring to FIG. 12A , the flexible hood 576 may be removable, and may have a hinge region 578 . In an alternative embodiment pictured in FIG. 12B , the flexible hood 676 snaps on to the outer end 670 of the shaft 672 , e.g., facilitated by grooves 677 in the outer end 670 of the shaft 672 which receive edges defined by holes 680 in the hood 676 . FIG. 12B shows an unattached hood 676 and a shaft 672 . FIG. 12C shows the hood 676 attached to a shaft 672 , with the hood 676 in an extended position covering the bone-anchor mount 674 . FIG. 12D shows the hood configuration of FIG. 12C in its collapsed or compressed position, the flexible walls of the hood 676 bending outward allowing the bone anchor to protrude from the hood 676 . In this embodiment, when a bone anchor is installed, the hood 676 collapses and slides back on the bone anchor mount 674 as illustrated in FIG. 12C . Another version of the hood of the invention is illustrated in FIG. 12E . In this version, the hood comprises a chamber 682 shaped to fit the outer end 670 of the shaft 672 . In that embodiment, the hood 676 comprises a flared region 684 at the distal end of the hood 686 . The hood compresses in a manner analogous to that shown in FIG. 12D when the bone anchor is being placed. In a preferred embodiment, the material used to make the hoods is a soft or pliable material, such as soft rubber or silicone.
[0080] An alternative embodiment of the bone anchor implantation device 610 is shown in FIG. 13 . As illustrated therein, the shaft 612 has a generally straight proximal section 615 , a first generally bent section 617 , a generally straight median section 618 , a second bent section 620 , a generally curved section 622 , and a distal generally straight section 624 . The first bent section 617 may bend at an angle of from about 35° to about 55° relative to the straight proximal section 615 . Preferably, the first bent section 617 bends at an angle of from about 40° to about 50° relative to the straight proximal section 615 . More preferably, the first bent section 617 bends at an angle of about 45° relative to the straight proximal section 615 .
[0081] The second bent section 620 may bend at an angle of from about 125° to about 145° relative to the straight median section 618 . Preferably, the second bent section 620 bends at an angle of from about 130° to about 140° relative to the straight median section 618 . More preferably, the second bent section 620 bends at an angle of about 135° relative to the straight median section 618 .
[0082] The curved section 622 may curve through an arc of from about 70° to about 110° with a radius from about 0.2 inches to about 0.6 inches. Preferably, the curved section curves 622 through an arc of from about 80° to about 100° with a radius from about 0.3 inches to about 0.5 inches. More preferably, the curved section 622 curves through an arc of about 90° with a radius of 0.4 inches.
[0083] The bone anchor implantation device 610 may be inserted transvaginally as shown in FIG. 13 with the patient in the lithotomy position and the surgeon located between the patient's legs. As used herein, the terms “transvaginally” or “transvaginal access” refer to access through the vaginal introitus or from within the vagina. An incision in the anterior vaginal wall may be made. The shaft 612 may be inserted through the incision and the protective sheath may be positioned such that the proximal end of the second telescoping cylinder 632 contacts the pubic bone 630 . At this time, the first and second telescoping cylinders 626 , 632 are biased to a position in which they extend from the outer cylinder 634 to cover the bone anchor 629 . The bone anchor 629 may be inserted into the bone by applying a retrograde force to the bone anchor 629 . For example, the handle may be pulled in a retrograde direction (toward the user) to implant the anchor. As best illustrated in FIGS. 15 and 16 , as the device is pulled in a retrograde motion, the first and second telescoping cylinders 626 , 632 retract inside the cavity 636 of the outer cylinder and the bone anchor 629 may be driven into the pubic bone 630 . Because the patient's body weight provides an opposing force, the user need only apply a small amount of force, such as 10-20 pounds, in order to drive the bone anchor 629 into the bone 630 . The device 610 may then be pushed away from the implanted anchor to disengage the device from the anchor. The device may then be removed from the vagina, leaving the bone anchor 629 in the bone 630 with the suture extending therefrom. The bladder neck may then be compressed, suspended or stabilized using the suture(s) extending from the bone anchor(s) as described above.
[0084] In another version of the method, the handle 616 may be rotated after insertion into the vagina and prior to providing the retrograde force for implanting the bone anchor. FIG. 13 illustrates a bone anchor delivery device in a first position. By compressing the handle 616 and rotating the handle 616 relative to the shaft 612 as described previously herein, the handle 616 can be moved to a second position, e.g., as illustrated in FIG. 14 . Once in the second position, a retrograde force can be applied to insert the bone anchor 629 into the bone 630 .
[0085] The methods and devices of the present invention drive a bone anchor through, for example, the vaginal wall and into the posterior portion of the pubic bone or symphysis pubis. At least one bone anchor may be driven into the pubic bone on either side of the urethra. However, one of skill in the art will appreciate that a single bone anchor may also be used. At least one suture may be attached to the bone anchors which may extend through the vaginal wall and may then be attached to the endopelvic fascia, the vaginal wall, a sling, or other material to stabilize and/or slightly compress the urethra, thereby improving or maintaining the patient's urinary continence.
[0086] Although this invention has been described in terms of certain preferred embodiments, other embodiments which will be apparent to those of ordinary skill in the art in view of the disclosure herein are also within the scope of this invention. Accordingly, the scope of the invention is intended to be defined only by reference to the appended claims. | 1a
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REFERENCE TO RELATED APPLICATIONS
This application obtains the benefit of the earlier filing date of Provisional Patent Application No. 61/341,874 filed on Apr. 6, 2010.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to dish carriers, and more particularly to an interlocking panel assembly conformed to support arrays of dishes both in the course of their delivery and as a stationary support.
2. Description of the Prior Art
Those engaged in preparing and serving food for consumption by others have consistently faced the burdens an array of dishes entails, particularly when more than one person is being served a full meal at a dining table. In commercial settings this burdensome task has been partly assisted by large carrying trays that were then placed either on any adjacent vacant table, or more frequently, on collapsible stands temporarily erected next to the table being served. The manipulative difficulty of a large tray on its fully loaded path from the kitchen has nonetheless become legendary, even providing endless comedic sequences in many of our films, and various mechanical alternatives were therefore devised to assist the overburdened food service provider.
These earlier assisting mechanical alternatives fall generally into three groupings of dish carrier assemblies that also serve as a stand, the first arranged as a cage within which the dishes are suspended by their edges or arranged as a stack, exemplified by the teachings of U.S. Pat. Nos. 5,064,236 to Stanfield; 5,542,731 to Wills; and others; the second in which dish supporting trays, supports or shelves are cantilevered from a common axis that is provided with a support base, as in U.S. Pat. Nos. 953,007 to Haller; 4,911,308 to Nylund; 6,749,208 to Orozco et el.; and others; and the third in which the peripheral edge of each dish is captured in a cantilevered manner within exteriorly directed notch structures around a common carrying axis that also serves as a support base, as in U.S. Pat. Nos. 5,088,605, 5,836,458 and 5,944,200 all to Nales; U.S. Pat. No. 7,520,550 and US publication 2009/0195005 to and by Lord; and many others.
Each of the foregoing, while suitable for the purposes intended, either entails a complex, costly and often cumbersome structure, as exemplified by those in the first two groupings, or the simpler, but more precariously suspended and therefore difficult to manipulate, carrying arrangement in which the engaged dish peripheries are relied on to carry the whole plate loading. Both these modalities are particularly bothersome in a busy restaurant setting and a simply constructed dish carrying arrangement that obtains the benefits and deployment convenience of the cantilevering dish edge capture, but in a more stable and redundant form, is therefore extensively desired and it is one such arrangement that is disclosed herein.
SUMMARY OF THE INVENTION
Accordingly, it is the general purpose and object of the present invention to provide a simply assembled dish carrying structure in which the carried food laden dishes are resiliently retained in cantilevered engagement at varying levels of insertion.
Other objects of the invention are to provide a dish carrying assembly which is easily separated into conveniently stored panels.
Yet further and additional objects of the invention shall become apparent upon the examination of the description that follows in conjunction with the illustrations appended hereto.
Briefly, these and other objects are accomplished within the present invention by providing a pair of generally similar orthogonally interlocking structures each defined as a vertically elongate rectangular panel provided at the top and bottom edges with corresponding co-planar upper and lower lateral extensions each notched by opposingly aligned transverse grooves conformed for crossed mating receipt within each other. Once thus interlocked the resulting crossed structural combination then provides the necessary three dimensional engagement which can either serve as a stand or as a carrying assembly which may be facilitated by forming a handle in the panel that is provided with the upwardly open interlocking grooves.
The panel edges between the lateral extensions are each provided with matching cut-outs each covered with a resilient edge covering and each shaped so that in their crossing interlocked combination conformingly matched edge recesses are provided in which correspondingly shaped peripheral portions of dishes are receivable for a resiliently effected cantilever moment capture of the dish. In this manner various dish shapes may conveniently accommodated by the simple expedient of the cut-out shape, reducing fabrication costs and the need for specialized inventory. Of course, the planar nature of the two main components of this inventive assembly, and also their similar planforms, provide both manufacturing and great storage convenience when not in use.
Thus an easily disassembled and easily stored structural combination is obtained which can be rendered in any convenient material form and which, by the shaping convenience of the edge capturing recesses, can include multiple geometric shapings of the capturing edges to accommodate various dish forms so that inadvertent dropping of the dishes received therein are minimized.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG.. 1 is a perspective illustration of a first embodiment of the inventive dish carrying structural assembly in its interlocked and deployed form;
FIG.. 2 is a perspective illustration of a first embodiment of the inventive dish carrying structural assembly shown in FIG.. 1 separated by its parts;
FIG.. 3 is a plan view, again separated by parts, of the inventive dish carrying structural assembly shown in FIG.. 1 ;
FIG.. 4 is a side view of the inventive dish carrying structural assembly shown in FIG.. 2 ;
FIG.. 5 is a side view detail of one portion of the inventive dish carrying shown in FIG.S. 1 - 4 ;
FIG.. 6 is a diagrammatic top view illustrating the various dish alignments in various cantilevered captures rendered possible within the capturing recesses provided within the inventive dish carrier structural assembly; and
FIG.. 7 is yet another side view, separated by parts, of an alternative embodiment of the inventive dish supporting structural assembly.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
As shown in FIG.S. 1 - 5 the inventive dish carrier assembly, generally designated by the numeral 10 , comprises a pair of substantially similar generally planar panels which by their substantial similarity shall be designated herein by the trailing numerals 1 and 2 , where the respective panels 11 - 1 and 11 - 2 are each of an elongate, generally rectangular planform respectively defined by inner and outer longitudinal edges 11 - 1 i and 11 - 1 o and 11 - 2 i and 11 - 2 o . Transversely an upper and a lower edge 11 - 1 u and 11 - 11 and 11 - 2 u and 11 - 2 l limit the planform of the respective panels 11 - 1 and 11 - 2 , each of the upper and lower edges extending beyond the corresponding inner edges 11 - 1 i and 11 - 2 i to continue as the exterior edges of corresponding upper and a lower planar extensions 12 - 1 u and 12 - 11 and 12 - 2 u and 12 - 2 l , with the lower extensions 12 - 1 l and 12 - 2 l on each panel being greater in width and spanning further from the corresponding inner edges 11 - 1 i and 11 - 2 i than the upper extensions 12 - 1 u and 12 - 2 u.
To effect an interlock between the panels the interior edge of the upper extensions of panel 11 - 1 , immediately proximate its inner edge 11 - 1 i , is transversely notched by an downwardly open notch 11 - 1 nd with a conformingly similar, but upwardly directed, transverse notch 11 - 2 nu formed in the corresponding upper edge 11 - 2 u of panel 11 - 2 with a similar, opposingly directed, set of conforming notches 11 - 2 nu and 11 -l nd formed in the lower inner edge of the extension 12 - 11 and the lower extension 12 - 21 . These last opposing notches, and also the corresponding extensions in which they are formed, are each somewhat deeper, and correspondingly also wider in their planform, in order to simplify and render convenient their sequential engagement to interlock the panels 11 - 1 and 11 - 2 in a crossed relationship.
In this interlocked configuration the inner edges 11 -l i and 11 - 2 i align in a closely adjacent, but substantially orthogonal, relationship with the crosswise engaged lower extensions 12 - 11 and 12 - 21 forming a supporting base for this interlocked panel combination. A handle 14 formed in the upper extension 12 - 2 u of panel 11 - 2 is then useful to lift the engaged panel combination from ground to serve as a conveniently assembled, and also conveniently disassembled and stored, carrier structure for dishes D that are suspended in cantilever from a set of matching panel recesses 15 - a through 15 - n that are formed in each of the panels in the form of mutually aligned cut-outs from the inner edges 11 -l i and 11 - 2 i into the corresponding panel and to assure a secure cantilevered engagement a resilient strip 16 , such as an adhesively attachable foam rubber strip, is applied to each of the edges of the recesses 15 - a through 15 - n .
Those skilled in the art will appreciate that the foregoing structure is directed for use in settings where a large number of dishes need to be handled. Of course, such settings rarely involve dishes that are each an ‘object d'art’, i.e., a precious, extremely fragile artistic piece, but dishes D that are appropriately designed with correct contemplation for strength of materials, the sanitary aspects of the finish, mass density and the like. Simply, dishes appropriately designed for convenient handling with appropriate attention to notions like scaling laws and commercially expedient materials are those that need the handling assistance disclosed herein. These typically include a fairly large circular base with a well defined base edge circle BD supporting the bowl BW surrounded by a peripheral wall PW which either extends upwardly for those dishes that convey fluid foods or that projects generally radially to form a peripheral surface PS. In virtually all instances, however, there is a well-defined, flat, circular bottom surface BS surrounded by a peripheral edge PE that is either substantially above the bottom surface BS or close to the plane thereof.
These attributes are successfully used to advantage in the edge shaping of each of the recesses 15 a through 15 n by providing a convex curvature, or bulge, 17 in the bottom portion of the recess edge with a complementary conforming, but radially further from the inner edges 11 -l i or 11 - 2 i , upper edge convolution 18 that is generally spaced from the convex curvature 17 by a radial and vertical gap similar to the gap between the base surface BS and the peripheral edge PE of the particular dish configuration that is to be received in the recess. Since this geometric relationship provides a generally fixed distance between the fulcrum point supporting the base surface BS on the convex curvature 17 and the opposing contact point between the peripheral edge PE at the complementary convolution 18 in each of the panels 11 - 1 and 11 - 2 the resulting cantilevered engagement accommodates substantial misalignments of the dish D while still maintaining moment levels of the cantilevered suspension that is within the material strength capacity of the dish D.
Thus each of the recesses 15 a through 15 d can be conformed to accept a particular family of dishes, assuring in each instance a self-correcting shift in the fulcrum contact between the dish bottom surface BS and the curvature 17 which occurs within the recesses in both panels 11 - 1 and 11 - 2 , compensating for a wide range of misalignments in the handling of the dish. Moreover, where the number of recesses is insufficient for the dish variety used the upper convolution 18 may be segmented as illustrated by the recess 15 n where a substantially higher inner convolution segment 18 - i extends partly into the recess to accommodate dishes that have a substantial peripheral wall PW while the remaining outer portion 18 - o then drops to a closer spacing to accommodate flat dishes characterized by a substantial peripheral edge PE that, of course, requires deeper insertion.
In this manner all sorts of complementing dish conFIG.urations can be easily accommodated in a structure that is inexpensive to produce, easily disassembled and stored and conveniently used. The simple planar nature of all the interlocking components of the present invention assures all the foregoing benefits including the packaging convenience benefit when accompanying a sale of complementing dishes.
Moreover, as illustrated in FIG. 6 the crossed interlocking of the panels 11 - 1 and 11 - 2 results in an accommodating cantilevered capture at various degrees of dish offsets illustrated as Da through Dn. Simply, a well centered positioning of each dish is not required as the capturing engagement can translate both along and across each panel.
While the foregoing conFIG.uration includes the provision of a handle to conform the interlocked combination into a dish carrier, a somewhat simpler implementation illustrated in FIG.. 7 may be conformed to serve only as a dish stand generally designated by the numeral 110 in which panels 111 - 1 and 111 - 2 are again interlocked but having the handle omitted. Like numbered parts functioning in a like manner to that previously described panels 111 - 1 and 111 - 2 are again defined by inner edges 11 - 1 i and 11 - 2 i which are each provided with recesses illustrated here as only recesses 15 a and 15 n where each are again composed of edge convolutions 18 opposed by the convex curvatures 17 . Of course, the previously described interlocking notches and panel extensions are all repeated in this conFIG.uration as is also the convenience of use of the upper edges 111 - 1 u and 111 - 2 u to support yet another dish, each lower support obtaining the forgiving nature of the cantilevered dish capture also previously described.
Obviously many modifications and variations of the instant invention can be effected without departing from the spirit of the teachings herein. It is therefore intended that the scope of the invention be determined solely by the claims appended hereto. | 1a
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to golf club attachments and more particularly pertains to a new Golf Swing Improvement Device for helping a golfer determine the impact point of his or her golf swing.
2. Description of the Prior Art
The use of golf club attachments is known in the prior art. More specifically, golf club attachments heretofore devised and utilized are known to consist basically of familiar, expected and obvious structural configurations, notwithstanding the myriad of designs encompassed by the crowded prior art which have been developed for the fulfillment of countless objectives and requirements.
Known prior art golf club attachments include U.S. Pat. Nos. 4,588,191; 4,213,614; D290,150; D247,919; 5,405,139 and 4,984,801.
While these devices fulfill their respective, particular objectives and requirements, the aforementioned patents do not disclose a new Golf Swing Improvement Device. The inventive device includes a cylindrical sleeve member having a circular bore therethrough adapted to receive a shaft of a golf club, and a shaft contact means provided within the circular bore for contacting and hugging the shaft of the golf club, whereby the cylindrical sleeve member is free to slidably travel along the length of the shaft of the golf club during a swing thereof.
In these respects, the Golf Swing Improvement Device according to the present invention substantially departs from the conventional concepts and designs of the prior art, and in so doing provides an apparatus primarily developed for the purpose of helping a golfer determine the impact point of his or her golf swing.
SUMMARY OF THE INVENTION
In view of the foregoing disadvantages inherent in the known types of golf club attachments now present in the prior art, the present invention provides a new Golf Swing Improvement Device construction wherein the same can be utilized for helping a golfer determine the impact point of his or her golf swing.
The general purpose of the present invention, which will be described subsequently in greater detail, is to provide a new Golf Swing Improvement Device apparatus and method which has many of the advantages of the golf club attachments mentioned heretofore and many novel features that result in a new Golf Swing Improvement Device which is not anticipated, rendered obvious, suggested, or even implied by any of the prior art golf club attachments, either alone or in any combination thereof.
To attain this, the present invention generally comprises a cylindrical sleeve member having a circular bore therethrough adapted to receive a shaft of a golf club, and a shaft contact means provided within the circular bore for contacting and hugging the shaft of the golf club, whereby the cylindrical sleeve member is free to slidably travel along the length of the shaft of the golf club during a swing thereof.
There has thus been outlined, rather broadly, the more important features of the invention in order that the detailed description thereof that follows may be better understood, and in order that the present contribution to the art may be better appreciated. There are additional features of the invention that will be described hereinafter and which will form the subject matter of the claims appended hereto.
In this respect, before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not limited in its application to the details of construction and to the arrangements of the components set forth in the following description or illustrated in the drawings. The invention is capable of other embodiments and of being practiced and carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein are for the purpose of description and should not be regarded as limiting.
As such, those skilled in the art will appreciate that the conception, upon which this disclosure is based, may readily be utilized as a basis for the designing of other structures, methods and systems for carrying out the several purposes of the present invention. It is important, therefore, that the claims be regarded as including such equivalent constructions insofar as they do not depart from the spirit and scope of the present invention.
Further, the purpose of the foregoing abstract is to enable the U.S. Patent and Trademark Office and the public generally, and especially the scientists, engineers and practitioners in the art who are not familiar with patent or legal terms or phraseology, to determine quickly from a cursory inspection the nature and essence of the technical disclosure of the application. The abstract is neither intended to define the invention of the application, which is measured by the claims, nor is it intended to be limiting as to the scope of the invention in any way.
It is therefore an object of the present invention to provide a new Golf Swing Improvement Device apparatus and method which has many of the advantages of the golf club attachments mentioned heretofore and many novel features that result in a new Golf Swing Improvement Device which is not anticipated, rendered obvious, suggested, or even implied by any of the prior art golf club attachments, either alone or in any combination thereof.
It is another object of the present invention to provide a new Golf Swing Improvement Device which may be easily and efficiently manufactured and marketed.
It is a further object of the present invention to provide a new Golf Swing Improvement Device which is of a durable and reliable construction.
An even further object of the present invention is to provide a new Golf Swing Improvement Device which is susceptible of a low cost of manufacture with regard to both materials and labor, and which accordingly is then susceptible of low prices of sale to the consuming public, thereby making such Golf Swing Improvement Device economically available to the buying public.
Still yet another object of the present invention is to provide a new Golf Swing Improvement Device which provides in the apparatuses and methods of the prior art some of the advantages thereof, while simultaneously overcoming some of the disadvantages normally associated therewith.
Still another object of the present invention is to provide a new Golf Swing Improvement Device for helping a golfer determine the impact point of his or her golf swing.
Yet another object of the present invention is to provide a new Golf Swing Improvement Device which includes a cylindrical sleeve member having a circular bore therethrough adapted to receive a shaft of a golf club, and a shaft contact means provided within the circular bore for contacting and hugging the shaft of the golf club, whereby the cylindrical sleeve member is free to slidably travel along the length of the shaft of the golf club during a swing thereof.
Still yet another object of the present invention is to provide a new Golf Swing Improvement Device that can be used by a golfer to help the golfer learn how to drive a golf ball correctly with maximum power.
Even still another object of the present invention is to provide a new Golf Swing Improvement Device that can be used by a golfer to improve the consistency and accuracy of his or her golf drives.
These together with other objects of the invention, along with the various features of novelty which characterize the invention, are pointed out with particularity in the claims annexed to and forming a part of this disclosure. For a better understanding of the invention, its operating advantages and the specific objects attained by its uses, reference should be had to the accompanying drawings and descriptive matter in which there is illustrated preferred embodiments of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention will be better understood and objects other than those set forth above will become apparent when consideration is given to the following detailed description thereof. Such description makes reference to the annexed drawings wherein:
FIG. 1 is an illustration of a new Golf Swing Improvement Device installed on a golf club according to the present invention.
FIGS. 2 through 4 are directed to a first embodiment of the present invention.
FIG. 2 is a top view of the first embodiment of the present invention from the perspective of line 2--2 of FIG. 1.
FIG. 3 is a cross sectional view of the first embodiment of the present invention taken along line 3--3 of FIG. 2.
FIG. 4 is a cross sectional view of the first embodiment of the present invention taken along line 4--4 of FIG. 2.
FIGS. 5 through 8 are directed to a second embodiment of the present invention.
FIG. 5 is a top view of the second embodiment of the present invention.
FIG. 6 is a side view of the second embodiment of the present invention.
FIG. 7 is a cross sectional view of the second embodiment of the present invention taken along line 7--7 of FIG. 5.
FIG. 8 is a cross sectional view of the second embodiment of the present invention taken along line 8--8 of FIG. 6.
FIGS. 9 and 10 are directed to an impact member of the present invention.
FIG. 9 is a top view of the impact member of the present invention from the perspective of line 9--9 of FIG. 1.
FIG. 10 is a cross sectional view of the impact member of the present invention taken along line 10--10 of FIG. 9.
FIG. 11 is an illustration of an elastomer ring of the present invention.
DESCRIPTION OF THE PREFERRED EMBODIMENT
With reference now to the drawings, and in particular to FIGS. 1 through 11 thereof, a new Golf Swing Improvement Device embodying the principles and concepts of the present invention and generally designated by the reference numeral 10 will be described.
More specifically, it will be noted that the Golf Swing Improvement Device 10 comprises a cylindrical sleeve member 20 having a circular bore 20c therethrough adapted to receive a shaft 3 of a golf club 2, and a shaft contact means 40 provided within the circular bore 20c for contacting and hugging the shaft 3 of the golf club 2, whereby the cylindrical sleeve member 20 is free to slidably travel along the length of the shaft 3 of the golf club 2 during a swing thereof.
As best illustrated in FIG. 1, it can be shown that the Golf Swing Improvement Device 10 is intended for use on a golf club 2 having a straight or tapered shaft 3 with a handle 4 at one end of the shaft 3 and a head 5 at an opposite end.
As best illustrated in FIGS. 2 through 4, it can be shown that the cylindrical sleeve member 20 has a top surface 20a, a bottom surface 20b, and a circular bore therebetween 20c. The cylindrical sleeve member 20 is preferably formed of aluminum. The cylindrical sleeve member 20 comprises a pair of semi-cylindrical members 21 each having a planar surface 22, a convex surface 23, a semi-circular top surface 24, and a semi-circular bottom surface 25. The planar surface 22 has a semi-circular groove 26 therein extending from the semi-circular top surface 24 to the semi-circular bottom surface 25. The semi-circular groove 26 has a pair of axially aligned cavities 27 therein. The semi-circular top surface 24 and the semi-circular bottom surface 25 each have a semi-annular groove 26 therein. The semi-annular groove 26 is undercut to form a semi-annular lip 29. The pair of semi-cylindrical members 21 are mateably joined to form a cylindrical sleeve member 20 having a circular bore 20c therethrough and form an annular groove 20d with an annular lip 20e in each of the top surface 20a and the bottom surface 20b.
A fastening means 30 is provided for joining the pair of semi-cylindrical members 21 to form the cylindrical sleeve member 20. The fastening means 30 joins the pair of semi-cylindrical members 21 around the shaft 3 of the golf club 2 whereby the cylindrical sleeve member 20 is slidably mounted on the shaft 3 of the golf club 2. The fastening means 30 comprises a snap ring 32 fitted within the annular groove 20d and under the annular lip 20e of each of the top surface 20a and the bottom surface 20b of the cylindrical sleeve member 20.
The shaft contact means 40 comprises a ball bearing 41 protruding from each of the pair of axially aligned cavities 27 into the circular bore 20c of the cylindrical sleeve member 20. The ball bearing 41 may be formed of either steel or nylon. A projection spring 42 is located within each of the pair of axially aligned cavities 27 and is positioned behind the ball bearing 41 whereby the projection spring 42 presses the ball bearing 41 against the shaft 3 of the golf club 2. As such, the cylindrical sleeve member 20 is free to slidably travel along the length of the shaft 3 of the golf club 2 during a swing thereof.
A ball bearing retention means 50 is provided for retaining the ball bearing 41 within each of the pair of axially aligned cavities 27 while joining the pair of semi-cylindrical members 21 around the shaft 3 of the golf club 2. The ball bearing retention means 50 comprises a pin (not shown) inserted through a pin hole 52 provided in each of the pair of semi-cylindrical members 21, whereby the pin compresses the ball bearing 41 into each of the pair of axially aligned cavities 27. The pin hole 52 extends from the semi-circular top surface 24 of each of the pair of semi-cylindrical members 21 to the semi-circular bottom surface 25, is provided adjacent the semi-circular groove 26 provided in each of the pair of semi-cylindrical members 21, and is axially aligned and contiguous with the pair of axially aligned cavities 27.
A second embodiment of the present invention is illustrated in FIGS. 5 through 8. The second embodiment is similar to the first embodiment in that the second embodiment comprises a cylindrical sleeve member 120 having a circular bore 120c therethrough adapted to receive a shaft 3 of a golf club 2, and a shaft contact means 140 provided within the circular bore 120c for contacting and hugging the shaft 3 of the golf club 2, whereby the cylindrical sleeve member 120 is free to slidably travel along the length of the shaft 3 of the golf club 2 during a swing thereof.
The cylindrical sleeve member 120 has a top surface 120a, a bottom surface 120b, and a circular bore 120c therebetween. The cylindrical sleeve member 120 comprises a pair of semi-cylindrical members 121 each having a planar surface 122, a convex surface 123, a semi-circular top surface 124, and a semi-circular bottom surface 125. The planar surface 122 has a semi-circular groove 126 therein extending from the semi-circular top surface 124 to the semi-circular bottom surface 125. The semi-circular groove 126 has a pair of axially aligned cavities therein 127. A first of the pair of semi-cylindrical members 121 has a plurality of holes 128 therethrough extending from the convex surface 123 to the planar surface 122. A second of the pair of semi-cylindrical members 121 has a plurality of threaded holes 129 therethrough extending from the planar surface 122 to the convex surface 123. The pair of semi-cylindrical members 121 are mateably joined to form a cylindrical sleeve member 120 having a circular bore 120c therethrough such that one each of the plurality of holes 128 is aligned with one each of the plurality of threaded holes 129.
A fastening means 130 is provided for joining the pair of semi-cylindrical members 121 to form the cylindrical sleeve member 120. The fastening means 130 joins the pair of semi-cylindrical members 121 around the shaft 3 of the golf club 2 whereby the cylindrical sleeve member 120 is slidably mounted on the shaft 3 of the golf club 2. The fastening means 130 comprises a threaded fastener 132 extending through one of the plurality of holes 128 and threadingly mating with one of the plurality of threaded holes 129.
The shaft contact means 140 comprises a button 141 protruding from each of the pair of axially aligned cavities 127 into the circular bore 120c of the cylindrical sleeve member 120. The button 141 has a concave contact surface 141a. A projection spring 142 is located within each of the pair of axially aligned cavities 127 and is positioned behind the button 141 whereby the projection spring 142 forces the concave contact surface 141a of the button 141 against the shaft 3 of the golf club 2. As such, the cylindrical sleeve member 120 is free to slidably travel along the length of the shaft 3 of the golf club 2 during a swing thereof.
A button retention means 150 is provided for retaining the button 141 within each of the pair of axially aligned cavities 127 while joining the pair of semi-cylindrical members 121 around the shaft 3 of the golf club 2. The button retention means 150 comprises a pin (not shown) inserted through a pin hole 152 provided in each of the pair of semi-cylindrical members 121 and along a groove 141b provided in the concave contact surface 141a of the button 141, whereby the pin compresses the button 141 into each of the pair of axially aligned cavities 127. The pin hole 152 extends from the semi-circular top surface 124 of each of the pair of semi-cylindrical members 121 to the semi-circular bottom surface 125, is provided adjacent the semi-circular groove 126 provided in each of the pair of semi-cylindrical members 121, and is axially aligned and contiguous with the pair of axially aligned cavities 127.
As best illustrated in FIG. 1 and FIGS. 9 through 11, it can be shown that an impact member 60 is provided around the shaft 3 of the golf club 2 adjacent the head 5 of the golf club 2. The impact member 60 is positioned intermediate the head 5 of the golf club 2 and the cylindrical sleeve member 20 so as to protect the head 5 of the golf club 2 from impact by the cylindrical sleeve member 20 as the cylindrical sleeve member 20 slidably travels along the length of the shaft 3 of the golf club 2 during a swing thereof. The impact member 60 has an impact surface 60a which receives the impact of the cylindrical sleeve member 20. The impact member 60 comprises a pair of semi-cylindrical impact members 62 each having a semi-circular groove 63 therein. The pair of semi-cylindrical impact members 62 are mateably joined to form a cylindrical impact member 61 having a circular bore 61a therethrough adapted to receive the shaft 3 of the golf club 2. The cylindrical impact member 61 is T-shaped wherein the cylindrical impact member 61 has a shoulder 61b adjacent the impact surface 60a. A joining means 64 is provided for joining the pair of semi-cylindrical impact members 62 around the shaft 3 of the golf club 2. An elastomer ring 70 is provided which may be placed around the shaft 3 of the golf club 2 adjacent the impact surface 60a of the impact member 60 so as to reduce the noise generated when the cylindrical sleeve member 20 contacts the impact surface 60a of the impact member 60.
In use, the pair of semi-cylindrical members 21 are mateably joined around the shaft 3 of the golf club 2 by the fastening means 30 to form the cylindrical sleeve member 20. The pin (not shown) is removed from the pin hole 52 such that the shaft contact means 40 is pressed against the shaft 3 of the golf club 2 by the projection spring 42. As such, the cylindrical sleeve member 20 is free to slidably travel along the length of the shaft 3 of the golf club 2. Before a user thereof swings the golf club 2, the Golf Swing Improvement Device 10 is slidably positioned adjacent the handle 4. While swinging the golf club 2, the cylindrical sleeve member 20 slidably travels down the shaft 3 and contacts the impact member 60. As such, a golfer can establish the "impact/power point" of his or her swing whereby during a correct swing of the golf club 2, the cylindrical sleeve member 20 will contact the impact member 60 at precisely the same time that the head 5 of the golf club 2 contacts a golf ball (not shown).
As to a further discussion of the manner of usage and operation of the present invention, the same should be apparent from the above description. Accordingly, no further discussion relating to the manner of usage and operation will be provided.
With respect to the above description then, it is to be realized that the optimum dimensional relationships for the parts of the invention, to include variations in size, materials, shape, form, function and manner of operation, assembly and use, are deemed readily apparent and obvious to one skilled in the art, and all equivalent relationships to those illustrated in the drawings and described in the specification are intended to be encompassed by the present invention.
Therefore, the foregoing is considered as illustrative only of the principles of the invention. Further, since numerous modifications and changes will readily occur to those skilled in the art, it is not desired to limit the invention to the exact construction and operation shown and described, and accordingly, all suitable modifications and equivalents may be resorted to, falling within the scope of the invention. | 1a
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TECHNICAL FIELD OF THE INVENTION
[0001] This invention generally relates to the field of nutrition, specifically nutraceutical compositions made from organic super foods, designed as “disease preventive food” for dietary and culinary intervention”. These shall contain all the nutrients needed to provide a daily nutritious, balanced diet in humans that promote general well-being. Such foods can be manufactured with purposely planned cooking methods and mechanical processes, without genetic modification or toxic ingredients that protect the food from losing their nutrients and medicinal properties.
BACKGROUND OF THE INVENTION
[0002] Literature surveys on similar foods that are also used as medicines, are found to be “chemically processed food” which embodies various inherent negativities. These being
Chemically processed food is killing humanity considering the fact that a human's body is a complex machine. “There is no food-based strategy for disease prevention” “Growth of chronic diseases burdens the world”.
Also, no other invention planned to create products or formulas as “disease preventive food” for “dietary and culinary interventions”, that contain the total nutrients needed to provide a daily balanced diet, or manufactured with thought-out mechanical processes that protect the food from genetic modification or toxicity from losing their nutrients and medicinal properties, thus helping to fix challenge, as explained below:
[0006] Challenges:
[0007] Challenge #1: The human body is a complex machine consisting of many separate, interconnected, individually vibrating machines. It is a chemical and mechanical factory within. It is most difficult to maintain so many inter-related processes and parameters, even with the most advanced computing power. The entire world has taken this challenge very lightly, without giving importance to the human need for the critical knowledge, to make people aware of the consequences of poor daily nutrition and how deficiencies slowly make us sick.
[0008] Challenge #2: “Chemically processed food is killing humanity”. With nearly 7 out of 10 Americans being overweight, 1 in 4 being affected with diabetes or pre-diabetes, 2 of every 3 people is diagnosed with cancer today, the heavily processed standard American diet, SAD, is clearly a devastating factor in today's and the future generation's health.
[0009] 2.1 Lots of Calories for Little Nutrition: Highly Processed foods over-stimulate the production of dopamine, aka the “pleasure” neurotransmitter, which can cause excessive cravings, leading to obesity, diabetes and cancer. A fast-food burger plus fries and coke count to almost an entire days worth of required calories, causing excess weight gain without receiving the vitamins and minerals, the live enzymes and micronutrients, the high-quality protein or healthy fats the body needs to function and thrive.
[0010] 2.2 Dangerous Food Additives: Many food additives—preservatives, flavorings, colors and other ingredients—while legal, they are not safe for long-term consumption. Some, such as sodium nitrate, BHA, BHT, aspartame, Blue 1, 2, and potassium bromate, have been linked to an increased risk of cancer. Studies show that various common food dyes, and the preservative, sodium benzoate—found in soft drinks, fruit juices and salad dressings—cause some children to become more hyperactive and distractible. Phosphate additives magnify taste, texture, and shelf-life, but its effects cause cardio-vascular damage, rapid aging, kidney failure, and weak bones.
[0011] 2.3 Fructose: Fructose, now the number one calorie source in the US, diminishes feelings of fullness since it does not stimulate a rise in leptin, a hunger and fat storage regulator in the body. Fructose also reduces the amount of leptin crossing the blood-brain barrier by raising triglycerides. Leptin plays a significant role in the development of heart disease, obesity, diabetes, osteoporosis, autoimmune diseases, reproductive disorders, and rate of aging.
[0012] GMO-Genetically Modified (GM) Organisms: Some 75 percent of processed foods contain GM ingredients, which are increasingly linked to serious health problems. The foundation of most processed foods in grocery stores today spring from laboratories, not nature. Genetically-modified organisms (GMOs), have been linked to infertility, organ damage, and cancer.
[0013] MSG: Monosodium glutamate (MSG), a flavor enhancer, is added to thousands of processed (canned soups, crackers, meats, salad dressings, frozen dinners, chips etc.), and restaurant foods. MSG is popular, because it enhances the flavor of food, making processed meat, frozen dinners and salad dressings taste fresher, and canned foods less tinny. However, it is also an excitotoxin, which overexcites brain cells causing varying degrees of nerve damage or cell death, and triggers or worsens learning disabilities, Alzheimer's, Parkinson's, Lou Gehrig's diseases and more.
[0014] 2.9 Fake food spoil your mind: Consuming junk food can cause people to become angry and depressed, have brain fog and difficulty in concentrating. Nutritionally-dense foods levels mood, maintain energy, and fosters productivity.
[0015] 2.10 Refined food ruin your insides: Alterations and deletions in refined food with their natural fibers, enzymes, vitamins, result in their longer shelf life. Consumption of packaged, processed foods wreaks havoc on the digestive system, pollutes the internal ecosystem, disrupts beneficial bacteria and increases infection.
[0016] 2.11. Processed foods are filled with pesticides: The GMOs used in processed food are grown by applying glyphosphate along with other pesticides and herbicides, which end up in the crop. Some breakfast cereals out there contain up to 70 different types of pesticides, fumigation chemicals, and other residues.
[0017] Challenge #3: There is no food-based strategy for disease prevention. The world culture doesn't have an integrated, chronic disease management model based on primary health care. With food-based strategy of “disease prevention and intervention”, the adverse trends and risk factors in the major chronic diseases can be slowed and reversed, premature deaths and unnecessary disability avoided.
[0018] Challenge #4: Unplanned high temperatures lose their nutrients and medicinal properties: People have been accustomed to cooking without awareness of high temperatures destroying the nutrients, and never considered the fundamentals of eating nutritiously. Despite the science of steam cooking being around for centuries and now a growing trend, changing to the ideal steam cooking method to prevent the loss of nutrients, while cooking food is a challenge, therefore, “culinary intervention” is the necessary purpose of the invention, and another “disease prevention strategy”. This is crucial to reverse the worldwide growing crisis of chronic diseases.
[0019] Challenge #5: “Growth of chronic diseases burden the world”. Chronic diseases are increasing in global prevalence and have become the dominant health burden in many developing countries and seriously threaten their ability to improve the health of their populations. This rise of lifestyle-related chronic disease in poor countries is the result of a complex constellation of social, economic, and behavioral factors.
[0020] The prime ingredient of a healthy lifestyle is to have a balanced diet or healthy eating plan. A healthy diet provides the body with essential nutrition to support energy needs without exposure to toxicity. The basic nutrition that a balanced daily diet must provide, are protein, folic acid, iron, calcium, magnesium, vitamins, enzymes, fibers, essential fatty acids and iodine. To take care of these, it must include several food groups since one single group cannot provide the best nutritious diet required for good health.
OBJECTIVES OF THE INVENTION
[0021] A primary objective of the present invention is to provide nutraceutical formulas or food compositions for improving health, preventing chronic diseases, postponing the aging process, increasing the life expectancy and supporting functions and integrity of the body.
[0022] Another objective of the present invention is to provide an alternative solution to chemically processed food wherein, the processing of food is done mechanically to retain the nutritional value of the ingredients used in the processed food.
[0023] Another objective of the present invention is to provide a food based strategy for disease prevention.
[0024] Still another objective of the present invention is to provide natural food compositions made from super foods, which includes the nutrients needed to provide a daily balanced diet with critical components like proteins, enzymes, minerals, vitamins, fiber, fatty acids and iodine to bring and maintain general well-being of the body.
[0025] Another objective of the present invention is to provide“mechanically processed food” or “real food” choices without genetic modification or presence of toxic ingredients like MSG, artificial flavors or sweeteners, preservatives, highly processed trans or hydrogenated fats.
[0026] Still further objective of the present invention is to provide a mechanical process of steam cooking which protects the food from losing its nutrients and medicinal properties creating a “culinary intervention” which is the necessary purpose of the invention, and another “disease prevention strategy”.
[0027] Another objective of the present invention is to provide mechanically processed food and food compositions in a way that creates “disease preventive food”, as an alternative to drugs.
[0028] Another objective of the present invention is to provide for food compositions or nutraceutical compositions that have been designed to meet the daily needs of the complex human body aiding in antioxidant defenses, cell proliferation, gene expression, safeguarding of mitochondrial integrity.
[0029] Still further objective of the present invention is to provide an alternative option to processed food.
SUMMARY OF THE INVENTION
[0030] A natural food composition or nutraceutical compositions made from organic super foods comprising of barley, brown rice, oats, quinoa, whole wheat, soybeans, black beans, honey, flaxseed, sunflower seeds, walnuts, black seed, moringa, goji berries, coconut, brown seaweeds and chaga mushrooms. The ingredients are combined in various proportions and in different combinations and prepared as various forms of food products designed as food intervention for disease prevention-focused food that includes the nutrients needed for a daily nutritious balanced diet with critical components like proteins, enzymes, minerals, vitamins, fiber, fatty acids and iodine to bring and maintain general well-being of the human body. These food compositions or nutraceutical compositions without genetic modification or toxic ingredients, are manufactured with thought-out mechanical processes that protect the food from losing their nutrients and medicinal properties.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0031] In utilization of the above mentioned organic super foods for various food compositions, broken down by element and weight percentage thereof, to form the desired food product are discussed hereof.
[0032] These organic super foods or nutraceutical compositions have been purposely designed to improve health, prevent chronic diseases, postpone the aging process, increase life expectancy and support functions and integrity of the body. In time, this nutraceutical intervention will control symptoms, treat, prevent and/or reverse different health issues.
[0033] The various effects of the nutritional food included in the present invention have been grouped into separate health groups as under:
HG #1: Inflammatory (Inflammation, joints, neuropathic pain, respiratory) HG #2: Brain health (General well-being, anxiety, depression, memory, insomnia, stress, alzheimer's and dementia) HG #3: Circulation (Heart and circulatory health, high blood pressure, cholesterol and triglycerides) HG #4: Weight loss and stomach health HG #5: Metabolic (Cancer protection, diabetes, blood sugar control) HG #6: Healthy skin, nails and hair, teeth and bones HG #7: Anti-aging, Eye health HG #8: Hormone balance, Menopause. HG #9: Immune System (Infections, Colds and Flu)
[0043] The following are various food compositions, broken down by element and weight percentage thereof, to form the desired food product and their effects on human health based on their nutritional functions and grouped as above.
Food Product—For Pasta and Ready to Serve Food
Formula #-1
Effecting health group: HG #1, HG #3,HG #4, HG #6, HG #8
[0044]
[0000]
Percentage by
Ingredient
weight (gram)
Seaweeds
10
Black seeds
24
Sunflower
100
Flaxseeds
50
Soyabean
170
Oats
120
Barley
120
Brown Rice
400
Total
1000
[0045] In order to produce a food composition as herein described, the preparation of dough for pasta involves pulverizing the above ingredients and placing & mixing them in a conventional mixing device thereby, slowly adding 400gram water and adding 50 gram of crushed flaxseeds. After waiting for 5 minutes, the next step involves placing the well-blended mixture in the pasta machine for 10 minutes after which the pasta sheets of different lengths and thicknesses gets prepared, whereby the prepared pasta sheets are placed in different machines accordingly, to make the pastas of the desired forms like ravioli, cannelloni, lasagna, long and short pastas. The pasta is then dried for 12 hours. These pastas have no preservatives, therefore it will be packed and sold with expiration date of 12 months. The customer is encouraged to prepare it at home using the steam technique, as used for their fish/vegetables, or at low boiling point/simmer water for 5-6 minutes. Ready to serve food has the same pasta formulas, and is served with raw foods, such as an avocado, papaya or other fresh food containing enzymes.
Formula #-2
Effecting Health Group; HG #1, HG #2,HG #3, HG #4, HG #5, HG #6, HG #7
[0046]
[0000]
Percentage by
Ingredient
weight (gram)
Chaga Mushroom
50
Seaweeds
10
Black seeds
35
Flax seeds
100
Moringa
100
Sunflower seeds
100
Brown rice
600
Walnuts
5
Total
1000
[0047] The mixture in this example can be prepared in the same manner as that used for formula 1.
Formula #-3
Effecting Health Group: HG #9, HG #1, HG #3, HG #4, HG #5
[0048]
[0000]
Percentage by
Ingredient
weight (gram)
Seaweed
5
Black seeds
10
Flaxseeds
100
Echinacea
15
Oats
150
Barley
150
Quinoa
150
Brown rice
420
Total
1000
[0049] The mixture in this example can be prepared in the same manner as that used for formula 1.
Formula #-4
Effecting Health Group: HG #1, HG #2, HG #3, HG #4, HG #5, HG #6, HG #7
[0050]
[0000]
Percentage by
Ingredient
weight (gram)
Brown rice
520
Black beans
300
flaxseeds
100
chaga
50
Black seeds
25
Seaweeds
5
Total
1000
[0051] The mixture in this example can be prepared in the same manner as that used for formula 1.
Food Product for Pizza, Bread, Tacos, Tortillas, Crackers, Arepas And Empanadas
Formula #-1
Effecting Health Group: HG #1, HG #3, HG #4, HG #6, HG #8
[0052]
[0000]
Percentage by
Ingredient
weight (gram)
Seaweeds
2
Blackseeds
3
Sunflower Oil
15
Flaxseeds
10
Soybean
20
Brown Rice
100
Total
152
[0053] In order to produce a food composition as herein described, the preparation of dough for bread/pizza/tacos/tortillas/crackers/arepas/empanadas involves pulverizing the above ingredients and placing & mixing them in a conventional mixing device, thereby, slowly adding 90 gram water and adding 20 gram of sunflower oil. The next step involves placing the well-blended mixture in the mixing device for 10 minutes, which produces the required dough for making different pasta shapes for the different products, wherein filling those different products shapes with nutritionally balanced food fillings, thereby producing the final nutraceutical composition for the bread/pizza/tacos/tortillas/crackers/arepas/empanadas.
[0054] The dough for crackers, is steam baked for 1-2 minutes and sold as such, whereas, the dough for bread/pizza/tacos/tortillas/arepas/empanadas, thus produced, are frozen and sold, and when ready to be consumed, they are steam baked for 15 minutes at a temperature of 200 degrees Fahrenheit for pizza and bread and 1-2 minutes for tacos, tortillas, arepas and empanadas.
Formula #-2
Effecting Health Group: HG #1, HG #2,HG #3, HG #4, HG #5, HG #6, HG #7
[0055]
[0000]
Percentage by
Ingredient
weight (gram)
Chaga Mushrooms
8
Seaweeds
2
Black seed
5
flaxseeds
15
Moringa
25
Sunflower oil
13
Walnuts
2
Barley
80
Total
150
[0056] The mixture in this example can be prepared in the same manner as that used for formula 1.
Formula #-3
Effecting Health Group: HG #9, HG #1,HG #3, HG #4, HG #5
[0057]
[0000]
Ingredient
Percentage by weight (gram)
Black seeds
5
Flaxseeds
5
Echinacea
10
Oats
10
Barley
80
Quinoa
30
Sunflower oil
10
Total
150
[0058] The mixture in this example can be prepared in the same manner as that used for formula 1.
Food Product—Cold/Hot Cereals/Snack Bars
Formula #-1
Effecting Health Group: HG #1, HG #3,HG #4, HG #6, HG #8
[0059]
[0000]
Ingredient
Percentage by weight (gram)
Oats
600
Barley
80
Soybean
80
Brown rice
50
Flaxseeds
50
Honey
50
Sunflower Oil
50
Blackseeds
20
Seaweeds
10
Gogi berries
10
Total
1000
[0060] In order to produce a food composition as herein described, the preparation of the granola for cold cereals and snack bar involves pulverizing the above ingredients, mixing and placing the mixture in a tray on the conveyer belt for wet steam baking at 150 degree Fahrenheit for 1 minute, thence, adding 50 gram of honey and dry steam baking for another minute.
[0061] Whereas, for hot cereal, all the above ingredients are combined in a large container and stored in a cool dry condition. Before consumption, water is added to the mixture and steamed in an oven for 3 to 5 minutes. Then, served hot with milk or yogurt, fruits, nuts or seeds.
Formula #-2
Effecting Health Group: HG #1, HG #2,HG #3, HG #4, HG #5, HG #6, HG #7
[0062]
[0000]
Ingredient
Percentage by weight (gram)
Oats
600
barley
90
Brown Rice
50
Moringa
50
Chaga Mushrooms
50
Flax seeds (crushed)
50
Sunflower Seeds
50
Gogi Berries
35
Sea Weeds
10
Walnuts
10
Black seeds
5
Total
1000
[0063] The mixture in this example can be prepared in the same manner as that used for formula 1.
Formula #3
Effecting Health Group: HG #9, HG #1,HG #3, HG #4, HG #5
[0064]
[0000]
Ingredient
Percentage by weight (gram)
Oats
600
Quiona
100
Barley
90
Brown Rice
80
Honey
50
Flaxseeds (crushed)
50
Black seeds
15
Seaweeds
5
Coconut
10
Total
1000
[0065] The mixture in this example can be prepared in the same manner as that used for formula 1.
[0066] The above nutraceutical compositions are representative of unique formulas designed as “disease preventive food”. In time, this nutraceutical intervention will control symptoms, treat, prevent and/or reverse different health issues.
[0067] As stated, various combinations are possible, of the components herein described, in order to provide a food composition, which is capable of serving as a substitute for nutritionally imbalanced, chemically processed food, as an alternative to drugs.
[0068] The food compositions, of the instant invention, can be used to provide balanced proper nutrition for all age groups (developing and sustaining) and can be readily adapted to meet any of several nutritional lifestyles, as well as, provide the following benefits to the human body. The separate beneficial properties of the various natural ingredients included in the various food compositions are enumerated below.
[0069] SEAWEEDS: Seaweeds have unique mineral content like calcium, copper, and concentrated form of iodine (for healthy metabolism), bioavailable iron, magnesium, manganese, molybdenum, phosphorus, potassium, selenium, vanadium, as found in human blood. Seaweeds also offer a variety of unique phytonutrients, including sulfated polysaccharides, antioxidants (anti-inflammatory), polyphenol antioxidants (flavonoids) along with substantial amounts of protein, niacin, vitamin B1, vitamin B2, vitamin B5, vitamin B6 and B12 and a variety of enzymes (that reduce blood sugar level). Moreover, on account of the sulfated polysaccharides compounds, seaweeds/sea vegetables possess unique anti-inflammatory (especially osteoarthritis), anti-cancer (especially colon and breast cancers), anticoagulant, antithrombotic, and antiviral properties (herpes simplex virus). Seaweeds also acts as a “blood purifier” as well as neutralizing the over-acidic effect of diet by alkalizing blood. With their powerful chelating and detoxifying properties, seaweeds provide protection to environmental toxins and drawing out of body wastes.
[0070] MORINGA: Another natural sources of basic nutrients is Moringa Oleifera It contains more than 92 nutrients, 46 types of antioxidants and vitamins A-Z, 36 anti-In ammatones, 18 amino acids and 9 essential amino acids. It cures and prevent over 300 illness including diabetes, high blood pressure, arthritis, stroke and cancers. It is also commonly used for energy, beautiful skin, sleep and strengthening teeth. Besides, stimulating the body to feel good, fresh and energized, moringa has several thousand times more zeatin than any other known plant. It allows new skin cells to grow at a faster rate when old skin cells die. This results in a marked reduction of wrinkles on the face and other parts of the body, and a more youthful skin appearance. Moringa have our times more chlorophyll than Wheatgrass. Sulfur is the key ingredient to substances which make up human skin collagen, and keratin. While not all antioxidart are created equal, monngaoleifera leaves contain over 30 antioxidants which are well suited for skin health. There are 23 amino acids of which eight are considered essential These are the basis for the construction of new muscle. Scientists have identified Pterygospermin as the active compound in moringa that causes its antibacterial action. Moringa acts as a great natural sleeping aid because it contains the unique natural compound known as Nebedaye Moringa leaves possess anti-tumor and anti-cancel activities, due in part to a compound called niaziminin anti-viral activity in cases of Herpes simplex 1. The glucose-modifying, anti-diabetic effects of moringa may prove of great use amidst a virtual epidemic of Type 2 diabetes and obesity.
[0071] BARLEY has a good source of molybdenum, manganese, dietary fiber, selenium, copper, vitamin B1, chromium, phosphorus, magnesium, and niacin thataids in lowering blood cholesterol levels (possibly with propionic acid obtained from the insoluble fiber of barley), protects the intestine and colon (vide its “friendly bacteria” in the large intestine), besides, having anti-cancer, anti-diabetic properties. The propionic acid produced from barley's insoluble fiber may also be partly responsible for the cholesterol-lowering properties of fiber as well as the regularity and intestinal protection. Barley and other whole grains are rich sources of magnesium, a mineral that acts as a co-factor for more than 300 enzymes, including enzymes involved in the body's use of glucose and insulin secretion. The fiber can also help to prevent blood sugar levels from rising too high in people with diabetes.
[0072] CHAGA MUSHROOM offer a complex balance of active compounds, delivery mineral structures, and co-agents, more effective to sustaining a healthy immune balance than synthesized isolated compounds that ultimately slows the aging process. It has the highest ORAC (Oxygen Radical Absorbance Capacity) score for natural foods or supplements that protect every cell in the entire body from free-radical damage. It also promote cellular respiration and proliferation, helps regenerate cells and regenerate damaged tissue, promotes the growth of healthy cells and assist in cellular repair, enhances the immune system, maintains optimum alkalinity and pH levels, oxygenates the blood and helps stabilize blood sugar, protects DNA and anti-inflammatory benefits, improve neurological function, digestion and circulation of blood all over the body, alleviates stress and anxiety while increases energy and strength, fights chronic fatigue, reduces muscle and joint pain, supports normal kidney and vision health, balances hormones, manages weight and helps gain muscles, improves lymphocyte count, suppresses allergies, improves memory and concentration, helps optimize cardiovascular health, inhibits lipid peroxidation maintains healthy blood pressure and cholesterol levels, impedes tumor malignancy and boosts natural cancer-fighting ability, helps detoxification of all cells, skin, blood, liver, intestines, colon, kidney, bladder, lymphatic system, lung & respiratory, yeast & fungal, chemicals and heavy metals (including lead and mercury).
[0073] BROWN RICE: Brown rice is a rich source of manganese which helps in the synthesis of fatty acids and produces energy from protein and carbohydrates which are helpful in keeping the nervous system strong. Further, manganese is a critical component of superoxide dismutase which is responsible for providing protection against damage from free radicals produced during energy production and balancing the action of calcium in the blood vessels, thereby keeping the blood vessels relaxed and dilated, thus keeping pressure normal and preventing heart attack. It is also a rich source of selenium which helps in thyroid hormone metabolism, and strengthens the immune system. Selenium helps in inducing DNA repair, damaged cell synthesis and inhibits proliferation of cancer cells as well as being an important cofactor of glutathione peroxidase, an antioxidant enzyme, detoxifies the liver of harmful molecules and helps in preventing damage to the cellular DNA and development of cancer cells. Lowers LDL cholesterol and Lower Type-2 Diabetes. Magnesium, another nutrient for which brown rice is a good source, has been shown in studies to be helpful for reducing the severity of asthma, lowering high blood pressure, reducing the frequency of migraine headaches, and reducing the risk of heart attack and stroke.
[0074] QUINOA: Quinoa has significantly greater amounts of both lysine and isoleucine (especially lysine), which allows the protein in quinoa to serve as a complete protein source. Besides, it is also rich in RDA nutrients like folate, zinc, and phosphorus. The phytonutrient present in Quinoa provides significant amounts of antioxidants like ferulic, coumaric, hydroxybenzoic, and vanillic acid. Ouinoa also has anti-inflammatory properties due to the presence of phenolic acids like hydroxycinnamic and hydroxybenzoic acids, polysaccharides like arabinans and rhamnogalacturonans and vitamin E like gamma-tocopherol. The antioxidant and anti-inflammatory phytonutrients in quinoa also make it a likely candidate for cancer risk reduction in humans.
[0075] OATS contains a specific type of fiber known as beta-glucan which lowers the high cholesterol levels which significantly reduces the risk of cardiovascular disease and stroke. Due to the high fiber content in oats, it reduces the cholesterol levels. The presence of antioxidant compound avenanthramides prevents free radicals from damaging LDL cholesterol, thus reducing the risk of cardiovascular disease. Avenanthramides suppresses production of ICAM-1 (intracellular adhesion molecule-1) and VCAM-1 (vascular adhesion molecule-1), E-selectin, and the secretion of pro-inflammatory cytokines KL-6, chemokines IL-8 and protein MCP-1 (monocyte chemoattractant protein).
[0076] SOYBEAN is a source of pepetides like defensins, glycinins, conglycinins and lunasin which helps in improving blood pressure regulation, controlling blood sugar levels, and improving immune function. It is a good source of geistein, an isoflavone which reduces the risk of cancer. It is also rich in phytonutrrients like caffeic, coumaric, ferulic, and sinapic acid. Soybeans are also an important source of the minerals copper, manganese, molybdenum, phosphorus, and potassium; the B vitamin, riboflavin; and omega-3 fatty acids (in the form of alpha-linolenic acid). The area of bone health benefits from soy has been the finding in many studies of improved markers of bone health following consumption of soy.
[0077] FLAXSEEDS is a high source of omega-3 fatty acid especially alpha-linolenic acid, or ALA which helps in preventing excessive inflammation of blood vessels, thereby benefitting the cardiovascular system. Further, presence of ligans in flaxseeds imparts antioxidant properties to it. The mucilage content especially the presence of arabinoxylans and galactoxylansin flaxseeds benefits the digestive tract. Decrease the ratio of LDL-to-HDL cholesterol and to increase the level of apolipoprotein A1, and help reduce blood pressure. The antioxidant and anti-inflammatory benefits of flaxseeds aids on cancer prevention.
[0078] SUNFLOWER SEEDS: are an excellent source of vitamin E, which is a fat soluble antioxidant and neutralizes free radicals which are harmful to the cell membrane and brain cells. Being an antioxidant, vitamin E helps in preventing cardiovascular diseases, apart from preventing or reducing the occurrence of asthma, osteoarthritis and rheumatoid arthritis vide its anti inflammatory properties.
[0079] Sunflower seeds are also rich in manganese which helps in reducing the severity of asthma, lowering high blood pressure, preventing migraine headaches, and reducing the risk of heart attack and stroke. Magnesium is also necessary for healthy bones and energy production. A trace element selenium present in Sunflower seeds induces DNA repair and synthesis in damaged cells, inhibits proliferation of cancer cells and induces their apoptosis, thereby protecting the cells from becoming cancerous. Furthermore, selenium is instrumental in developing body's most powerful antioxidant enzymes, glutathione peroxidase that is used in the liver to detoxify a wide range of potentially harmful molecules.
[0080] WALNUTS are high sources of anti-inflammatory nutrients like omega-3 fatty acids including alpha-linolenic acid, phyto nutrients like tannins, phenolic acids, and flavonoids and quinines like juglone. The presence of anti-inflammatory nutrients (alpha-linolenic acid) helps the cardiovascular system and regulates the blood composition as well as blood pressure. It reduces problems in metabolic syndrome and is beneficial in the treatment of type-2 diabetes. The antioxidant properties of walnuts help lower risk of chronic oxidative stress. Also, walnut helps to keep bones strong and prevents prostrate and breast cancer.
[0081] BLACK BEANS are also rich sources of phytonutrients and anthocyanin flavonoids like delphinidin, petunidin, malvidin, kaempferol and quercetin. These phytonutrients and flavonoids impart both antioxidant and anti-inflammatory properties to the black beans. Black beans are also sources of hydroxycinnamic acids ferulic, sinapic, and chlorogenic acid, as well as numerous triterpenoids. Antioxidant minerals like zinc and manganese are also plentiful in black beans. Also, found in black beans is omega-3 fatty acids that helps control blood pressure and cardio-vascular system. Black beans are rich both in proteins as well as fibres. This combination is beneficial for smooth functioning of the digestive tract, in regulating the blood sugar system and the cardiovascular system.
[0082] COCONUTS have anti-viral, anti-bacterial, anti-fungal, and anti-parasite properties. It improves digestion and absorption of nutrients, vitamins, and minerals in the body thereby providing a natural source of quick energy in the body. It stimulates insulin secretion thereby guards against diabetes. It protects the body from degeneration by removing the free radicals present in the system.
[0083] GOJI BERRIES are excellent source of antioxidants such as polyphenols, flavonoids, carotenoids, vitamins like A, C and E apart from having potassium, zinc, iron, copper and riboflavin in them. They are also rich in polysaccharides which are a primary source of dietary fiber. Gogi berries, due to the presence of antioxidants, help neutralize the cell-damaging effects of free radicals and help guard us from degenerative diseases such as rheumatoid arthritis, Alzheimer's disease and most types of cancer. It also contain 8 polysaccharides, a primary source of dietary fiber.
[0084] HONEY: Honey is a real food that has been accessible to humans throughout evolutionary history and can still be obtained in its natural form. Existence of fructose and Omega-6 fatty acids despite being linked to health issues when isolated, in “real foods” have a completely different effect. Honey raises blood sugar less than dextrose (glucose) and sucrose (glucose and fructose). It reduces C-Reactive Protein (CRP)—a marker of inflammation, lowers LDL cholesterol, blood triglycerides and raises HDL cholesterol and also lowers Homocysteine, another blood marker associated with disease. Honey also contains an abundance of various antioxidants that are associated with improved health and lower risk of disease. Two human studies revealed that consumption of buckwheat honey increases the antioxidant value of the blood
[0085] BLACK SEEDS Black cumin used as a spice is considered a natural remedy for asthma, hypertension, diabetes, inflammation, cough, bronchitis, headache, eczema, fever, dizziness, and influenza. The seeds are known to be carminative, stimulant, and diuretic. Similarly, seeds of herbaceous plant are used in the prevention of inflammation, antioxidant activities, antimicrobial activity, and anti -carcinogenic and antiulcer activity.
[0000]
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OTHER REFERENCES
[0086] Food As Medicine, How Are Food and the Environment Related?, How Does Food Impact Health? What Should I Eat for My Specific Condition ? http://www.takingcharge.csh.umn.edu/our-experts/karen-lawson-md
DRAWINGS
[0087] Non Applicable
SEQUENCE LISTING
[0088] Non Applicable
[0089] While there have been shown and described what are at present, the preferred embodiments of the invention, it will be obvious to those skilled in the art that various changes and modifications may be made therein without departing from the scope of the invention as defined by the appended claims.
[0090] For a better understanding of the present invention, together with other and further objects, advantages and capabilities thereof, reference is made to the following disclosure and appended claims. | 1a
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FIELD OF INVENTION
[0001] The present invention relates in general to absorbent devices and in particular to absorbent devices for toilet-related use and for methods of using such devices.
BACKGROUND OF INVENTION
[0002] Floors, particularly the floor areas surrounding a toilet, are often subject to spills or other stray moisture resulting from a variety of causes.
[0003] Existing floor coverings for the vicinity of toilets in the home are often either hard non-absorbent material such as tile, or an absorbent but non-disposable material, such as a rug or carpet. The former fails to absorb and contain spills, while the latter may contain spills but may do so without revealing the fact or degree of such absorption, leading to an unhygienic and perhaps malodorous condition.
[0004] An unmet need therefore exists for a means of contending with such unwanted spills in a manner that is hygienic, that renders the undesirable spills detectable and their treatment tractable, convenient and inexpensive.
SUMMARY OF INVENTION
[0005] The present invention addresses, at least in part, the long felt, but previously unmet needs described above as well as other needs. In particular, the present invention provides a toilet mat comprising matting, the matting comprising disposable absorbent material, for being placed in proximity to a base of the toilet. In another embodiment, the absorbent matting may also comprise a wetness or moisture indicator for exhibiting a detectable indication in response to being contacted with moisture associated with a bodily fluid, water from the toilet or other sources.
[0006] Yet another aspect of the present invention provides a method for enabling a user to maintain the hygienic integrity of a floor area surrounding a toilet base. The method comprises the steps of: placing a disposable liquid absorbent matting, having a wetness indicator, in proximity to the toilet base, wherein the liquid absorbent matting absorbs urine spills occurring during use of the toilet and the absorption activates the wetness indicator; detecting a urine spill on the absorbent matting by observing the wetness indicator in an activated state; and; replacing the absorbent matting with an unused absorbent matting after the urine spill has been detected.
[0007] An object of the present invention is to provide a disposable matting for protecting a toilet floor from urine spills.
[0008] Another object of the present invention is to provide a disposable matting that visually indicates the area of urine spills on the matting and when the matting should be replaced.
[0009] It is yet another object of the present invention to provide a disposable matting that encourages a user to adopt the improved toilet habits. Many other objects and advantages will become apparent to those of ordinary skill in this field upon reading the following description and claims in connection with the accompanying figures.
BRIEF DESCRIPTION OF DRAWINGS
[0010] FIG. 1 illustrates a side perspective exploded view of a disposable absorbent toilet mat, in an embodiment of the present invention.
[0011] FIG. 2 illustrates a top and front view of a disposable absorbent toilet mat including footprint indicia, in use, in an embodiment of the present invention.
[0012] FIG. 3 illustrates the use of a wetness indicator, and of footprint indicia within the disposable absorbent toilet mat, in an embodiment of the present invention.
[0013] FIG. 4 illustrates the relative dimensions in an embodiment of a disposable absorbent toilet mat according to the present invention.
[0014] FIG. 5 illustrates a flow chart for use of the disposable absorbent toilet mat, in use, in an embodiment of an aspect of the present invention.
DETAILED DESCRIPTION
[0015] FIG. 1 presents a side perspective exploded view of a disposable absorbent toilet mat in an embodiment of an aspect of the present invention. In the illustrated embodiment, but without limitation, mat 10 comprises multiple layers and has a thickness of approximately 0.125 (⅛″) of an inch, as indicated at 12 . Top layer 14 is of a porous material capable of passing liquid spills through to deeper layers of the mat 10 . In one embodiment, such passage occurs via micro holes (not shown). This passage of spills to a deeper layer enhances hygiene by allowing a user to stand on the mat without coming into contact with the spilled liquid. Layer 14 permits the spilled liquid to pass through to transition layer 16 , which is located directly below top layer 14 . Thus, spilled liquid that is received via the micro holes (not shown) in layer 14 , is transferred to an absorbent layer 18 via transition layer 16 . At absorbent layer 18 , the spilled liquid is absorbed in order to confine the spilled liquid to that layer and avoid the liquid from coming into contact with either the floor area under the matting, or the top layer 14 on which the user of the mat 10 may stand. Buffer layer 20 , isolates the absorbent layer 18 holding the spilled liquid, from floor contact layer 22 , which provides a non-slip surface 24 for ensuring that mat 10 does not slip on the bathroom floor. Top layer 14 also includes an adhesive collar 26 having an adhesive surface 28 , which creates a seal between the base of a toilet and collar 26 . The utility of the adhesive collar 26 will be further described in relation to FIG. 2 .
[0016] Generally, the disposable absorbent toilet mat is made from any material intended to be used until soiled, that is, a small number of time, or ever a single time, single-use or otherwise disposable, as distinguished from a mat or rug of fabric that wouldn't ordinarily be intended to be used only once or a small number of times until soiled. The absorbent material of the disposable absorbent toilet mat may comprise any known material such as those incorporated in diapers, feminine pads or panty liners, or other such articles that absorb moisture away from a top surface that initially comes in contact with the top surface and that most preferably contain a spill. Typically, the layers utilized in disposable absorbent materials may comprise a liquid permeable top layer for passing liquid spills, a liquid absorbent layer for absorbing the liquid, and a liquid impermeable bottom layer for confining the spilled liquid. The liquid absorbent layer may also comprise one or more chemical reagents that can change color when they come into contact with the liquid. The reagents many also exhibit a change in coloration in response to a substance within the liquid.
[0017] Other numbers, arrangements and thicknesses of layers in the mat 10 , as known or may become known in the art, are also contemplated by, and fall within the scope of, the present invention. However, the material, or materials are, in accordance with an aspect of the present invention, most preferably disposable materials, as opposed to durable fabric and rubber material used in those toilet mats that are known in the art for repeated, indefinite use.
[0018] The positioning of mat 10 in relation to a toilet 30 , in an embodiment of an aspect of the present invention, is shown in FIG. 2 . Mat 10 has a cut-away region 32 along an edge 34 , where the cut-away region 32 abuts toilet base 36 . As shown in the figure, the adhesive surface 28 ( FIG. 1 ) of collar 26 adheres the periphery of cut-away region 30 to the bottom region of toilet base 36 , thus, creating a seal between the toilet base 36 and the cut-away region 32 . In this manner, the seal provides additional stability for keeping the mat 10 in position, and therefore prevents the mat from slipping on the floor surface. It also provides additional protection from urine spills that may occur in areas that are in relatively close proximity to the toilet base 34 .
[0019] The mat 10 may be of any desired shape. For example, mat 10 may be square, rectangular, or other multi-sided shape, oval or round. Also, depending on the location, orientation, and design of the toilet, mat 10 may not have a cut-away region. For example, some toilet units such as urinals may not have a base that is in contact with the floor. Accordingly, the shape of the mat 10 may be conformed for such use. The mat 10 may, for example, have straight sides instead of a cut-away region on one side. In this case, one of the sides of the mat abuts the wall to which one or more urinals is attached and may cover the floor under one or a plurality of urinals. Similarly, some toilet units are attached to the vertical walls, rather than being connected to the floor by means of a toilet base, such as toilet base 36 shown in FIG. 1 . In this case, as with the urinal, mat 10 may not comprise a cut away region but may still be provided with adhesive strips. In terms of aligning and positioning the mat 10 with the toilet, the toilet base may be referred to as both an actual base, such as toilet base 36 , or the area or region underneath the toilet bowl structure for toilet units not having an actual base (i.e., toilet units designed for attachment to a vertical wall). Other toilet units may include children's potties or generally any device designed to accommodate both children and/or adults in the act of releasing bodily fluids.
[0020] Mat 10 also includes optional footprint-shaped indicia 38 for encouraging a male user to stand on during urination. The indicia 38 are provided in order to suggest an appropriate stance during use. Any other indicia, such as advertising, or none at all, can be used.
[0021] In an embodiment of one aspect of the invention, indicia 38 (whether in the shape of footprints or another configuration) may incorporate a visually enhancing material (e.g., phosphorescent, or fluorescent products), which glows in the dark or otherwise exhibits a luminous or reflective effect. This will serve as a means of attracting the person's attention to the existence of the indicia 38 . Indicia having luminous effects are I useful when the mating is being used in a darkened room.
[0022] Mat 10 comprises, in one embodiment, a wetness indicator. The mat 10 may be treated with a substance that undergoes a change in color when it is contacted with a liquid. For example, a hydra-table salt mixture may be applied to a liquid permeable layer such as top layer 14 and/or transition layer 16 , whereby when the layer comes into contact with a liquid, a visible color change can be visually perceived by the user. Also, chemical reagents, which exhibit a change in coloration upon contact with a liquid as known in the art, may be applied to a layer of the mat 10 , such as absorbent layer 18 , without limitation. As illustrated in FIG. 3 , when a urine spill passes through a treated layer (e.g., layer 14 ), a color change is visually detected, as indicated by wetness indications 40 . The intensity of the color change may vary according to the volume of liquid contacting the mat. In this manner, based on the detected wetness indications 40 caused e.g., by urine spills, it can be determined whether or not the mat 10 should be disposed of, and replaced. In addition to a wetness indicator that provides a visually detectable wetness indication 40 on contact with a liquid (e.g., urine), an olfactory indication may also be provided to enhance urine detection. By incorporating an olfactory indicator into mat 10 , a particular scent may be released when the mat comes into contact with liquid.
[0023] The wetness indicator is a reactant layer that exhibits a characteristic change in response to coming in contact with urine and/or other liquids that are spilled on the matting. For example, if a urine spill were to occur, the absorbent matting would not merely change color (i.e., yellow) as a result of urine staining, the wetness indicator would react to the urine and generate a detectable change (e.g., color, smell, etc.) Various types of coatings or materials that are known in the art for exhibiting a color change upon hydration can be used. Materials or substances that react to the chemical content of urine may also be incorporated in the matting, according to an aspect of the present invention, not only to provide a visual indication of a urine spill, but also to detect certain characteristics of the urine. For example, a person or user of the toilet that is dehydrated or suffers from another condition susceptible to detection by a component of the wetness indicator (e.g., diabetes or kidney ailments) may be alerted to the existence of the condition by the mat.
[0024] As shown in FIG. 3 , both the wetness indications 40 and the indicia 38 are used to facilitate proper use of the toilet 30 and to alert the user, or others, to excessive use, errors, non-hygienic conditions, or even a medical condition of a user.
[0025] FIG. 4 illustrates approximate dimensions of an embodiment of disposable absorbent toilet mat 10 according to the present invention. These dimensions may vary, or be scaled depending on the type or size of toilet 30 , or the space the toilet 30 may occupy, or other factors, without departing from the spirit or scope of the invention.
[0026] FIG. 5 illustrates a flow chart for a method of use of the disposable absorbent toilet mat 10 , in an embodiment of an aspect of the present invention. At step 42 , a mat having a wetness indicator is placed around the periphery of a toilet base in order to protect the toilet floor from spills. At optional step 44 , users of the toilet are encouraged to stand on footprint indicia located on the mat during use of the toilet. At step 46 , a user or other responsible party may detect a spill by observing a region of activated wetness indicator in the absorbent mat. As indicated in step 48 , the user or responsible party may determine the extent of the spill by observing the are of wetness indicator. If it is determined that the wetness indicator shows any or an excessive amount of spill, at step 50 , the mat is replaced with another, unused mat. If the user or responsible party determines that the wetness indicator does not show an appreciable or excessive amount of spill, the mat is not replaced, and as indicated at step 44 , the users are continued to be encouraged to use the indicia during use of the toilet.
[0027] In addition to the embodiments of the aspects of the present invention described above, and with respect to the appended figures, those of skill in the art will be able to arrive at a variety of other arrangements and steps which, if not explicitly described in this document, nevertheless embody the principles of the invention and fall within the scope of the appended claims. For example, the ordering of method steps is not necessarily fixed, but may be capable of being modified without departing from the scope and spirit of the present invention. | 1a
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Patent Application No. 60/734,587, filed on Nov. 8, 2005, and U.S. Provisional Patent Application No. 60/836,001, filed on Aug. 7, 2006, each of which are hereby incorporated by reference herein in their entirety.
TECHNOLOGY AREA
[0002] The disclosed subject matter relates to apparatuses and methods for delivering one or more deliverables into a body.
BACKGROUND
[0003] Assisted reproductive technology (ART) can be utilized to assist women to overcome infertility. In-vitro fertilization (IVF), which is one type of ART, generally involves surgically removing an egg from a female and exposing the egg with sperms in a laboratory dish. If the egg fertilizes and begins cell division, the resulting embryo is transferred into the female's uterus. If implantation of the embryo in the endometrial lining occurs, the embryo will further develop, resulting in a normal pregnancy. Other types of ART include gamete intrafallopian transfer (GIFT), zygote intrafallopian transfer (ZIFT), pronuclear stage tubal transfer (PROST). GIFT involves introducing a mixture of sperms and eggs (gamete) into the fallopian tube where the eggs are fertilized. ZIFT involves fertilizing eggs to form zygotes in vitro and then introducing the zygotes into the fallopian tube. PROST involves fertilizing eggs in vitro and then introducing the fertilized eggs into the fallopian tube before cell division occurs.
[0004] An ART procedure may be performed in conjunction with medications that stimulate the ovaries to produce multiple eggs, in order to increase the likelihood of successful fertilization. Also, multiple eggs or embryos/zygotes may be transferred into the female's uterus or fallopian tube to increase the likelihood of successful implantation.
[0005] In a GIFT, ZIFT, or PROST procedure, introduction of gamete, zygotes, or fertilized eggs occurs through an incision in the abdomen (laproscopy) which is undesirable. In an IVF procedure, it is difficult to transfer eggs into a female's uterus and implanting the embryo into the endometrial lining of the uterus. To perform this task, an embryo transfer device, typically including a catheter, needs to be inserted to a desired depth in the endometrial cavity. Before the catheter reaches into the endometrial cavity, it must first pass the cervical canal, which can be very difficult because of unusual contours in the canal or dramatic angles between the cervix and the body of the uterus. Difficult and traumatic transfers have been associated with lower IVF pregnancy rates.
[0006] Conventionally, insertion of the embryo transfer device is performed blindly (by “feel”), or under transabdominal ultrasound guidance. While ultrasound guidance is frequently helpful for positioning a catheter in the endometrial cavity, it is of little use in negotiating a passage for the catheter through the cervical canal. Ultrasound is also not helpful in all females, especially females with thicker abdominal walls, where resolution of the ultrasound beam can be limited. Blind or ultrasound-guided insertion of a catheter may also result in the creation of “false passages” that cause reproductive complications. Therefore, direct visualization of the cervical canal and the uterus during the insertion of the embryo transfer device is desirable.
[0007] Direct visualization can be enabled by the use of hysteroscopes, which are intrauterine endoscopes that allow visualization of the uterus. However, because of the size of conventional hysteroscopes, dilation of the cervix may be necessary, and the patients may require anesthesia during the procedure. However, dilation of the cervix is highly undesirable at the time of an embryo transfer.
SUMMARY
[0008] Apparatuses and methods for delivering one or more deliverables into a body are provided. In some embodiments, apparatuses for delivering one or more deliverables into a body are provided, the apparatuses comprising: a sheath; an endoscope having a distal portion and a proximal portion and including a microfiberoptic disposed at the distal portion, said endoscope being capable of being inserted at least partially within the sheath, and capable of guiding insertion of the sheath into a configuration in the body; and a catheter capable of being inserted into the sheath, and capable of delivering one or more deliverables to the location in the body based upon the configuration of the sheath; wherein the inner diameter of the outer sheath is less than the sum of the outer diameter of the microfiberoptic and the outer diameter of the catheter.
[0009] In some embodiments, methods for delivering one or more deliverables into a body are provided, the methods comprising: inserting an endoscope inside a sheath; inserting the endoscope and the sheath into the body; removing the endoscope from the sheath while leaving the sheath in the body; inserting a catheter capable of carrying one or more deliverables into the sheath; and delivering the deliverables to the location in the body using the catheter.
[0010] In some embodiments, apparatuses for delivering one or more deliverables into a body, the apparatuses comprising: means for inserting an endoscope inside a sheath; means for inserting the endoscope and the sheath into the body; means for removing the endoscope from the sheath while leaving the sheath in the body; means for inserting a catheter capable of carrying one or more deliverables into the sheath; and means for delivering the deliverables to the location in the body using the catheter.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] FIG. 1 is a side view of a microfiberoptic endoscope of a microfiberoptic transfer catheter of in accordance with some embodiments of the disclosed subject matter.
[0012] FIG. 2A is a side view of an outer sheath of a microfiberoptic transfer catheter of in accordance with some embodiments of the disclosed subject matter.
[0013] FIG. 2B is a cross sectional view of an outer sheath of a microfiberoptic transfer catheter of in accordance with some embodiments of the disclosed subject matter.
[0014] FIG. 3 is a side view of an inner catheter of a microfiberoptic transfer catheter of in accordance with some embodiments of the disclosed subject matter.
[0015] FIG. 4 is a side view illustrating a first stage in a deliverable transfer method utilizing a microfiberoptic transfer catheter of in accordance with some embodiments of the disclosed subject matter.
[0016] FIG. 5 is a side view illustrating a second stage in deliverable transfer method utilizing a microfiberoptic transfer catheter of in accordance with some embodiments of the disclosed subject matter.
[0017] FIG. 6 is a side view illustrating a third stage in a deliverable transfer method utilizing a microfiberoptic transfer catheter of in accordance with some embodiments of the disclosed subject matter.
DETAILED DESCRIPTION
[0018] Apparatuses and methods for delivering one or more deliverables into a body are provided. In some embodiments, a microfiberoptic transfer catheter can include at least the following three components: a steerable, flexible microfiberoptic endoscope (see FIG. 1 ); a flexible outer sheath (see FIGS. 2A and 2B ), inside which the endoscope can be fitted; and a flexible inner catheter (see FIG. 3 ), which can fit inside the outer sheath.
[0019] FIG. 1 , shows a side view of a microfiberoptic endoscope 201 . According to some embodiments, the endoscope 201 can include a microfiberoptic 203 , a distal tip 205 , a demarcator 207 , a connector 209 , a steering lever 211 , a light source 213 , a coupler 215 , an eyepiece 217 , and lens 219 . The catheter can be in any size or dimension as long as it is configured to be inserted into a desired location of the human body.
[0020] In some embodiments, the microfiberoptic 203 can be approximately 25 centimeters long. The outer diameter of the microfiberoptic 203 can be any suitable size. For example, the outer diameter of the microfiberoptic 203 can be approximately 1.5 millimeters when utilized to deliver deliverables into the uterus. As another example, the outer diameter of the microfiberoptic 203 can be approximately 0.05 millimeters when utilized to deliver deliverables into the intramural portion of the fallopian tube. Other suitable sizes for desired delivery location will be readily apparent to one of ordinary skill in the art. The microfiberoptic 203 can be flexible for easier and less traumatic insertion.
[0021] The distal tip 205 of the microfiberoptic 203 can be of any suitable size. For example, distal tip 205 can be approximately 1-2 centimeters long. Various sizes and dimensions are provided herein only as examples. A lens 219 can be located at the distal end of the distal tip 205 . Endoscope 201 can have any suitable angle of view. For example, 0 degrees, 10 degrees, 30 degrees, 70, degrees and the like can be suitable. In some embodiments, the angle of view of endoscope 201 can vary. For example, the angle of view can vary from 0 to 90 degrees, from 20 to 80 degrees, from 30 to 70 degrees, and the like. The angle of view can be determined by the cant of lens 219 .
[0022] A demarcator 207 on the microfiberoptic 203 can indicate the proximal end of the flexible tip 205 . A connector 209 can be located on the microfiberoptic 203 . Connector 209 can be any suitable mechanism for connecting two parts. For example, a suitable connector 209 can be a locking mechanism, such as a Luer lock. In some embodiments, the position of the connector 209 is adjustable. Alternatively, the connector 209 can be fixed on the microfiberoptic 203 .
[0023] An eyepiece 217 can also be located at the proximal portion of the endoscope 201 . Eyepiece 217 can include one or more lens element. A user may look through eyepiece 217 directly. A coupler 215 can also be attached to the eyepiece 217 and can be located at the proximal end of the endoscope 201 . The coupler 215 can be used to couple optically the eyepiece 217 with a video monitoring device (not shown). The video monitoring device can, for example, include a video camera, which can be further attached to a video monitor. Any suitable video equipment can be used. For example, video equipment that can be used is commercially available and currently in use for other endoscopic applications. For example, the video equipment can be a TRICAM camera head and a Medi Pack terminal from Karl Storz Endoscopy-America, Inc., Culver City, Calif., or a Visera System from Olympus America, Inc., Melville, N.Y. The microfiberoptic 203 can be disinfected and sterilized in gas or liquid solution.
[0024] A steering lever 211 and a light source 213 can be attached to the eyepiece 217 . The distal tip 205 can be bent by the steering lever 211 . Bending of the distal tip 205 can allow easier and less traumatic insertion of the endoscope 201 . In some embodiments, the distal tip 205 can be bent because the microfiberoptic 203 includes small flexible wires that are attached to the steering lever 211 on the eyepiece 217 of the endoscope 201 . Pulling the lever 211 in one direction pulls the wires (not shown) in that direction, causing distal tip 205 to bend in the same direction. This bending or steering mechanism can be the same as that used in other endoscopes, such as endoscopes used for colonoscopy or other gastrointestinal applications.
[0025] Another component of the microfiberoptic embryo transfer catheter is illustrated in FIG. 2A , which is a side view of the outer sheath 301 . FIG. 2B is a cross-sectional view of the outer sheath 301 . The outer sheath 301 is preferably made of non-toxic polymers safe for medical use, such as polyethylene, polyvinylchloride, polypropylene, polystyrene and/or any other suitable material. Outer sheath 301 can be designed for a single use. The outer sheath 301 can be flexible for easier and less traumatic insertion. In some embodiments, the distal tip 303 can be slightly beveled. A beveled tip allows easier and less traumatic insertion than a tip with a blunt end.
[0026] In some embodiments, the distal tip 303 can also be echolucent so that the position of the distal tip 303 of the outer sheath 301 can be confirmed by ultrasound. A threaded locking mechanism 305 can be located at the proximal end of the outer sheath 301 so that the outer sheath 301 can be secured to the microfiberoptic endoscope 201 illustrated in FIG. 1 , using the connector 209 located on the microfiberoptic endoscope 201 . Locking mechanism 305 can be, for example, a Luer lock. In some embodiments, the outer surface of the outer sheath 301 can be demarcated (shown as 307 ) with gradations for every centimeter (or any other unit of measure) starting from the distal tip 303 . The outer sheath 301 can be designed in different lengths (e.g., 12-18 centimeters) to accommodate variations in pelvic anatomy. In some embodiments, the connector 209 on the microfiberoptic endoscope 201 can be adjusted to accommodate different lengths of the outer sheath 301 .
[0027] As FIG. 2B illustrates, the outer sheath 301 can have an inner diameter (ID) that is slightly larger than the outer diameter (OD) of microfiberoptic 203 . For example, if the outer diameter (OD) of microfiberoptic 203 is about 1.5 millimeters, the inner diameter (ID) of outer sheath 301 can be approximately 1.6 millimeters, so that the microfiberoptic 203 can be fitted within the outer sheath 301 . The outer diameter (OD) of the outer sheath 301 can be less than about several millimeters. For example, the outer diameter (OD) of the outer sheath 301 can be about 1.9 millimeters. Although 1.9 millimeters is not meant to be the absolute maximum, a small outer diameter (OD) of the outer sheath 301 can reduce the difficulty and trauma associated with the insertion of the device.
[0028] Yet another component of the microfiberoptic embryo transfer catheter is illustrated in FIG. 3 , which is a side view of the inner catheter 401 . The inner catheter 401 can also be made of nontoxic polymer safe for medical use, such as polyethylene, polyvinylchloride, polypropylene, polystyrene and/or any other suitable material. In some embodiments, one inner catheter can be packaged together with one outer sheath for a single use. The outer diameter of the inner catheter 401 can be of any suitable size capable of fitting inside the inner diameter of the outer sheath 301 . For example, if the inner diameter of outer sheath 301 is about 1.6 millimeters, the outer diameter of inner catheter 401 can be approximately 1.5 millimeters, so that it can be fitted inside the outer sheath 301 . The inner catheter 401 can also be flexible, so that it can be inserted into the outer sheath 301 when the outer sheath 301 is contorted.
[0029] The length of the inner catheter 401 can vary to accommodate variations in human anatomy. In some embodiments, the length of inner catheter 401 can be approximately several centimeters longer than the outer sheath in the same package. For example, the length of inner catheter 401 can be about 8 to 10 centimeters longer than the outer sheath.
[0030] In some embodiments, the distal tip 403 of the inner catheter 401 can be echolucent so that position of the inner catheter 401 can be confirmed by ultrasound. In some embodiments, demarcations 409 with 1 centimeter (or any other unit of measure) gradations are present in order to measure the depth of insertion. The first gradation on the distal side can be at a distance that signifies the length of the outer sheath 301 . For example, if the outer sheath 301 is 15 centimeters long, the first gradation on the inner catheter 401 can be 15 centimeters from its distal tip 403 . In this way, when the inner catheter 401 is introduced inside the outer sheath 301 to the depth of the first gradation, the distal tip 403 of the inner catheter 401 can be flush with the distal tip 303 of the outer sheath 301 . When the inner catheter 401 is introduced further into the outer sheath 301 , successive gradations on the inner catheter 401 can indicate the depth that the distal tip 403 has reached beyond the outer sheath. The proximal end of the inner catheter 401 can be fitted with threaded locking mechanisms 405 and 407 , so that the inner catheter 401 can be secured distally to an outer sheath and proximally to a standard syringe. Locking mechanisms 405 , 407 can be, for example, Luer locks.
[0031] FIGS. 4-6 illustrate an example deliverable delivery procedure using the microfiberoptic catheter to deliver embryo into a uterus. More specifically, FIG. 4 illustrates the first stage of the procedure. As shown, microfiberoptic 203 of the microfiberoptic endoscope 201 can be fitted inside the outer sheath 301 . The distal tip 303 of the outer sheath 301 can be aligned with the demarcater 207 on the microfiberoptic endoscope 201 , leaving the distal tip 205 of the microfiberoptic endoscope 201 outside the outer sheath 301 . The threaded connector 209 of the microfiberoptic endoscope 201 can be used to lock with the locking mechanism 305 of the outer sheath 301 , so that the microfiberoptic 203 is secured inside the outer sheath 301 . Before insertion of the microfiberoptic endoscope 201 and the outer sheath 301 , the patient can be positioned and prepped per usual procedure for an embryo transfer, and the devices can be sterilized. Prepping a patient can include, for example, comfortably positioning the patient in dorsal lithotomy position, placing a speculum in the vagina of the patient, and aseptically cleansing the cervix and vagina of the patient.
[0032] FIG. 5 illustrates the second stage of the procedure, wherein the outer sheath 301 and the distal portion of the microfiberoptic endoscope 201 have been inserted through the external opening 601 of the cervical canal. As shown, the distal tip 205 of the endoscope 201 has reached beyond the internal opening 603 of the cervical canal so that it is inside the endometrial cavity 605 . This can been accomplished by using the steering lever 211 on the endoscope 201 to steer and negotiate a passage through the cervical canal and the endometrial cavity. In some embodiments, a video camera and a video monitor 609 can be attached to the endoscope 201 through the coupler 215 to display images provided by endoscope 201 , allowing direct visualization during the insertion. Alternatively, a person performing the procedure can directly look through the eyepiece 217 of the endoscope 201 .
[0033] The microfiberoptic endoscope 201 can provide direct visualization of a steeply flexed junction between the cervix and the body of the uterus. The flexibility of the microfiberoptic and the outer sheath 301 , as well as the steering of the distal tip 205 , may allow the endoscope 201 and the outer sheath 301 to negotiate obstacles during the insertion through the cervical canal and the endometrial cavity. In some embodiments, after the endoscope 201 reaches beyond the internal opening 603 of the cervical canal, the outer sheath 301 can be inserted over the endoscope 201 . Alternatively, the endoscope 201 can be inserted together with the outer sheath 301 . According to some embodiments, the depth of insertion of the outer sheath 301 can be determined by gradations on the surface of the outer sheath 301 . In some embodiments, the distal tip 303 of the outer sheath 301 can be echolucent and the position of the distal tip 303 can be determined by ultrasound. After the outer sheath 301 reaches a desired depth, the endoscope 201 can be removed, with the outer sheath 301 left in place.
[0034] FIG. 6 illustrates the third stage in the procedure, wherein the microfiberoptic endoscope has been removed, with the outer sheath 301 left in place. The inner catheter 401 can be inserted through the outer sheath 301 and introduced to the appropriate depth. In some embodiments, the depth of insertion of the inner catheter 401 can be determined by gradations on the inner catheter 401 and the outer sheath 301 . In some embodiments, the distal tip 403 of the inner catheter 401 can be echolucent and the position of the distal tip 403 can therefore be determined by ultrasound. The inner catheter 401 can be locked to the outer sheath 301 through the locking mechanism 405 . A syringe 701 can be locked with the inner catheter 401 through the locking mechanism 407 . The inner catheter 401 can be loaded with embryos in a volume of fluid determined by an embryologist, and the syringe 701 can be used to inject the embryos and the fluid into the endometrial cavity, or to implant the embryos onto the endometrial lining. After the injection, both the outer sheath 301 and inner catheter 401 can be removed together.
[0035] As FIGS. 4-6 illustrate, in some embodiments, the microfiberoptic endoscope 201 and the inner catheter 401 are not inserted into the endometrial cavity 605 at the same time. Instead, each piece can fit inside the outer sheath 301 and can be inserted one at a time. This allows the outer sheath 301 to be thin, because the inner diameter of the outer sheath 301 only needs to be slightly larger than the larger of the diameter of the microfiberoptic 203 of the microfiberoptic endoscope 201 and the outer diameter of the inner catheter 401 .
[0036] However, in other embodiments, microfiberoptic endoscope 201 and inner catheter 401 can simultaneously fit inside the outer sheath 301 . The combination of microfiberoptic endoscope, inner catheter 401 , and outer sheath 301 can then be simultaneously inserted into the human body so that delivery of the deliverables can be monitored after insertion into the human body.
[0037] It will be readily apparent to one of ordinary skill in the art that systems and methods according to some embodiments can be used to deliver any suitable deliverables, such as an egg, sperm, gamete, fertilized egg, zygote, embryo, and the like, to any suitable and/or desired location within the human body, such as the uterus, the fallopian tube, and the like.
[0038] Other embodiments, extensions, and modifications of the ideas presented above are comprehended and within the reach of one skilled in the field upon reviewing the present disclosure. Accordingly, the scope of the present invention in its various aspects is not to be limited by the examples, applications, and embodiments presented above. The individual aspects of the present invention, and the entirety of the invention are to be regarded so as to allow for modifications and future developments within the scope of the present disclosure. Various features of the invention can be used in any suitable combination. The present invention is limited only by the claims that follow. | 1a
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FIELD OF THE INVENTION
This invention relates to a pacifier or dummy comprising an elastic nipple consisting of a mouthpiece and a tubular portion, a guard having an opening through which said tubular portion extends, and a plug, which comprises a plug body, which extends into that end of the tubular portion which is opposite to the mouthpiece, and a base, which is supported by the guard on that side thereof which is opposite to the mouthpiece.
DESCRIPTION OF THE PRIOR ART
It is known that the guard can be provided at its opening with beveled surfaces for locating the tubular portion in conjunction with complementary beveled surfaces. This is included.
Such a pacifier or dummy is known from Austrian patent specification No. 338,440. In that known device, the base for a plug body which has a larger thickness in the tubular portion, consists of a hemispherical cover cap, which is substantially outwardly curved and is secured by a snap joint, adhesive joint or welded joint to a thicker portion of the guard, which thicker portion is disposed adjacent to and surrounds the opening in the guard. The beveled surfaces for locating the tubular body are provided on that edge of the opening in the guard which faces the guard and in one embodiment constitute a widened portion of that edge of said opening which faces the mouthpiece, and the plug body which has been inserted into the tubular portion is hollow and formed with slots, which extend from that end of the plug body which faces the mouthpiece. As a result, the plug body comprises laminae, which tend to spring inwardly. Outwardly directed detent projections are provided at the ends of the blades and urge the adjoining part of the tubular portion against the beveled surfaces at the rim of the opening in the guard. In response to tension applied to the nipple in that embodiment, the blades of the plug body can spring back. That pacifier or dummy can be taken apart rather easily. The hemispherical base provided in the known device is shaped to be non-yieldable and if it were resilient the connections between the parts of the known pacifier or dummy would be loose.
It is also known from said Austrian patent specification that the plug body may widen in the shape of a frustum of a cone in order to effect an additional clamping of the rolled-up edge of the nipple at that portion which faces the hemispherical cover cap or base. As a result, that rolled-up edge is always compressed against the guard at an edge which extends at right angles to the longitudinal axis of the plug body. This does not strengthen the connections between the parts of the assembly.
It is also known to provide a circular or oval cross-section adjacent to the tubular portion.
Austrian patent specification No. 339,501 discloses a pacifier or dummy which has a flat plug body that is provided at its narrow sides with projections, which are received by mating outwardly bulged portions of the tubular portion. But when the device has been assembled said arrangement is disposed beside the opening in the guard and serves to define the position of the nipple on the plug body relative to the guard.
SUMMARY OF THE INVENTION
It is an object of the invention so to design a pacifier or dummy of the kind described first hereinbefore that the parts of the device, particularly the only three parts of the device consisting of the nipple and of two parts which are particularly made from plastic material and consist of the guard and of the plug body and base are held more firmly together and the connections between these parts will be even strengthened in response to a pull exerted on the nipple.
This object is accomplished according to the invention in that the base is resilient in the direction of the longitudinal axis of the nipple and the plug has projections, which interengage with the tubular portion and are movable along the axis of the nipple and preferably comprise beveled surfaces of the plug body, and are adapted to respond to tension applied to the nipple in that said projections are moved toward beveled surfaces of the guard adjacent to the opening therein so as to increasingly clamp the tubular portion in conjunction with a resilient deformation of the base.
As a result of this compliance only in an axial direction, the clamping at said surfaces, which are preferably beveled, can be increased in response to tension and a centering action can be effected at the same time, whereas the parts will return to their normal position in response to a relief so that the strain on the material of the nipple, consisting particularly of rubber, will be reduced.
In a desirable embodiment, the projections are provided on the resilient base of the plug so that pressure will be applied in direct response to the resilient yielding of the resilient base.
In accordance with another desirable feature of the pacifier or dummy projections are provided at two narrow sides of a flat plug body and are engaged by part of the tubular portion and said part is movable against an opposite surface of the guard upon a pull on the tubular portion. Within the scope of the invention, a suitable alignment can be ensured in that the opening in the guard and the cross-section of the plug body and the cross-section of the tubular portion are elongated and larger in one direction than in the other. This will be particularly advantageous if the nipple has a shape which is desirable from an orthodontic aspect. This is also included. The invention includes also a tubular portion which is circular in cross-section and a corresponding circular opening in the guard and a plug body which is circular in cross-section. In a preferred embodiment, projections are provided on a broadside of the plug body and are disposed behind an opening which is formed in the guard and receives the tubular portion, said projections rise from said opening and engage a bead of the tubular portion, and the rim of the opening in the guard is beveled inwardly on the side facing the base. In that embodiment, a yielding of the base will also result in a stronger clamping action.
Particularly in conjunction with a resiliently deformable base of the plug, the connections between the parts of the device can be strengthened in that, in a preferred embodiment, the outwardly protruding projections provided at the narrow sides of the flat plug body are oversize with respect to the clearance between lugs which are formed on the guard and extend into the opening thereof. This results in a particularly strong adhesion. This embodiment can be further improved in that the plug body is provided adjacent to the projections with openings, which extend toward the resilient base and are defined on the outside by webs of plug material adjacent to the projections, which webs are adapted to be resiliently forced inwardly. Owing to the properties of the plug body material, that web can be resiliently depressed and particularly can spring back so that in this embodiment the plug body, which is oversize adjacent to the projections, can be reliably inserted. In this connection, resilient inserts may be provided in the openings.
In another particularly preferred embodiment for use in conjunction with the above-mentioned oversize, the base is disclike and hinged to a plug body, which is formed with the beveled surfaces and with the outwardly extending projections, which are oversize with respect to the clearance between lugs formed on the guard and extending into the opening thereof. Owing to that hinge, the plug with its oversize projections can be threaded in an oblique direction through the opening in the guard, which opening is constricted in that region. The hinge may be provided by a constricted, flexible neck portion between the base and the plug body, which is provided with the beveled surfaces. In that connection a particularly preferred feature resides in that the annular rib comprises a step, which supports the rim of a disclike base and defines a recess for centering said base, and the disclike base is held in position in said recess owing to the elasticity of the base and the elasticity of the tubular portion held between confronting surfaces of the plug body and of the guard portion defining the opening.
In both embodiments, even an oversize plug body, particularly a plug body having oversize projections, can be inserted into the base to interengage therewith so that the plug body will be reliably locked in position. That embodiment constitutes a pacifier or dummy having two resilient elements, namely, the resilient base, which engages the guard, and plug body portions, such as the neck, or other plug body portions which carry the projections and permit the plug body to be folded as it is inserted and permit it to expand when it has been inserted. To facilitate the assembling the lateral projections of the plug body are rounded at that edge which merges into the end of the plug body.
In a particularly preferred embodiment the opening in the guard is flush with that surface of the guard which is on the same side as the mouthpiece, the guard is formed on the opposite side with an annular rib, which surrounds a recess, and the resilient base is disclike and held in position at the annular rib. In that case the resilience of the disclike base will be desirably utilized. The rim of the opening is preferably provided with inwardly directed lugs beside the recess, which lugs define between them a clearance which is smaller than the distance between the outer ends of the projections provided on the narrow sides of the plug body.
The invention covers also the provision of a flat plug body on a resilient disclike base which covers the region around the opening in the guard, and the provision of a plug body which has a length that is equal to the depth of the opening in the guard and which is oversize with respect to the clearance between inwardly protruding lugs provided in the opening in the guard, which lugs and projections are axially spaced apart and disposed adjacent to the opening when the plug body has been inserted.
In response to tension applied to the mouthpiece of the nipple, the projections extending into a recess formed in the rim of the opening in the guard will be pulled toward the mouthpiece so that the clamping action will be increased. In response to a relief, the at least two projections will return to a centered position so that the material of the tubular portion will be relieved.
The plug body, even if it is circular in cross-section, may be provided with an annular peripheral bead, which is associated with and conforms to a recess formed in the rim of the opening in the guard. The invention thus includes also a plug body which has an end portion that is constricted and circular in cross-section and disposed at the center of the disc-shaped base.
The resilient base may consist of webs which extend diagonally across the opening or which are star-shaped. In a particularly preferred embodiment the resilient base consists of a disc-shaped cover over the guard in a region which surrounds the opening therein so that a closure is also provided.
In a desirable embodiment, the plug body has an end portion that is constricted and particularly circular in cross-section and disposed at the center of the disc. The closing of the assembly on that side which faces away from the mouthpiece can be improved in that the resilient base consists of a disc-shaped cover over the guard in a region which surrounds the opening therein. This can also be used in conjunction with a flat plug body.
In the embodiment just described, the disc-like cover is held in position at protruding profiled portions of the guard, particularly at an annular rib of the guard, and can be fixed by any of the means described hereinbefore. The disclike cover consists preferably of plastic material. The substantially flat, disclike cover may have a wave-shaped profiled portion which surrounds the center of the cover so that a predetermined compliance can be provided for. For this purpose, the wall thickness of the disclike cover may be desirably selected and may decrease outwardly or toward the central portion.
BRIEF DESCRIPTION OF THE DRAWING
The invention will now be explained with reference to illustrative embodiments shown on the accompanying drawing, in which
FIG. 1 is a diagrammatic side elevation showing a pacifier or dummy,
FIG. 2 is a view that is similar to FIG. 1 and shows another embodiment,
FIG. 3 is a view that is similar to FIG. 1 and shows a preferred embodiment. The various figures show also covers having different cross-sectional shapes,
FIG. 4 is a top plan view showing a specially designed flat plug body and a resilient base,
FIG. 5 is an enlarged view showing that plug body inserted in a guard, and
FIG. 6 is a side elevation corresponding to FIG. 5. FIGS. 4 to 6 are partial sectional views or sectional views.
FIG. 7 is a view that is similar to FIG. 4 and shows another embodiment of a plug body and a resilient base.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
In all figures of the drawings, the interengaging portions are shown on an enlarged scale.
In the figures of the drawings, a nipple 1 consisting of a mouthpiece 2, which may have an orthodontically desirable shape, and a tubular portion 3 terminating in a rolled-up rim 4, are shown. The tubular portion extends through an opening 5 in a guard 6. The opening 5 conforms in cross-section to the cross-section of the tubular portion 3. A plug body 7 which has been inserted is similarly shaped in cross-section.
On the side facing away from the mouthpiece 2, the guard is formed around the opening 5 with a projecting portion 8, which may consist of a rib and to which a base 9 or 10 or 11 is secured, e.g., in that the rim of the base is adhesively joined to the projecting portion or in that said rim has been caused to snap into profiled clamping portions. The embodiments shown in FIGS. 1 to 3 have different bases.
The bases may consist of webs, star-shaped elements or the like and consist preferably of a disc.
In the embodiment shown in FIG. 1, the rim 12 of the opening 5 is beveled on the side facing the base 9 and tapers toward the mouthpiece 2. The rolled-up rim 4 of the nipple is disposed adjacent to the beveled surface. The disclike base 9 is resilient and in this embodiment carries projections 13, e.g., in the form of a peripheral annular bead adjacent to the rolled-up rim 4. The disclike base is connected to a centrally disposed plug body 7, which extends through the tubular portion 3 and holds the latter against the rim of the opening 5 and holds the rolled-up rim between the projections 13 and the beveled edge 12 of the opening. The plug body 7 flares toward its inner end 14 and may be provided there with an outwardly directed bead so that tension applied to the mouthpiece will cause the disclike base to bend inwardly so as to clamp the rolled-up rim with a progressively increasing force.
The disclike base 9 consists of a relatively thin disc, which may preferably be made of plastic material or may consist of metal.
In the embodiment shown in FIG. 2 the plug body 7 has also a wider inner end and is provided with projections 15, which may constitute a peripheral annular collar, which holds and clamps the rolled-up rim 4 against the beveled edge 12 of the opening 5. The plug body 7 has a constricted end portion 16, which is circular in cross-section, even if the remainder of the plug is flat in cross-section. The end portion 16 is disposed at the center of the disclike base 10. That disc has a small thickness at its rim, which is secured to the projecting portion 8, and increases in thickness toward the central portion. That design provides for an adequate resilience.
In the embodiment shown in FIG. 3 the guard 6 is formed in the rim of the opening 5 with an outwardly directed, inwardly open recess 17 in the middle of the height of the rim. The projections 18 provided on the plug body may consist of a peripheral annular bead and conform to the recess 17 but are undersize so that the tubular portion 3 when pulled over the plug will have a bulge 19, which is initially held under a low contact pressure in the recess 17. The plug has a constricted end portion 16, which is secured to the disclike base 11 in one of the ways which have been described. The rolled-up rim 4 is disposed on the rear of the guard 6, below the disclike base 11.
Upon a pull on the mouthpiece 2, the plug body, which is closely embraced by the tubular portion 3 at the bead or at the projections 18, will be carried along so that a clamping is effected at the inwardly contracting wall surface 20 of the recess 17 and will result in an increase of the strength of the joint as the pull on the mouthpiece 2 is increased. Upon a release of the mouthpiece, the arrangement springs back to its centered position.
In the embodiment shown in FIG. 3, wave-shaped profiled portions extend around the center of the disclike base and permit an improvement or adjustment of its resilience.
The disclike bases 9 to 11 constitute also a centrally disposed cover over the central portion of the guard on that side which faces away from the mouthpiece 2.
In FIGS. 4 to 6, a guard 6 and a base 10 are also apparent and it is seen that the resilient base is connected by a constricted end portion 16 to the flat plug body 22. The flat plug body is provided at its inserted end portion 23 with the outwardly directed projections 24, 25, which are oversize with respect to the clearance between inwardly directed lugs 26, 27 provided at the narrow ends of the opening in the guard. This is mainly apparent from FIG. 5. On that side of the lugs which faces away from the mouthpiece 2, the plug body defines inside the protruding rib 8 a chamber 28, which contains the rolled-up rim 4 of the nipple. As described hereinbefore, the resilient base 10 bears on the protruding portion 8, particularly on a step 29 of said portion.
As the plug body is inserted into the guard, the projections 24, 25 moving past the lugs 26, 27 are forced inwardly by the latter. The projections can yield because the plug body is formed adjacent to the projections 24, 25 with cavities 30, 31, which are defined on the outside by webs 32, 33, which can resiliently yield inwardly toward the opening 30 or 31. That resiliency is improved in that the webs 32, 33 taper toward the base at 36 or 37 on the outside, behind the projections 24, 25, e.g., owing to the provision of a beveled surface 34 or 35. That taper promotes the ability of the webs to yield inwardly. The resilient plastic material of the plug body ensures that the webs will stretch after the plug body has been inserted so that the projections 24, 25 and the lugs 26, 27 will interengage. It is virtually impossible to take the resulting assembly apart because the projections 24, 25 and the lugs 26, 27 have mutually confronting, parallel surfaces 38 and 39, respectively, and because said beveled surfaces 32, 33 defining a labyrinthlike passage for the tubular portion ensure that a pull on the mouthpiece will result in an increasingly stronger clamping action.
As is apparent from FIGS. 4 to 6, the plug body is provided at its narrow sides with wedgelike surfaces 40, 41, which rise toward the base 10 and face beveled surfaces 42, 43 of the rim of the opening in the guard 6. The inclinations may be different. This feature will also ensure that the rolled-up rim 4 of the nipple 1 will be increasingly clamped if a pull is exerted on the mouthpiece and that the plug body can yield owing to the resilience of the base.
The embodiment shown in FIGS. 4 to 6 affords the advantage that the end face of the inserted end portion 23 can be flush with the concave inner boundary surface 44 of the guard 6 because the reliable interengagement and the clamping means are restricted to the short region defined by the thickness of the guard.
As is particularly shown in FIG. 5, resilient inserts 45, 46 may be disposed in the cavities 30, 31 as resilient backings on the inside of the webs 32, 33. Such inserts may consist of rubber fillers in the openings, rubber buffers or transverse springs in the openings. Instead of rubber, a suitable plastic material may be used.
In that case an advantage will be afforded by the fact that the outwardly directed projections 24, 25 act on the webs 32, 33 virtually like levers tending to bend the webs 32, 33 inwardly, particularly because the latter are tapered at 36, 37.
As in the embodiment shown in FIG. 4, the plug 47 of FIG. 7 comprises a disclike base 10 consisting of a resiliently flexible disc, which is connected to the flat plug body 49 by a constricted neck 48. The latter is so small in cross-section that the disclike base 10 is hinged to the plug body. The neck 48 is flexible so that when the oversize projections 24, 25 are threaded in an oblique orientation into the opening in the guard 6 between the inwardly directed lugs 26, 27 (FIG. 5), the disclike base can be laterally displaced initially over the crest of the rib 8. As a result, that portion of the plug body 49 which is disposed above the projections 24, 25 can be reciprocated so that said projections are moved under the lugs 26, 27. When this has been accomplished, the rim of the disclike resilient base enters the step-shaped recess 29 at the crest of the rib 8 so that the plug body can be centered in such a manner that the projections 24, 25 in a symmetric arrangement engage the lugs 26, 27 from below. In that case the resilience of that part of the tubular portion 3 which extends between the described beveled surfaces and between the projections and lugs ensures a resilient and captive mounting. In this embodiment a plug body having projections 24, 25 which are substantially oversize can be inserted without exerting a nonpermissible stress on the material of the tubular portion.
Because the neck 48 is flexible, the elongated plug body 49 is suitably provided at its narrow ends under the disclike base 10 with upstanding abutments 50, 51, which are spaced below the base when the latter has been aligned. These abutments limit the pivotal movement of the disclike base 10.
The plug body is also provided on its longitudinal sides with the wedge surfaces 40, 41, which have been described with reference to FIG. 6 and rise toward the base 10. One of said surfaces is shown in FIG. 7.
In all embodiments shown and described, a guard (6) is provided, which is formed with a through opening (5) and on one side with axially protruding supporting means (8) spaced around said opening. A nipple (1) has a tubular portion (3), which extends through the opening (5), and a mouthpiece (2), which is integral with the tubular portion (3) and disposed on the other side of the guard (6). A plug comprises a plug body (7; 22; 49) and a base (9; 10; 11) connected to the plug body and disposed on said one side of said guard and bearing on said supporting means. The plug body extends into the opening (5) and is surrounded in part of its length by the tubular portion (3). The guard is formed with first clamping surfaces (12; 20; 26, 27), which are disposed on the outside of the tubular portion (3) and face the base. The plug is formed with second clamping surfaces (13; 15; 18; 34, 35), which are disposed on the inside of said tubular portion and face said first clamping surfaces. The first and second clamping surfaces comprise beveled surfaces. The tubular portion is in force-transmitting frictional contact with said plug body. The tubular portion (3) extends between said first and second clamping surfaces and is in force-transmitting frictional contact with said plug body in said opening. Said base is resilient in the longitudinal direction of said nipple to permit a movement of said second clamping surfaces toward said first clamping surfaces in said longitudinal direction whereby said tubular portion will be clamped more strongly between said clamping surfaces upon a pull on the mouthpiece. | 1a
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CROSS-REFERENCE TO RELATED APPLICATION
[0001] The present application is a divisional of U.S. application Ser. No. 11/500,997, filed Aug. 9, 2006 and claims the benefit of U.S. Provisional Patent Application Ser. No. 60/793,245 filed Apr. 20, 2006 entitled “Wash/Rinse System For a Drawer-Type Dishwasher.”
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention pertains to the art of dishwashers and, more is particularly, to a wash/rinse system for a drawer-type dishwasher.
[0004] 2. Discussion of the Prior Art
[0005] Drawer-type dishwashers are widely known in the art and, once again, gaining popularity with consumers. Typically, a drawer-type dishwasher will include a drawer or washing tub that is slidably mounted in a cabinet. A dish rack is provided within the washing tub to support to dishware and the like during a washing operation. In any event, various models of drawer-type dishwasher are available to today's consumers. The dishwasher can range from a single drawer unit to multi-compartment units that are arranged in upper and lower or side-by-side configurations. The multi-compartment units include either multiple is drawers or, a combined drawer and conventional type dishwasher. However, regardless of the particular configuration, a drawer-type dishwasher includes a lid that selectively seals the washing tub during a wash operation.
[0006] During the washing operation, washing fluid is sprayed onto kitchenware and the like situated in the washing tub. The washing fluid is directed from a lower wash arm and, often times, from a wash arm mounted to the lid. In this manner, the manufacturer ensures that all of the kitchenware is exposed to jets of washing fluid during the washing operation. While effective at establishing a more uniform distribution of washing fluid, upper or lid mounted wash arms are prone to leak or drip water onto internal dishwasher components when the drawer is withdrawn from the cabinet. Water dripping onto internal machine components can cause erosion problems that may ultimately create maintenance or premature failure issues for the consumer.
[0007] Thus, based on the above, there still exists a need in the art for a drawer-type dishwasher that includes a wash/rinse system that directs sprays of washing fluid into upper portions of a washing chamber wherein, when the drawer is removed for unloading/loading dishwasher, washing fluid does not drip onto internal dishwasher components.
SUMMARY OF THE INVENTION
[0008] The present invention is directed to a wash/rinse system for a drawer-type dishwasher including an outer support body, a drawer slidingly received in the outer support body having front, rear, bottom and opposing side walls that collectively define a washing chamber, a lid is shiftably mounted in the outer support body for selectively closing the washing chamber, and a dishrack positioned in the washing chamber for supporting articles to be exposed to a washing operation. In accordance with the invention, the wash/rinse system includes a wash mechanism having a paddlewheel provided with at least one deflector member and a spray bar. The spray bar is provided with at least one nozzle and is mounted in the washing chamber adjacent the paddlewheel.
[0009] In further accordance with the invention, the at least one nozzle is positioned so as to deliver a jet of washing fluid onto the at least one deflector member in order to impart a rotational force to the paddlewheel. Upon impacting the at least one deflector member, the jet of washing fluid diverges into a stream(s) of washing fluid which is sprayed onto articles supported in the washing chamber during the washing operation. Preferably, the spray bar includes a plurality of nozzles which direct multiple jets of washing fluid onto a corresponding plurality of deflector members.
[0010] In the most preferred form of the invention, the paddlewheel is mounted at an upper portion of the back wall of the washing chamber, with the plurality of deflector members being positioned at various angles or orientations so as to create random streams of washing fluid that are sprayed about the washing chamber. In this manner, the random streams of washing fluid combine with washing fluid emanating from a lower wash arm to clean the articles supported upon the rack.
[0011] Additional objects, features and advantages of the present is invention will become more readily apparent from the following detailed description of preferred embodiments when taken in conjunction with the drawings wherein like reference numerals refer to corresponding parts in the several views.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] FIG. 1 is an upper right perspective view of a drawer-type dishwasher incorporating a wash/rinse system constructed in accordance with the present invention;
[0013] FIG. 2 is an upper right, partially cut-away perspective view of a drawer portion of the dishwasher of FIG. 1 illustrating the wash/rinse system mounted in accordance with the present invention;
[0014] FIG. 3 is an upper right perspective view of the wash/rinse system of FIG. 2 ;
[0015] FIG. 4 is a perspective view of an inlet nozzle portion of the wash/rinse system;
[0016] FIG. 5 is an exploded view of a feed member portion of the wash/rinse system;
[0017] FIG. 6 is a perspective view of the inlet nozzle of FIG. 4 being attached to the feed member of FIG. 5 at a rear wall of the wash chamber;
[0018] FIG. 7 is a rear view of the washing chamber of FIG. 2 is illustrating a flow sensor mounted in accordance with the present invention; and
[0019] FIG. 8 is a wash/rinse system constructed in accordance with an alternative embodiment of the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0020] With initial reference to FIGS. 1 and 2 , a dishwasher constructed in accordance with the present invention, is generally indicated at 2 . Dishwasher 2 includes an outer support body 4 which is positioned below a kitchen countertop 6 along side a plurality of cabinets 8 . As shown, cabinets 8 include drawers 9 - 12 and a door 13 . As further shown, dishwasher 2 includes an upper washing unit or drawer 16 , as well as a lower washing unit or drawer 18 . As each washing unit 16 , 18 is similarly constructed, a detailed description will be made with respect to upper washing unit 16 with an understanding that lower washing unit 18 includes corresponding structure.
[0021] Upper washing unit 16 includes a front wall 20 , a rear wall 21 , a bottom wall 22 and opposing side walls 23 and 24 that collectively define an upper washing chamber 28 . A dishrack 30 is positioned within upper washing chamber 28 to support kitchenware, indicated generally at 31 , which may include plates, cups or the like. Upper washing unit 16 is slidably supported within outer support body 4 through a pair of extensible drawer glides, one of which is indicated at 33 . Finally, dishwasher 2 is shown to include a lid 37 that is selectively shiftable relative to washing chamber 28 as drawer 16 is moved into and out of outer support body 4 .
[0022] Dishwasher 2 selectively performs a washing operation in washing chamber 28 during which sprays or jets of washing fluid are directed onto kitchenware 31 by a lower wash arm 47 , as well as an upper washing mechanism 50 . In the embodiment shown, upper washing mechanism 50 is positioned at an upper portion of rear wall 21 . As best shown in FIGS. 2 and 3 , upper washing mechanism 50 includes a water delivery portion 56 having an inlet conduit 58 which directs a flow of washing fluid towards a spray bar 60 . In accordance with the invention, inlet conduit 58 includes a first end section 63 that extends to a second end section 64 through an intermediate section 65 . First end section 63 is preferably domed-shaped so as to receive an inlet nozzle 69 therein (see FIG. 4 ) as will be discussed more fully below.
[0023] As further shown in FIG. 3 , spray bar 60 includes a first end portion 90 that extends to a second end portion 91 through an intermediate portion 92 that defines a central trough 97 . First and second end portions 90 and 91 actually define support members in a manner that will be detailed more fully below. In any event, spray bar 60 is actually fluidly connected to second end section 64 of inlet conduit 58 so as to receive a flow of washing fluid from inlet nozzle 69 . The flow of washing fluid is directed outward from central trough 97 through a plurality of nozzles 104 - 111 . Actually, trough 97 is divided into first and second lateral sections or zones 114 and 115 by a central support member 112 , with nozzles 104 - 107 being positioned in first lateral zone 114 and nozzles 108 - 111 being positioned in second lateral zone 115 .
[0024] Upper washing mechanism 50 also includes a paddlewheel member 119 rotatably supported within trough 97 of spray bar 60 . Paddlewheel member 119 actually includes a first paddle support 121 having a first end section 122 that extends to a second end section 123 through an intermediate section 124 . First paddle support 121 is arranged within first lateral zone 114 of trough 97 . Arranged alongside first paddle support 121 , in second lateral zone 115 , is a second paddle support 129 . In a manner similar to that described above, second paddle support 129 includes a first end section 130 , a second end section 131 and an intermediate section 132 . First and second paddle supports 121 and 129 are rotatably supported upon a central rod 135 that extends substantially the entire length of trough 97 . Towards that end, central rod 135 includes first and second outer bearing elements 137 and 138 that are rotatably supported upon first and second end sections 90 and 91 of spray bar 60 , as well as a central bearing/support portion 139 that rests upon central support member 112 . In any case, as each paddle support 121 , 129 is substantially, identically constructed, a detailed description will be made with respect to first paddle support 121 with an understanding that second paddle support 129 is correspondingly constructed.
[0025] First paddle support 121 includes a plurality of disk-shaped deflector members 145 - 147 positioned adjacent nozzles 104 , 106 and 107 respectively, as well as a paddle-shaped deflector member 150 positioned is adjacent to nozzle 105 . With this arrangement, a jet of washing fluid exiting nozzle 105 impacts paddle-shaped deflector member 150 causing first paddle support 121 to rotate about an axis defined by central rod 135 . As first paddle support 121 rotates, additional jets of washing fluid emanating from nozzles 104 , 106 and 107 impact disk-shaped deflector members 145 - 147 respectively, causing the jets of washing fluid to diverge into streams of washing fluid which are directed onto kitchenware supported upon dishrack 30 .
[0026] As discussed above, washing fluid is introduced into upper washing mechanism 50 through inlet nozzle 69 illustrated in FIG. 4 . In accordance with the invention, inlet nozzle 69 includes a main body portion 160 having a base section 162 , provided with a circular flange 163 , which extends through an intermediate section 164 to a tapered or nozzle section 165 . Nozzle section 165 is provided with a plurality of openings, one of which is indicated at 167 , as well as a diffuser 169 . Diffuser 169 includes an aperture 171 that receives a mechanical fastener 174 (see FIG. 3 ) which secures upper washing mechanism 50 to washing chamber 28 . In addition to mechanical fastener 174 , upper washing mechanism 50 is also retained against rear wall 21 by a mounting bracket 184 .
[0027] In further accordance with the invention, mounting bracket 184 includes a main body 186 having a ring portion 188 from which extends an intermediate or planar portion 189 before terminating in a support portion 190 . Support portion 190 includes first and second ear elements 192 and 193 , each provided with a corresponding tab element 196 , 197 that snap-fittingly engages inlet conduit 58 . As will be discussed more fully below, mounting bracket 184 is secured against rear wall 21 of washing chamber 28 through circular flange 163 of inlet nozzle 69 .
[0028] As best shown in FIGS. 5 and 6 , inlet nozzle 69 is connected to and receives a flow of washing fluid through an inlet feed member 206 extending through rear wall 21 of washing chamber 28 . Inlet feed member 206 includes a conduit portion 208 and a base portion 210 . Conduit portion 208 includes a main body section 214 having a base section 215 from which extend an inlet nipple 216 and an outlet nipple 217 . Main body section 214 also includes a flange 222 having a pair of mounting ears, one of which is indicated at 225 . As will be discussed more fully below, flange 222 acts as an interface between conduit portion 208 and base portion 210 .
[0029] Outlet nipple 217 includes a hollow interior portion 228 that leads into base section 215 and fluidly connects to inlet nipple 216 . Outlet nipple 217 also includes a plurality of external threads 231 which, as best shown in FIG. 6 , engage with inlet nozzle 69 . More specifically, outlet nipple 217 extends through rear wall 21 of washing chamber 28 and ring portion 188 of mounting bracket 184 . Once in place, inlet nozzle 69 is secured to inlet feed member 206 through threads 231 , with circular flange 163 trapping mounting bracket 184 against rear wall 21 . Finally, inlet nipple 217 is shown to include a pair of outer rings 235 and 236 which provide a positive engagement for a hose 238 that is secured through a clamp 239 (see FIG. 7 ). With this arrangement, inlet feed member 206 receives a flow of washing fluid from a pump (not shown) through inlet nipple 216 . The flow of washing fluid is thereafter is redirected outward through outlet nipple 217 into inlet nozzle 69 and into spray bar 60 .
[0030] As stated above, conduit portion 208 is supported upon a base portion 210 through flange 222 . Towards that end, base member 210 is provided with a main housing 245 that includes a mounting member 247 and a cover 248 . Mounting member 247 is provided with a pair of supports 260 and 261 that align with mounting ears 225 . Supports 260 and 261 are adapted to receive mechanical fasteners, one of which is shown at 265 , to secure conduit portion 208 to base portion 210 . Mounting member 247 further includes a central opening 267 that leads into main housing 245 . A seal 269 extends about central opening 267 and engages with flange 222 of conduit portion 208 . In addition, cover 248 is pivotally connected to mounting member 247 through a hinge 270 and secured through a tab member 273 . Actually, main housing 245 serves as an enclosure for electronic circuitry 280 (see FIG. 7 ) associated with a flow sensor 283 , such as a diaphragm positioned across central opening 267 . Sensor 283 senses the flow of washing fluid through conduit portion 208 during an overall washing operation.
[0031] Reference will now be made to FIG. 8 in describing an alternative embodiment of the present invention. As shown, an upper wash mechanism 350 includes a water delivery portion 356 having an inlet conduit 358 that is connected to a spray bar 360 . Spray bar 360 includes a first end section 390 that extends to a second end section 391 through an intermediate section 392 . Actually, arranged at intermediate section 392 is a “T” member 394 that directs a flow of washing fluid into a first lateral zone 360 and a second lateral zone 361 . Each lateral zone 360 , 361 includes a plurality of nozzles 404 - 406 and 407 - 409 respectively. Jets of washing fluid emanating from nozzles 404 - 409 impact upon a paddlewheel member 419 that is rotatably mounted to a pair of laterally spaced first and second support members 421 and 429 . Actually, paddlewheel member 419 is provided with a pair of bearings, one of which is indicated at 438 , that provide smooth rotation as paddlewheel 419 is impacted and rotated by jets of washing fluid emanating from nozzles 404 - 409 . In addition, paddlewheel member 419 is provided with a slight twist or spiral which ensures continued exposure to the jets of washing fluid. Thus, in accordance with the embodiment shown, paddlewheel member 419 constitutes an overall deflector member 445 that causes the jets of washing fluid to diverge into a plurality of streams which subsequently impact upon kitchenware supported upon dishrack 30 during an overall washing operation.
[0032] At this point, it should be readily understood that the present invention provides for an efficient upper washing mechanism for directing water to an upper portion of a washing chamber in a drawer-type dishwasher. More particularly, mounting the upper washing mechanism to a wall of the wash chamber advantageously provides protection to various wash system components arranged within outer housing 4 . More specifically, the particular positioning of the upper washing mechanism ensures that any residual water remaining within the wash system drops directly into the washing chamber and not onto various components carried within outer housing 4 as would be the case with a wash arm mounted to, for example, lid 37 . In addition, the paddlewheel configuration establishes an extremely efficient and is effective washing fluid distribution arrangement that creates streams of washing fluid sprayed randomly about the washing chamber. In any case, although described with reference to preferred embodiments of the invention, it should be readily understood that various changes and/or modifications can be made to the invention without departing from the spirit thereof. For instance, the overall shape, angular orientation, number and spacing of the deflector members can vary in accordance with the present invention. In general, the invention is only intended to be limited by the scope of the following claims. | 1a
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This is a divisional of application(s) Ser. No. 09/223,212 filed on Dec. 30, 1998, now U.S. Pat. No. 6,051,147, which is a division of Ser. No. 08/606,189, filed on Feb. 23 1996 (now U.S. Pat. No. 5,865,785).
FIELD OF THE INVENTION
The invention generally relates to blood processing systems and methods. In a more specific sense, the invention relates to systems and methods for removing leukocytes from blood components collected for therapeutic purposes.
BACKGROUND OF THE INVENTION
Today blood collection facilities routinely separate whole blood into its various therapeutic components, such as red blood cells, platelets, and plasma.
One separation technique that is in widespread use today uses a multiple blood bag system. The bag system includes a primary blood bag and one or more transfer bags, which are integrally connected to the primary bag by tubing. The technique collects from a donor a single unit (about 450 ml) of whole blood in the primary blood bag. The donor is then free to leave.
The donor's whole blood later undergoes centrifugal separation within the primary bag into red blood cells and plasma rich in platelets. The plasma rich in platelets is expressed out of the primary bag into a transfer bag, leaving the red blood cells behind. The plasma rich in platelets then undergoes further centrifugal separation within the transfer bag into a concentration of platelets and plasma poor in platelets. The plasma poor in platelets is expressed from the transfer bag into another transfer bag, leaving the concentration of platelets behind.
Using multiple blood bag systems, all three major components of whole blood can be collected for therapeutic use. However, the yield for each component collected is limited to the volume of the components that are contained in a single unit of whole blood. Furthermore, because red blood cells are retained, United States governmental regulations prohibit collecting another unit of whole blood from the donor until six weeks later.
Certain therapies transfuse large volumes of a single blood component. For example, some patients undergoing chemotherapy require the transfusion of large numbers of platelets on a routine basis. Multiple blood bag systems simply are not an efficient way to collect these large numbers of platelets from individual donors.
On line blood separation systems are today used to collect large numbers of platelets to meet this demand. On line systems perform the separation steps necessary to separate concentration of platelets from whole blood in a sequential process with the donor present. On line systems establish a flow of whole blood from the donor, separate out the desired platelets from the flow, and return the remaining red blood cells and plasma to the donor, all in a sequential flow loop.
Large volumes of whole blood (for example, 2.0 liters) can be processed using an on line system. Due to the large processing volumes, large yields of concentrated platelets (for example, 4×10 11 platelets suspended in 200 ml of fluid) can be collected. Moreover, since the donor's red blood cells are returned, the donor can donate whole blood for on line processing much more frequently than donors for processing in multiple blood bag systems.
Regardless of the separation technique used, when collecting blood components for transfusion, it is desirable to minimize the presence of impurities or other materials that may cause undesired side effects in the recipient. For example, because of possible febrile reactions, it is generally considered desirable to transfuse red blood cells and platelets that are substantially free of leukocytes, particularly for recipients who undergo frequent transfusions.
Several United States Patents are directed to the removal of leukocytes from red blood cells and platelet components in multiple blood bag systems. For example, see U.S. Pat. Nos. 4,767,541; 5,089,146; 5,100,564; and 5,128,048.
U.S. Pat. No. 5,427,695 is directed to the removal of leukocytes from platelet-rich plasma during on line blood processing.
The platelet-rich suspension product obtained using prior on line blood collection systems and methods may still lack the desired physiologic characteristics imposed by the end user (typically a blood bank or hospital) for long term storage and transfusion. For example, the platelet-rich suspension may include residual leukocytes that, while very small in relation to the leukocyte population in whole blood, are still greater than the leukocyte population standards desired by the end user.
Therefore, despite significant advances in blood processing technology, a need still exists for further improved systems and methods for removing undesired matter like leukocytes from blood components in a way that lends itself to use in high volume, on line blood collection environments.
SUMMARY OF THE INVENTION
The invention provides on line blood processing systems and methods for obtaining a finished platelet suspension having a desired physiologic characteristic. In a preferred embodiment, the desired physiologic characteristic comprises a desired reduced residual population of leukocytes.
The systems and methods that embody features of the invention establish on line communication between a container and a source of blood containing leukocytes and platelets, such as a human donor. The systems and methods create a centrifugal field between the source of blood and the container. The centrifugal field separates from the blood an unfinished suspension of platelets having a first physiologic characteristic different than the desired physiologic characteristic. In a preferred embodiment, the unfinished platelet suspension contains an initial leukocyte population greater than the desired residual leukocyte population.
According to the invention, the systems and methods pump the unfinished platelet suspension outside the centrifugal field through a finishing device. The finishing device changes the first physiologic characteristic to the desired physiological characteristic, thereby creating the finished platelet suspension. In a preferred embodiment, the finishing device reduces the leukocyte population by filtration. The systems and methods convey the finished platelet suspension from the finishing device directly into the container for storage or transfusion.
The systems and methods that embody the features of the invention function without interrupting the on line communication between the container and the source of blood.
Other features and advantages of the invention can be found in the drawings, accompanying description, and claims of this Specification.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a diagrammatic view of a blood processing system, which includes a finishing device that embodies the features of the invention; and
FIG. 2 is a diagrammatic view of a centrifugal blood processing system that can be use in association with the finishing device shown in FIG. 1 .
The invention may be embodied in several forms without departing from its spirit or essential characteristics. The scope of the invention is defined in the appended claims, rather than in the specific description preceding them. All embodiments that fall within the meaning and range of equivalency of the claims are therefore intended to be embraced by the claims.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
FIG. 1 shows in diagrammatic form an on line blood processing system 10 that embodies features of the invention. According to the invention, the on line system 10 provides a finished, high quality platelet-rich blood product (PLT FIN ), with a significantly reduced residual population of leukocytes and/or other enhanced physiological properties, suited for long term storage and transfusion.
As used in this Specification, the term “on line blood separation process” refers to a blood separation system or method that (i) establishes communication between a blood source (typically, a human blood donor) and an extracorporeal flow path; (ii) draws a blood volume from the donor into the flow path; and (iii) maintains communication with the circulatory system of the donor for at least a portion of the time that the blood volume undergoes separation within the extracorporeal flow path.
As used in this Specification, an “on line blood separation process” can separate the blood volume either in a continuous manner or in an interrupted manner. However, an “on line blood separation process” maintains communication between the flow path and the donor for at least a portion of the time the separation process occurs within the flow path, regardless of specific timing or sequencing of the separation process itself.
As used in this Specification, an “on line blood separation process” can include external or internal valves or clamps to interrupt flow within the path to or from the donor. However, in the context of this Specification, such valves or claims do not break the communication between the blood donor and the flow path. Instead, the valves or clamps control fluid flow within the path while maintaining communication between it and the blood donor.
The on line system 10 draws whole blood (WB) from a donor through a phlebotomized tubing flow path 12 . WB contains, as its principal components, red blood cells, platelets, leukocytes, and plasma. The system 10 adds anticoagulant to the drawn WB and conveys anticoagulated WB into a centrifugal field 14 for processing.
In the centrifugal field 14 , the system 10 ultimately separates anticoagulated WB into two components. The first component is a red blood cell concentration. It is desirable that the red blood cell concentration also carry with it a majority of the leukocyte population (LK) present in the WB. For this reason, the first component is referred to as RBC LK+ .
RBC LK+ is returned to the donor during processing. This avoids depletion of the donor's red blood cell and leukocyte populations while high volume yields of platelets are obtained.
The second component comprises an unfinished platelet-rich plasma suspension PLT UN . PLT UN is considered “unfinished” because the platelet-rich plasma suspension still lacks the desired physiologic characteristics imposed by the end user (typically a blood bank or hospital) for long term storage and transfusion. Centrifugal processing within the field 14 often cannot provide these desired characteristics.
The specific physical makeup of the platelet-rich suspension comprising PLT UN can vary. The makeup will largely depend upon the efficiency of the centrifugal separation process in terms of the how many platelets are separated (i.e., the platelet yields) and how much platelet-poor plasma product is withdrawn and not returned to the donor.
As used in this Specification, PLT UN is intended to encompass any suspension in which platelets are present in concentrations greater than in whole blood. PLT UN can comprise what is commonly referred to as platelet-rich plasma (PRP) or platelet concentrate (PC), or suspensions of platelets and plasma lying in between.
PLT UN can include, in addition to platelets, other components or ingredients, depending upon the choice of the end user. For example, PLT UN can include essentially only plasma as the platelet suspension media. Alternatively or in addition to plasma, PLT UN can include a specially formulated platelet storage media to suspend the platelets.
The structural details of the centrifugation field 14 can vary and are not essential to the invention. For example, the field 14 can comprise a centrifuge and multiple stage centrifugal processing chambers of the type shown in Brown U.S. Pat. No. 5,427,695 or Brown U.S. Pat. No. 5,370,802, both of which are incorporated herein by reference.
As FIG. 2 shows in diagrammatic form, the multiple stage processing chambers that Brown '695 and '802 embody separate WB into RBC and PRP in a first stage separation chamber 16 . The special fluid flow dynamics that occur in the first stage chamber 16 shown in Brown '802 or '695 keep a large majority of leukocytes out of PRP and with the RBC in the first stage chamber 16 for return to the donor as RBC LK+ . The special fluid flow dynamics occurring in the first stage chamber 16 in Brown '802 or Brown '695 also provide a high yield of platelets in the PRP.
In Brown '802 or '695, PRP is transported from the first stage chamber 16 . A portion is recirculated back to the WB entering the first stage chamber 16 , and the rest is conveyed into a second stage chamber 18 . The PRP is separated in the second stage chamber 18 into PC and platelet-poor plasma (PPP).
PC retained in the second stage chamber 18 is later resuspended in a volume of PPP or (optionally) a suitable platelet storage medium for transfer from the second stage chamber as PLT UN . A portion of the PPP is returned to the donor, while another portion of PPP is retained for use as a recirculation or keep-open or rinse-back or resuspension media, or for storage for fractionation or transfusion.
One reason why PLT UN can be considered “unfinished” in the context of the above described system is the presence of residual leukocytes in the platelet suspension. This residual population of leukocytes with the platelets, while small, still can be greater than the leukocyte population standards demanded by the end user.
Often, centrifugal processing alone often is not effective at isolating enough leukocytes from PRP to meet these demands. Unintended perturbations and secondary flows along the interface between RBC and plasma, where leukocytes reside, can sweep lighter leukocyte species away from RBC into the plasma. Other desirable flow patterns that sweep heavier leukocytes species in the interface back into the RBC mass can also fail to develop to their fullest potential. The dynamic processes under which leukocytes are separated from platelets during centrifugation are complex and subject to variation from donor to donor.
Additional steps can be provided to augment the primary centrifugal separation process to thereby reduce the number of residual leukocytes present in PLT UN . For example, as disclosed in Brown '695, a leukocyte filter 20 can be provided after the first stage chamber 16 to filter leukocytes from PRP before entering the second stage chamber 18 for separation into PC and PPP. The filter 20 is preferably located outside the centrifugal field 14 , being connected by a rotating umbilicus arrangement 22 of conventional construction. Alternatively, though, the filter 20 can be located within the centrifugal field 14 .
Alternatively, or in combination with such other ancillary leukocyte-reduction devices, PLT UN can be subject to particle bed separation effects within the centrifugal field 14 to separate leukocytes from the platelets. Still, the degree of leukocyte reduction demanded by the user can exceed the capabilities of even these ancillary steps during the centrifugal separation process.
For this reason (see FIG. 1 ), the system 10 includes an in line finishing device 24 located outside the centrifugal field 14 . A pump 26 conveys PLT UN under pressure from the centrifugal field 14 through the finishing device 24 . In FIG. 1, the pump 26 is shown downstream of the centrifugal field 14 . Alternatively, the pump 26 could be located upstream of the centrifugal field 14 , thereby supplying the requisite machine pressure to convey PLT UN from the centrifugal field 14 .
The finishing device 24 serves to affect a desired alteration in the makeup or physiological of PLT UN that could not be effectively achieved in the centrifugal field 14 , such as, for example, a further incremental reduction in the leukocyte population. The in line finishing device 24 performs its function on line, while the donor remains connected in communication with the system 10 .
The output of the finishing device 24 is a finished platelet-rich suspension(PLT FIN ). PLT FIN is considered “finished” because the platelet-rich plasma suspension possesses the desired physiologic characteristics imposed by the end user for long term storage and transfusion. In the context of the illustrated embodiment, the platelet-rich suspension comprising PLT FIN possesses a more-reduced leukocyte population and/or additional physiological attributes not present in PLT INI .
As used in this Specification, the term “reduced” or “more-reduced” does not denote that all the residual leukocytes have been removed. The term is intended to more broadly indicate only that the number of residual leukocytes have been incrementally reduced by the finishing device 24 , compared with the number before processing by the finishing device.
The finishing device 24 can accomplish its function by centrifugation, absorption, columns, chemical, electrical, and electromagnetic means. In the illustrated and preferred embodiment, the finishing device 24 comprises a filter that employs a non-woven, fibrous filter media 28 .
The composition of the filter media 28 can vary. The media 28 comprises fibers that contain nonionic hydrophillic groups and nitrogen-containing basic functional groups. Fibers of this type are disclosed in Nishimura et al U.S. Pat. No. 4,936,998, which is incorporated herein by reference. Filter media containing these fibers are commercially sold by Asahi Medical Company. Filter media containing these fibers have demonstrated the capacity to remove leukocytes while holding down the loss of platelets. Alternatively, the filter media 28 can comprise fibers that have been surface treated as disclosed in Gsell et al U.S. Pat. No. 5,258,127 to increase their ability to pass platelets while removing leukocytes. Gsell et al. U.S. Pat. No. 5,258,127 is also incorporated herein by reference.
Furthermore, because the pump 26 is used to convey PLT INI through the finishing device 24 , the external machine pressure it creates can be used to overcome passive resistance of the finishing media 28 . Therefore, the finishing media 28 can be densely packed within the finishing device 24 to achieve maximum efficiencies.
The system 10 conveys PLT FIN to one or more containers 30 suitable for transfusion or long term storage. The container(s) 30 intended to store PLT FIN can be made of polyolefin material (as disclosed in Gajewski et al U.S. Pat. No. 4,140,162) or a polyvinyl chloride material plasticized with tri-2-ethylhexyl trimellitate (TEHTM). These materials, when compared to DEHP-plasticized polyvinyl chloride materials, have greater gas permeability that is beneficial for platelet storage.
The system 10 shown in FIG. 1 can be readily incorporated into a continuous single or double needle on line blood processing systems.
As used in this Specification, the “on line blood separation process” differs from a multiple blood bag process. In a multiple blood bag process, the donor's circulatory system does not remain in communication with the flow path where separation of the collected blood volume occurs. In a multiple blood bag system, after a given blood volume is collected in the primary bag, the donor's circulatory system is disconnected from the primary bag before separation occurs within the bag. Also, in a multiple blood bag system, the separation processes do not occur continuously. The first stage separation of red blood cells and plasma rich in platelets and the second stage separation of platelets from plasma occur at different points in time as separate, discontiguous steps.
Various features of the inventions are set forth in the following claims. | 1a
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[0001] This application claims the benefit of U.S. Provisional Application No. 60/240,877, filed Oct. 13, 2000.
FIELD OF THE INVENTION
[0002] The present invention relates, in general, to an improved surgical biopsy device and, more particularly, to an improved firing mechanism for use in a surgical biopsy device.
BACKGROUND OF THE INVENTION
[0003] The diagnosis and treatment of patients with cancerous tumors, pre-malignant conditions, and other disorders has long been an area of intense interest in the medical community. Non-invasive methods for examining tissue and, more particularly, breast tissue include palpation, X-ray imaging, MRI imaging, CT imaging, and ultrasound imaging. When a physician suspects that tissue may contain cancerous cells, a biopsy may be done using either an open procedure or in a percutaneous procedure. In an open procedure, a scalpel is used by the surgeon to create an incision to provide direct viewing and access to the tissue mass of interest. The biopsy may then be done by removal of the entire mass (excisional biopsy) or a part of the mass (incisional biopsy). In a percutaneous biopsy, a needle-like instrument is inserted through a very small incision to access the tissue mass of interest and to obtain a tissue sample for examination and analysis. The advantages of the percutaneous method as compared to the open method are significant: less recovery time for the patient, less pain, less surgical time, lower cost, less disruption of associated tissue and nerves and less disfigurement. Percutaneous methods are generally used in combination with imaging devices such as X-ray and ultrasound to allow the surgeon to locate the tissue mass and accurately position the biopsy instrument.
[0004] Generally there are two ways to percutaneously obtain a tissue sample from within the body, aspiration or core sampling. Aspiration of the tissue through a fine needle requires the tissue to be fragmented into small enough pieces to be withdrawn in a fluid medium. Application is less intrusive than other known sampling techniques, but one can only examine cells in the liquid (cytology) and not the cells and the structure (pathology). In core biopsy, a core or fragment of tissue is obtained for histologic examination which may be done via a frozen or paraffin section. The type of biopsy used depends mainly on various factors and no single procedure is ideal for all cases.
[0005] A number of core biopsy instruments which may be used in combination with imaging devices are known. Spring powered core biopsy devices are described and illustrated in U.S. Pat. Nos. 4,699,154, 4,944,308, and Re. 34,056. Aspiration devices are described and illustrated in U.S. patents: U.S. Pat. Nos. 5,492,130; 5,526,821; 5,429,138 and 5,027,827.
[0006] U.S. Pat. No. 5,526,822 describes and illustrates an image-guided, vacuum-assisted, percutaneous, coring, breast biopsy instrument which takes multiple tissue samples without having to re-puncture the tissue for each sample. The physician uses this biopsy instrument to “actively” capture (using the vacuum) the tissue prior to severing it from the body. This allows the physician to sample tissues of varying hardness. The instrument described in U.S. Pat. No. 5,526,822 may also be used to collect multiple samples in numerous positions about its longitudinal axis without removing the instrument from the body. A further image-guided, vacuum-assisted, percutaneous, coring, breast biopsy instrument is described in commonly assigned U.S. application Ser. No. 08/825,899, filed on Apr. 2, 1997 and in U.S. patents: U.S. Pat. Nos. 6,007,497; 5,649,547; 5,769,086; 5,775,333; and 5,928,164. A handheld image-guided, vacuum-assisted, percutaneous, coring, breast biopsy instrument is described in U.S. Pat. No. 6,086,544 and in U.S. Pat. No. 6,120,462. The instrument described therein moves drive motors and other electronic components into a control unit separate from and remotely located from the biopsy probe. Biopsy probe cutter rotational and translational motion is transferred from the motors in the control unit to the biopsy probe via flexible coaxial cables. This arrangement greatly improves the cleanability of the reusable hardware that remains in close proximity to the biopsy site as well as improves the life and durability of the electric motors and electronic components now remotely located from the biopsy probe. The biopsy instrument described and illustrated in U.S. Pat. No. 6,086,544 and in U.S. Pat. No. 6,120,462 was designed primarily to be a “hand held” instrument to be used by the clinician in conjunction with real time ultrasound imaging. The majority of breast biopsies done today, however, utilize an x-ray machine as the imaging modality. Using x-ray requires that the biopsy instrument be affixed to the x-ray machine by some type of bracket arrangement. Since the biopsy instrument is fixed to a portion of the x-ray machine there is now a need for a means to conveniently advance the biopsy probe into the breast. It is highly desirable to have the capability to “fire” the biopsy probe via some type of stored energy system, to rapidly advance the biopsy probe into the target area of the breast. Such a instrument, utilizing the cable driven arrangement of Hibner et al, would inherit the cleanability and durability attributes of the Hibner et al instrument while providing the added flexibility to attach the biopsy instrument to an x-ray machine and “fire” the probe into the breast. Several image-guided, vacuum-assisted, percutaneous, coring, breast biopsy instruments are currently sold by Ethicon Endo-Surgery, Inc. under the Trademark MAMMOTOME™.
[0007] Many breast biopsies done today utilizing image-guided, vacuum-assisted, percutaneous, coring, breast biopsy instruments are still done utilizing x-ray machine. In actual clinical use the biopsy instrument (probe and driver assembly) is mounted to the three axis positioning head of the x-ray imaging machine. The three axis positioning head is located in the area between the x-ray source and the image plate. The stereotactic x-ray machines are outfitted with a computerized system which utilizes two x-ray images, of the breast taken at two different positions to calculate the x, y and z axis location of a suspect abnormality. In order to take the stereo x-ray images the x-ray source must be movable. The x-ray source is, therefore, typically mounted to an arm which, at the end opposite the x-ray source, is pivotally mounted to the frame in the region of the x-ray image plate. In a breast biopsy the breast is placed between the x-ray source and the image plate. In order to take the necessary stereo images, the clinician manually positions the x-ray source on one side and then the other of the center axis of the machine (typically 15-20 degrees to each side of the center axis), obtaining an x-ray image on each side of the breast. The computer will then, calculate the precise x, y and z location of the suspect abnormality in the breast and automatically communicate to the clinician or directly to the positioning head the targeting coordinates for the biopsy device. The clinician can there manually, or automatically, position the biopsy probe into the breast at the precise location of the abnormality.
[0008] There are generally two styles of stereotactic x-ray machines in wide spread use for breast imaging. One style is a prone stereotactic x-ray machine, because the patient lies face down on a table during the x-ray and biopsy procedures. The other style, in more wide spread use, is an upright stereotatic x-ray machine. The center axis of the upright imaging machine is vertical to the floor and the patient sits in front of the machine during the x-ray and biopsy procedures.
[0009] It would, therefore, be advantageous to design an image-guided, vacuum assisted, percutaneous, coring, cable driven breast biopsy instrument which may be conveniently mounted to an x-ray machine, and incorporate a firing mechanism used to rapidly advance the biopsy probe into the breast.
SUMMARY OF THE INVENTION
[0010] The present invention is directed to a biopsy instrument including a base assembly including a firing mechanism moveably attached to a distal end of the base assembly, a probe assembly detachably mounted to the base assembly and a drive assembly detachably mounted to the cutter assembly. The probe assembly includes a cutter assembly and a piercer assembly. The cutter assembly includes a cutter and a gear mechanism adapted to move the cutter. The piercer assembly includes a piercer and a probe mount. The piercer includes a distal port, a vacuum lumen and a central lumen wherein the central lumen is adapted to receive the cutter. The probe mount includes a central lumen adapted to allow the cutter to pass through the probe mount and a fork coupling detachably connected to the firing mechanism. The drive assembly, being detachably mounted to the cutter assembly, includes a flexible drive shaft operatively connected to the gear mechanism. Further, a proximal end of the probe housing is slideably movable with respect to a distal end of the cutter assembly.
[0011] The present invention is further directed to a biopsy instrument including a base assembly including a firing mechanism, a probe assembly detachably mounted to the base assembly, a piercer assembly and a drive assembly detachably mounted to the cutter assembly. The firing mechanism including a firing fork moveably attached to a distal end of the base assembly and a firing assembly attached to the firing fork. The probe assembly including a cutter assembly and a gear mechanism. The cutter assembly including a cutter with a central lumen extending through the cutter, a sharpened edge at a distal end of the cutter and a first drive gear. The gear mechanism adapted to move the cutter, wherein the gear mechanism includes a second drive gear adapted to mesh with the first drive gear. The piercer assembly including a piercer and a probe mount. The piercer including distal tissue port adapted to receive tissue, a first central lumen extending from a proximal end of the piercer to the tissue port, the central lumen being adapted to receive the cutter and a vacuum lumen fluidly connected to the tissue port. The probe mount connecting the piercer to the cutter assembly wherein a proximal end of the probe housing is slideably moveable with respect to a distal end of the cutter assembly. The probe mount comprising including a second central lumen adapted to allow the cutter to pass through the probe mount to the first central lumen and a fork coupling detachably connectable to the firing fork. The drive assembly including a flexible drive shaft adapted to be connected at its proximal end to a control unit including a motor and transmission adapted to connect a distal end of the flexible drive shaft to the cutter assembly, wherein rotation of the flexible drive shaft rotates the second drive gear.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] The novel features of the invention are set forth with particularity in the appended claims. The invention itself, however, both as to organization and methods of operation, together with further objects and advantages thereof, may best be understood by reference to the following description, taken in conjunction with the accompanying drawings in which:
[0013] [0013]FIG. 1 is an isometric view of a surgical biopsy system of the present invention comprising a biopsy device, control unit, and remote.
[0014] [0014]FIG. 2 is an isometric view of the biopsy probe assembly and base assembly, shown separated, with the upper base housing shown removed.
[0015] [0015]FIG. 3 is an isometric view of the biopsy probe assembly with the top shell and bottom shell shown separated to expose internal components.
[0016] [0016]FIG. 4 is an exploded isometric view of the biopsy probe assembly of the present invention without the top shell and bottom shell.
[0017] [0017]FIG. 5 is a longitudinal section view of the distal end of the biopsy probe assembly.
[0018] [0018]FIG. 6 is an exploded isometric view of the lower transmission assembly of the present invention.
[0019] [0019]FIG. 7 is an isometric view of the transmission showing the upper transmission assembly exploded.
[0020] [0020]FIG. 8 is an isometric view of the biopsy probe assembly and base assembly, separated, with the upper base housing not shown, as viewed from the proximal end.
[0021] [0021]FIG. 9 is an exploded isometric view of the firing mechanism of the present invention.
[0022] [0022]FIG. 10 is an exploded isometric view of an embodiment of the firing fork assembly.
[0023] [0023]FIG. 11 is an exploded isometric view of the triggering mechanism of the present invention.
[0024] [0024]FIG. 12 is an isometric view of the safety latch.
[0025] [0025]FIG. 13 is an isometric view of the safety button.
[0026] [0026]FIG. 14 is a top view of the firing mechanism of the present invention showing the mechanism in the post-fired position.
[0027] [0027]FIG. 15 is a partial, plan sectional view of the firing mechanism in the post-fired position showing the firing latch and firing rod.
[0028] [0028]FIG. 16 is a top view of the firing mechanism of the present invention showing the mechanism in the pre-fired position.
[0029] [0029]FIG. 17 is a partial, plan sectional view of the firing mechanism in the pre-fired position showing the firing latch and firing rod.
[0030] [0030]FIG. 18 is a top view of the firing mechanism of the present invention showing the arming mechanism in the relaxed position.
[0031] [0031]FIG. 19 is a partial, plan sectional view of the firing mechanism in the relaxed position showing the firing latch and firing rod.
[0032] [0032]FIG. 20 is an isometric view of the safety latch and safety button shown in the locked position.
[0033] [0033]FIG. 21 is an isometric view of the safety latch and safety button shown in the firing position.
[0034] [0034]FIG. 22 is an exploded isometric view of an alternate embodiment of the firing fork assembly.
DETAILED DESCRIPTION OF THE INVENTION
[0035] [0035]FIG. 1 is an isometric view showing a surgical biopsy system 10 comprising biopsy device 40 , a control unit 100 , and remote 20 . Biopsy device 40 comprises probe assembly 42 operatively and removably attached to base 44 . Base 44 is removably attached to a moveable table 12 such as a stereotactic guidance system as may be found on mammographic x-ray machines, an example of which is Model MAMMOTEST PLUS/S available from Fischer Imaging, Inc., Denver, Colo.
[0036] Probe assembly 42 includes an elongated piercer 70 having a piercer tip 72 for penetrating soft tissue of a surgical patent. Piercer 70 comprises a piercer tube 74 and vacuum chamber tube 76 . Vacuum chamber tube 76 of piercer 70 may be fluidly connected to control unit 100 . Similarly, axial vacuum to probe assembly 42 may be obtained by fluid connection to control unit 100 . MAMMOTOME system tubing set Model No. MVAC1 available from Ethicon Endo-Surgery Inc., Cincinnati, Ohio is suitable for use to permit detachable fluid connection of lateral vacuum line 32 and axial vacuum line 34 to control unit 100 . Lateral vacuum line 32 and axial vacuum line 34 are made from a flexible, transparent or translucent material, such as silicone tubing, allowing for visualization of the material flowing through them. Lateral connector 33 and axial connector 35 are female and male luer connectors, respectively, commonly known and used in the medical industry. Base 44 is operatively connected to control unit 100 by control cord 26 , translation shaft 22 , and rotation shaft 24 . Translation shaft 22 and rotation shaft 24 are preferably flexible so as to permit for ease of mounting of biopsy device 40 to moveable table 12 .
[0037] Control unit 100 is used to control the sequence of actions performed by biopsy device 40 in order to obtain a biopsy sample from a surgical patient. Control unit 100 includes motors and a vacuum pump, and controls the activation of vacuum to probe assembly 42 and the translation and rotation of the cutter (not visible) in probe assembly 42 . A suitable Control unit 100 is a MAMMOTOME system control module Model No. SCM12 with software Model No. SCMS1 available from Ethicon Endo-Surgery Inc., Cincinnati, Ohio.
[0038] Remote 20 is operatively and removably connected to control unit 100 . Remote 20 may be used by the surgical biopsy system operator to control the sequence of actions performed by biopsy device 40 . Remote 20 may be a hand operated or foot operated device. A suitable remote 20 is MAMMOTOME Remote Key-pad Model No. MKEY1 available from Ethicon Endo-Surgery Inc., Cincinnati, Ohio.
[0039] [0039]FIG. 2 is an isometric view showing probe assembly 42 and base 44 separated. Upper base housing 50 is normally fixedly attached to base 44 , but has been shown removed from base 44 to provide a view of transmission 301 . Top shell tab 46 is located on the distal end of cantilever beam 41 and projects above the top surface of gear shell 18 . Top shell tab 46 inserts into tab window 48 in upper base housing 50 upon assembly of probe assembly 42 to base 44 . Once probe assembly 42 and base 44 are properly assembled, top shell tab 46 must be pushed down through tab window 48 by the user before probe assembly 42 and base 44 can be separated. A plurality of raised ribs 58 is provided on gear shell 18 to improve the user's grip on the instrument. Post 14 extends above the top surface of base shell 38 and inserts into keyhole 16 (not visible) located on the underside of gear shell 18 . Tube slot 68 in upper base housing 50 provides clearance for axial vacuum line 34 . First tang 54 and second tang 56 protrude from opposite sides of probe housing 52 and insert into first recess 64 and second recess 66 , respectively, in firing fork 62 . The proximal end of probe housing 52 fits slidably within gear shell 18 and firing fork 62 fits slidably within base shell 38 . Thus, once probe assembly 42 and base 44 are operatively assembled, probe housing 52 and firing fork 62 are able to move a fixed linear distance in a distal and proximal direction in front of gear shell 18 and base shell 38 . FIGS. 1 and 2 show probe housing 52 and firing fork 62 in their most distal position.
[0040] [0040]FIGS. 3 and 4 are views of probe assembly 42 . FIG. 3 is an isometric view of probe assembly 42 with the top shell 17 and bottom shell 19 shown separated, the top shell 17 rotated ninety degrees, to expose internal components. FIG. 4 is an exploded isometric view of the same probe assembly 42 without top shell 17 or bottom shell 19 . Gear shell 18 is formed from top shell 17 and bottom shell 19 , each injection molded from a rigid, biocompatible thermoplastic material such as polycarbonate. Upon final assembly of probe assembly 42 , top shell 17 and bottom shell 19 are joined together by ultrasonic welding along joining edge 15 , or joined by other methods well known in the art. Probe assembly 42 comprises piercer 70 having an elongated, metallic piercer tube 74 and a piercer lumen 80 (see FIGS. 4 and 5). On the side of the distal end of piercer tube 74 is port 78 for receiving tissue to be extracted from the surgical patient. Joined along side piercer tube 74 is an elongated, tubular, metallic vacuum chamber tube 76 having a vacuum lumen 82 (see FIGS. 4 and 5). Piercer lumen 80 is in fluid connection with vacuum lumen 82 via a plurality of vacuum holes 77 (See FIG. 5) located in the bottom of the “bowl” defined by port 78 . Vacuum holes 77 are small enough to remove the fluids but not large enough to allow excised tissue portions to be removed through lateral vacuum line 32 , which is fluidly connected to vacuum lumen 82 . A metallic, sharpened piercer tip 72 is fixedly attached to the distal end of piercer 70 . It is designed to penetrate soft tissue, such as the breast tissue of a female surgical patient. In the present embodiment piercer tip 72 is a three sided, pyramidal shaped point, although the tip configuration may also have other shapes.
[0041] Refer now, momentarily, to FIG. 5. FIG. 5 is a section view of the distal end of probe assembly 42 , illustrating primarily probe housing 52 , piercer 70 , and union sleeve 90 . The proximal end of piercer 70 is fixedly attached to union sleeve 90 having a longitudinal bore 84 through it. Union sleeve 90 contains a first o-ring groove 27 and second o-ring groove 28 , spaced apart so as to allow for a traverse opening 37 between them in fluid communication with longitudinal bore 84 . First o-ring 29 and second o-ring 30 mount in first o-ring groove 27 and second o-ring groove 28 , respectively. Sleeve gear 36 is integral to union sleeve 90 and is located at its most proximal end. Lead-in cone 25 is a conical shaped metallic structure that attaches to the proximal end of union sleeve 90 . Union sleeve 90 is inserted into housing bore 57 located in the distal end of probe housing 52 , and rotatably supports the proximal end of piercer 70 . Positioning wheel 31 slides over piercer 70 and the distal end of union sleeve 90 and rotatably attaches to probe housing 52 , hence trapping lead-in cone 25 and union sleeve 90 within housing bore 57 in the distal end of probe housing 52 . Locating projection 11 on the distal end of union sleeve 90 functionally engages alignment notch 13 in positioning wheel 31 . Thus, rotating positioning wheel 31 likewise causes the rotation of piercer 70 . This allows port 78 to be readily positioned anywhere within the 360° axis of rotation of piercer 70 .
[0042] Referring again to FIGS. 3 and 4, housing extension 47 is located at the proximal end of probe housing 52 . Housing flange 53 is located at the most proximal end of housing extension 47 on probe housing 52 and is assembled just inside of top shell front slot 55 in top shell 17 . Shell insert 39 is assembled into top shell front slot 55 . First insert tab 59 and second insert tab 60 , both located on shell insert 39 , engage first shell recess 61 and second shell recess 63 , located within top shell front slot 55 , respectively. Thus, upon complete assembly of probe assembly 42 , the most proximal end of probe housing 52 containing housing flange 53 is trapped within gear shell 18 , yet slideable along housing extension 47 distal and proximal within top shell front slot 55 . Tissue sampling surface 65 is a recessed surface within probe housing 52 which provides a surface where each tissue sample will be deposited during the operation of the present invention, prior to retrieval by the clinician.
[0043] An elongated, metallic, tubular cutter 96 (see FIG. 5) is axially aligned within cutter bore 51 of probe housing 52 , longitudinal bore 84 of union sleeve 90 , and piercer lumen 80 of piercer 70 so that cutter 96 may slide easily in both the distal and proximal directions. Cutter 96 has a cutter lumen 95 through the entire length of cutter 96 . The distal end of cutter 96 is sharpened to form a cutter blade 97 for cutting tissue held against cutter blade 97 as cutter 96 is rotated. The proximal end of cutter 96 is fixedly attached to the inside of cutter gear bore 102 of cutter gear 98 . Cutter gear 98 may be metal or thermoplastic, and has a plurality of cutter gear teeth 99 , each tooth having a typical spur gear tooth configuration as is well known in the art. Cutter seal 79 is a lip type seal and is fixedly attached to the proximal end of cutter gear 98 , and is made of a flexible material such as silicone. Tissue remover 132 fits rotatably and slidably through cutter seal 79 . Probe seal 81 is also a lip type seal made of a flexible material such as silicone rubber and is fixedly inserted into the proximal end of cutter bore 51 at the proximal end of probe housing 52 . Cutter 96 fits rotatably and slidably through cutter seal 79 . Cutter seal 79 and probe seal 81 operate to prevent fluids from entering the space within gear shell 18 during a surgical biopsy procedure.
[0044] Still in FIGS. 3 and 4, cutter gear 98 is driven by elongated drive gear 104 having a plurality of drive gear teeth 106 designed to mesh with cutter gear teeth 99 . The function of elongated drive gear 104 is to rotate cutter gear 98 and cutter 96 as they translate in both longitudinal directions. Elongated drive gear 104 is preferably made of a thermoplastic material, such as liquid crystal polymer. Distal drive axle 108 projects from the distal end of elongated drive gear 104 and mounts rotatably into an axle support rib (not visible) molded on the inside of top shell 17 and held in place by first gear support rib located on bottom shell 19 . Gear shaft 110 projects from the proximal end of drive gear 104 and is rotatably supported by a gear shaft slot 69 located in the proximal end of top shell 17 and by second gear support rib 137 located on bottom shell 19 . Drive gear slot 101 is located on the most proximal end of gear shaft 110 as a means for rotationally engaging drive gear 104 .
[0045] Still referring to FIGS. 3 and 4, cutter carriage 124 is provided to hold cutter gear 98 and to carry cutter gear 98 as it is rotated and translated in the distal and proximal directions. Cutter carriage 124 is preferably molded from a thermoplastic material and is generally cylindrically shaped with a threaded bore 126 through it and with carriage foot 130 extending from its side.. Carriage foot 130 has a foot recess 128 formed into it and foot slot 127 for rotatably holding cutter gear 98 in the proper orientation for cutter gear teeth 99 to mesh properly with drive gear teeth 106 . Lower carriage guide 103 projects down from cutter carriage 124 and slidably engages lower guide slot 107 molded on the inside surface of bottom shell 19 . Upper carriage guide 105 projects up from carriage foot 130 and slidably engages a upper guide slot 109 molded on the inside of top shell 17 . Cutter carriage 124 is attached via threaded bore 126 to elongated screw 114 , which is parallel to drive gear 104 . Screw 114 has a plurality of conventional lead screw threads 116 and is preferably made of a thermoplastic material. The rotation of elongated screw 114 in one direction causes cutter carriage 124 to move distally, while the reverse rotation of elongated screw 114 causes cutter carriage 124 to move proximally. As a result, cutter gear 98 moves distally and proximally according to the direction of the screw rotation, which in turn advances cutter 96 distally or retracts it proximally. In the present embodiment, elongated screw 114 is shown with a right hand thread so that clockwise rotation (looking from the proximal to distal direction) causes cutter carriage 124 to translate in the proximal direction. Distal screw axle 118 projects from the distal end of elongated screw 114 and mounts rotatably into an axle support rib (not visible) molded on the inside of top shell 17 and held in place by first screw support rib 111 located on bottom shell 19 . Screw shaft 120 projects from the proximal end of elongated screw 114 and is rotatably supported by a screw shaft slot 71 located in the proximal end of top shell 17 and by second screw support rib 112 located on bottom shell 19 . Lead screw slot 122 is located on the most proximal end of screw shaft 120 as a means for rotationally engaging elongated screw 114 .
[0046] At this point in the detailed description it should be pointed out that during the operation of the biopsy instrument cutter 96 translates in either direction between a fully retracted position, just proximal to tissue sampling surface 65 as referenced by cutter blade 97 , and a fully deployed position wherein cutter blade 97 is located just distal to port 78 . As cutter 96 translates between these end points there are a number of intermediate positions wherein adjustments may be made to the cutter rotational and translational speed as commanded by control unit 100 . These intermediate positions and the adjustments made to the cutter depend on the programming of control unit 100 .
[0047] Referring now to FIG. 5, the distal end of lateral vacuum line 32 is attached to lateral fitting 92 located on the distal end of probe housing 52 . Lateral fitting 92 has lateral hole 117 through it along its axis in fluid communication with housing bore 57 . Lateral hole 117 in lateral fitting 92 is positioned within housing bore 57 such that when union sleeve 90 is inserted into housing bore 57 lateral hole 117 is located in the space created between first and second o-rings, 29 and 30 respectively. Locating lateral hole 117 in the space between first and second o-rings 29 and 30 , respectively, allows for the communication of fluids between vacuum lumen 82 and control unit 100 .
[0048] Referring again to FIGS. 3 and 4, axial vacuum line 34 is fluidly attached to tissue remover support 129 which is in turn fluidly attached to the proximal end of an elongated, metallic, tubular tissue remover 132 . Axial vacuum line 34 allows for the communication of fluids between piercer lumen 80 , cutter lumen 95 , and control unit 100 . Tissue remover support 129 fits into axial support slot 73 located in the proximal end of top shell 17 . Strainer 134 is located on the distal end of tissue remover 132 and functions to prevent passage of fragmented tissue portions through it and into control unit 100 . Tissue remover 132 inserts slidably into cutter lumen 95 of cutter 96 . During the operation of the biopsy instrument, tissue remover 132 is always stationary, being fixedly attached at its proximal end to tissue remover support 129 which is fixed within axial support slot 73 located in the proximal end of top shell 17 . When cutter 96 is fully retracted to its most proximal position, the distal end of tissue remover 132 is approximately even with the distal end of cutter 96 (see FIG. 5). The distal end of cutter 96 , when at its most proximal position, and probe housing 52 at its most distal position, is slightly distal to housing wall 67 which is proximal and perpendicular to tissue sampling surface 65 .
[0049] Probe rotation rod 85 is an elongated, solid metal rod. Rotation rod gear 86 is a spur gear fixedly attached to the distal end of probe rotation rod 85 . Rotation rod flat 87 is located at the proximal end of probe rotation rod 85 . Rotation rod flat 87 is approximately one-third to one-half the rod diameter in depth and extending from its proximal end approximately one inch in length. Rotation rod flat 87 thus creates a “D” shaped geometry at the proximal end of probe rotation rod 85 . Rod bushing 88 is made of molded thermoplastic and is cylindrical in shape. At its distal end is bushing bore 89 which is a “D” shaped hole approximately one inch in depth, designed to slidably receive the proximal end of probe rotation rod 85 . Rod bushing 88 fits rotatably into axial support slot 73 below tissue remover support 129 at the proximal end of top shell 17 . The longitudinal position of rod bushing 88 is fixed by the raised sections on both sides of bushing groove 93 , upon assembly into the proximal end of top shell 17 . Rod bushing drive slot 91 is located on the most proximal end of rod bushing 88 as a means for rotationally engaging rod bushing 88 . Rotation gear 86 is rotatably fixed into gear cavity 115 on the underside of probe housing 52 , the opening being in communication with housing bore 57 (see FIG. 5). Rotation rod gear 86 operably engages sleeve gear 36 located at the proximal end of union sleeve 90 . The distal end of probe rotation rod 85 with rotation rod gear 86 attached is rotatably fixed to the underside of probe housing 52 by rotation gear cover 94 . Rotation gear cover 94 is molded from a thermoplastic material and is fixedly attached to probe housing 52 by four raised cylindrical pins which press fit into four holes (not visible) in probe housing 52 . Probe rotation rod 85 inserts rotatably and slidably through rod hole 43 in shell insert 39 . The proximal end of probe rotation rod 85 slidably engages bushing bore 89 in rod bushing 88 . Thus, rotation of rod bushing 88 causes rotation of probe rotation rod 85 which is fixedly attached to rotation rod gear 86 causing rotation of union sleeve 90 which is fixedly attached to piercer 70 , which contains port 78 .
[0050] It is important for the user of the surgical biopsy system of the present invention to be able to “fire” the piercer 70 into the tissue of a surgical patient. It is also important that the user be able to rotate piercer 70 about its axis so as to properly position port 78 , regardless of linear position of piercer 70 pre-fired vs. post-fired (positions discussed later). The slidable interface between probe rotation rod 85 and rod bushing 88 plays an important role in providing this capability. Probe rotation rod 85 follows the linear movement of piercer 70 , while the linear movement of rod bushing 88 is restricted by the fact that it is rotatably attached to top shell 17 . Thus the “D” shaped geometry on the proximal end of rotation rod 85 and the “D” shaped hole in the distal end of rod bushing 88 , designed to slidably receive the proximal end of rotation rod 85 , permit the user to turn port rotation knob 45 , which is operably connected to rod bushing 88 through a chain of elements described later, and effect the rotation of piercer 70 , irrelevant of the linear position of piercer 70 .
[0051] Bottom shell 19 fixedly attaches to top shell 17 as described earlier. Its function is to hold in place and contain the elements previously described, which have been assembled into top shell 17 . Keyhole 16 is centered at the distal end of bottom shell 19 . It slidably and removably engages post 14 (See FIG. 2), permitting probe assembly 42 to be operatively and removably connected to base 44 . First screw support rib 111 and second screw support rib 112 are each integrally molded to bottom shell 19 and support the distal and proximal ends, respectively, of elongated screw 114 . First gear support rib 136 and second gear support rib 137 likewise are each integrally molded to bottom shell 19 and support the distal and proximal ends, respectively, of elongated drive gear 104 . Rod bushing support rib 139 integrally molded to bottom shell 19 supports the distal end of rod bushing 88 .
[0052] [0052]FIG. 6 is an exploded isometric view of lower transmission assembly 302 . Translation shaft 22 and rotation shaft 24 is each a flexible coaxial cable comprising a flexible rotatable center core surrounded by a flexible tubular casing, as is well known in the art. At their most proximal ends is provided a coupling means for removably and operatively connecting translation shaft 22 and rotation shaft 24 to control unit 100 . The distal ends of translation shaft 22 and rotation shaft 24 each insert through first boot bore 309 and second boot bore 311 , respectively. Flex boot 303 is molded from a thermoplastic elastomer such as, for example, polyurethane, and functions as a “flex relief” for translation shaft 22 , rotation shaft 24 , and control cord 26 . Rotation shaft ferrule 305 is a metallic tubular structure comprising a through bore with a counter bore at its proximal end for fixedly attaching, via crimping or swaging as is well known in the art, to the outer tubular casing of rotation shaft 24 . At the distal end of rotation shaft ferrule 305 is a flared, counter bored section for receiving first bearing assembly 315 . A suitable example of first bearing assembly 315 is Model No. S9912Y-E1531PSO, available from Stock Drive Products, New Hyde Park, N.Y. Rotation shaft adapter 319 is made of stainless steel and has a proximal end with a counter bore. Its proximal end inserts through the bore of first bearing assembly 315 and the counter bore slips over the distal end of the rotatable center core of rotation shaft 24 and is fixedly attached by crimping or swaging. The distal end of rotation shaft adapter 319 is inserted through the bore in first bevel gear 321 and is fixedly attached by a slotted spring pin. Similarly, translation shaft ferrule 307 is a metallic tubular structure comprising a through bore with a counter bore at its proximal end for fixedly attaching, via crimping or swaging, to the outer tubular casing of translation shaft 22 . At the distal end of translation shaft ferrule 307 is a flared, counter bored section for receiving thrust washer 317 . Translation shaft adapter 323 is made of stainless steel and has a proximal end with a counter bore. Its proximal end inserts through the bore of thrust washer 317 and the counter bore slips over the distal end of the rotatable center core of translation shaft 22 and is fixedly attached by crimping or swaging. The distal end of translation shaft adapter 323 is slotted as a means to engage the proximal end of encoder shaft 312 , which extends through encoder 310 . Encoder 310 communicates information to control unit 100 about the translation position and translation speed of cutter 96 . Encoder 310 includes an electrical cord containing a plurality of electrical conductors, which has an electrical connector affixed at its most distal end for removable electrical connection to printed circuit board 262 (See FIG. 9). A suitable miniature encoder 310 is commercially available as Model sed10-300-eth2 from CUI Stack, Inc. Encoder shaft 312 has two opposing flats on its proximal end, which engage translation shaft adapter 323 , and a cylindrical distal end which is inserted into a counter bore in the proximal end of gear adapter 316 and is fixedly attached by a slotted spring pin. The distal end of gear adapter 316 is inserted through the bore of second bearing assembly 318 , through the bore of shaft spacer 322 , and finally through the bore in second bevel gear 325 which is fixedly attached to gear adapter 316 by a slotted spring pin.
[0053] Encoder housing assembly 329 comprises left encoder housing half 326 and right encoder housing half 328 , which are molded thermoplastic shells. When assembled, left encoder housing half 326 and right encoder housing half 328 encase encoder 310 and capture the distal end of translation shaft 22 and rotation shaft 24 . Left encoder housing half is attached to transmission plate 330 (see FIG. 7) using a cap screw. Encoder 310 is placed in first shell cavity 332 , preventing rotational or lateral movement of the outer housing of encoder 310 . The distal end of rotation shaft ferrule 305 rests in second shell cavity 334 , which prevents lateral movement of rotation shaft 24 . The distal end of translation shaft ferrule 307 rests in third shell cavity 336 , which again prevents lateral movement of translation shaft 22 . Second bearing assembly 318 rests in fourth shell cavity 338 . Right encoder housing half 328 , containing essentially a mirror image of the cavities found inside left encoder housing half 326 , assembles to left encoder housing half 326 and transmission plate 330 via two cap screws.
[0054] Still referring to FIG. 6, control cord 26 is flexible and contains a plurality of electrical conductors for communication information between biopsy device 40 and control unit 100 (see FIG. 1). At the proximal end of control cord 26 is provided a means of removable electrical connection to control unit 100 . The distal end of control cord 26 inserts through third boot bore 313 located in flex boot 303 . Control cord strain relief 369 is a flexible thermoplastic material and is over molded to the distal end of control cord 26 and is fixedly attached to transmission plate 330 in a recessed area at strain relief bore 371 (see FIG. 7), to restrict linear and rotational movement of the distal end of the cord. The most distal end of control cord 26 contains a connector for removably and electrically affixing control cord 26 to printed circuit board 262 (see FIG. 9).
[0055] [0055]FIG. 7 is an isometric view of transmission 301 . Upper transmission assembly 304 is shown exploded. Translation coupling assembly 337 consists of translation drive coupling 340 , third bearing assembly 344 , first coupling spacer 348 , and third bevel gear 350 . Third bearing assembly 344 is press fit into first counter bore 345 in transmission plate 330 . Translation drive coupling 340 has a flat bladed distal end which will operatively couple with lead screw slot 122 (see FIG. 8) located at the proximal end of elongated screw 114 . The cylindrical proximal end of translation drive coupling 340 inserts through first counter bore 345 , through the bore of third bearing assembly 344 , through the bore of first coupling spacer 348 , and finally through the bore in third bevel gear 350 which is fixedly attached to translation drive coupling 340 by a slotted spring pin. The gear teeth of third bevel gear 350 mesh with the gear teeth of second bevel gear 325 . Thus, rotation of the center core of translation shaft 22 results in the rotation of translation drive coupling 340 . When translation drive coupling 340 is operatively coupled to elongated screw 114 via lead screw slot 122 , rotation of translation shaft 22 causes rotation of elongated screw 114 which results, as discussed earlier, in the distal or proximal translation of cutter 96 , depending on the direction of translation shaft 22 rotation.
[0056] In a similar manner, rotation coupling assembly 339 consists of rotation drive coupling 342 , fourth bearing assembly 346 , second coupling spacer 349 , and fourth bevel gear 351 . Fourth bearing assembly 346 is press fit into second counter bore 347 in transmission plate 330 . A suitable example of fourth bearing assembly 346 , as well as second and third bearing assemblies 318 and 344 , respectively, is available as Model No. S9912Y-E1837PSO, available from Stock Drive Products, New Hyde Park, N.Y. Rotation drive coupling 342 has a flat bladed distal end which will operatively couple with drive gear slot 101 (see FIG. 8) located at the proximal end of elongated drive gear 104 . The cylindrical proximal end of rotation drive coupling 342 inserts through second counter bore 347 , through the bore of fourth bearing assembly 346 , through the bore of second coupling spacer 349 , and finally through the bore in fourth bevel gear 351 , which is fixedly attached to rotation drive coupling 342 by a slotted spring pin. The gear teeth of fourth bevel gear 351 mesh with the gear teeth of first bevel gear 321 . Thus, rotation of the center core of rotation shaft 24 results in the rotation of rotation drive coupling 342 . When rotation drive coupling 342 is operatively coupled to elongated drive gear 104 via drive gear slot 101 , rotation of rotation shaft 24 causes rotation of elongated drive gear 104 , which results in the rotation of cutter 96 . A suitable example of first, second, third, and fourth bevel gears 321 , 325 , 350 , and 351 , respectively, is Model No. A1M-4-Y32016-M available from Stock Drive Products, New Hyde Park, N.Y.
[0057] Continuing in FIG. 7, port drive coupling 353 has a flat bladed distal end which will operatively couple with rod bushing drive slot 91 (see FIG. 8) located at the proximal end of rod bushing 88 . The cylindrical proximal end of port drive coupling 353 inserts through the bore in first port gear 355 , which is fixedly attached by a slotted spring pin, then inserted through first port coupling bore 359 . First coupling washer 362 slips over the proximal end of drive port coupling 353 and first coupling e-ring 364 snaps into a groove at the most proximal end of drive port coupling 353 , which now rotatably secures the assembly to transmission plate 330 . Knob post 367 is made of stainless steel, is generally cylindrical, and has a flange on its most distal end and a flat approximately one-third to one-half its diameter in depth and extending from its proximal end one half inch in length. Knob post 367 inserts through the bore of second port gear 357 , which is fixedly attached by a slotted spring pin to the distal end of knob post 367 . Suitable examples of first and second port gears 355 and 357 , respectively, are available as Model No. A1N1-N32012, available from Stock Drive Products, New Hyde Park, N.Y. The proximal end of knob post 367 is inserted through second port coupling bore 360 until second port gear 357 aligns and meshes with first port gear 355 . Second coupling washer 363 slips over the proximal end of knob post 367 and second coupling e-ring 365 snaps into a groove located adjacent to the distal end of knob post 367 , thus rotatably securing the assembly to transmission plate 330 . Port rotation knob 45 fixedly attaches to the proximal end of knob post 367 . A suitable port rotation knob 45 is Model No. PT-3-P-S available from Rogan Corp., Northbrook, Ill. Thus, when port drive coupling 353 is operatively coupled to rod bushing 88 via rod bushing drive slot 91 , user rotation of port rotation knob 45 causes rotation of rod bushing 88 which results in the rotation of piercer 70 . This allows port 78 to be readily positioned anywhere within the 360° axis of rotation of piercer 70 .
[0058] Transmission plate 330 attaches to the proximal end of upper base shell 161 via two screws.
[0059] There is an important benefit derived from the design of transmission 301 just described. The fact that the translation shaft 22 , rotation shaft 24 , and control cord 26 enter the biopsy device 40 at a right angle to the device's center axis permits for a short overall length for the biopsy device. This allows the device to fit into a smaller area than would accommodate a device with the shafts protruding directly out the back (proximal end) parallel to the center axis.
[0060] [0060]FIG. 8 is an isometric view of probe assembly 42 and base 44 , as viewed from their proximal ends. Upper base housing 50 is not shown so as to permit a clear view of transmission 301 fully assembled. Also clearly visible are lead screw slot 122 , drive gear slot 101 , and rod bushing drive slot 91 , which operably connect to transmission 301 as previously described.
[0061] [0061]FIG. 9 is an exploded isometric view of firing mechanism 160 . Upper base shell 161 is shown exploded and lower base shell 204 is shown exploded and rotated 90 degrees clockwise. Also exploded and rotated 90 degrees clockwise for clarity is printed circuit board 262 and frame screw 163 .
[0062] Firing mechanism 160 , shown in FIG. 9, operates to fire the distal end of probe assembly 42 into tissue. Base shell 38 (see FIG. 2) supports and houses firing mechanism 160 , and is assembled from upper base shell 161 and lower base shell 204 . Base hooks 165 on lower base shell 204 insert into base slots 162 in upper base shell 161 to enable assembly of the components to create base shell 38 . Frame screw 163 inserts through a clearance hole in frame bottom 204 and fastens into firing latch block 242 to tie upper base shell 161 and lower base shell 204 together.
[0063] Firing fork 62 extends from firing mechanism 160 through to the exterior of base shell 38 to accept probe housing 52 of probe assembly 42 (see FIG. 2). FIG. 9 shows firing fork 62 in its most distal allowable position and shows other components of firing mechanism 160 in appropriate positions for firing fork 62 to be at its most distal allowable position.
[0064] Upon mating of the probe assembly 42 with the base 44 , first tang 54 and second tang 56 insert into first recess 64 and second recess 66 , respectively, in firing fork 62 at the distal end of firing fork assembly 164 . Features on firing fork 62 also include probe slot 167 , which is approximately “U” shaped to accept probe assembly 42 , and clearance slot 169 , allowing clearance for probe rotation rod 85 .
[0065] Firing fork assembly 164 , shown exploded in FIG. 10, is a unique assembly detachable from the rest of firing mechanism 160 without the use of tools. Firing fork 62 slides over the outer diameter of firing spade 178 while firing fork keys 181 insert into firing spade slots 180 . Firing spade slots 180 prevent rotation of firing fork 62 relative to firing spade 178 . Firing spade 178 possesses a threaded internal diameter at its distal end and a proximal spade end 196 at its proximal end. Proximal spade end 196 can comprise a flattened section, resembling, for example, the working end of a flathead screwdriver. The threaded diameter at the distal end of firing spade 178 receives screw 182 to hold firing fork 62 to firing spade 178 . The head 184 of screw 182 abuts the distal end of firing spade 178 upon tightening. Abutting the head 184 of screw 182 against the distal end of firing spade 178 prevents tightening of the screw against the firing fork 62 . The head 184 of screw 182 and the proximal end 186 of firing spade slot 180 provide proximal and distal stops for firing fork 62 while allowing slight axial play.
[0066] Firing spacer 188 attaches at the proximal end of firing spade 178 with the aid of dowel pins 190 . Firing spacer 188 slips onto and is rotatable relative to firing spade 178 . It should be noted that minimizing the clearance between the inside diameter of firing spacer 188 and the outside diameter of firing spade 178 improves the stability of firing fork assembly 164 , an important attribute.
[0067] Near the proximal end of firing spacer 188 , easily visible depth marker line 189 is inscribed. Dowel pins 190 press into receiving holes 192 on firing spacer 188 and ride within firing spade groove 194 to allow rotation of firing spacer 188 relative to firing spade 178 while preventing axial movement of firing spacer 188 relative to firing spade 178 . A threaded internal diameter at the proximal end of firing spacer 188 facilitates assembly and removal of the firing fork assembly 164 for cleaning.
[0068] [0068]FIG. 9 shows that firing fork assembly 164 threads onto end fitting 166 , pinned at the distal end of firing fork shaft 168 . End fitting 166 can be made of a soft stainless steel for easy machining of slot and threads while firing fork shaft 168 can be made of a hardenable stainless to accommodate induced stress. Proximal spade end 196 fits into spade slot 198 of end fitting 166 to prevent rotation of firing fork assembly 164 relative to firing fork shaft 168 . The threaded internal diameter of the proximal end of firing spacer 188 screws onto the threaded outer diameter of end fitting 166 to removably attach firing fork assembly 164 . Small firing bushings 170 , fashioned from a plastic such as acetal, support firing fork shaft 168 and allow it to move proximally and distally. Proximal saddle support 172 and distal saddle support 173 , machined into upper base shell 161 , support small firing bushings 170 while long clamp plate 174 and short clamp plate 175 capture and retain small firing bushings 170 into proximal and distal saddle supports 172 and 173 , respectively. Long clamp plate 174 and short clamp plate 175 can attach to proximal saddle support 172 and distal saddle support 173 using fasteners, such as, for example, clamp plate mounting screws 176 . Flanges at each end of the small firing bushings 170 bear against the proximal and distal sides of saddle supports 172 and clamp plates 174 to restrain small firing bushings 170 from moving proximally and distally with the movement of firing fork shaft 168 . Additional support is gained by the large firing bushing 200 surrounding firing spacer 188 . Large firing bushing 200 , split for easy assembly, resides in firing bushing housing 202 machined into upper base shell 161 and lower base shell 204 .
[0069] Firing fork shaft 168 carries other parts that facilitate the operation of firing mechanism 160 . Spring collar roll pin 212 fixedly attaches spring collar 214 to firing fork shaft 168 . Shock pad 216 adheres to the distal side of spring collar 214 and contacts distal interior wall 218 of base shell 38 when firing fork shaft 168 is in its distal position. Shock pad 216 can be made from many shock- absorbing materials, such as, for example, rubber. Main spring 217 surrounds firing fork shaft 168 and bears against the distal side of distal saddle support 173 and the proximal side of spring collar 214 to force firing fork shaft 168 distally. Magnet holder roll pin 208 fixedly attaches magnet holder 206 to firing fork shaft 168 . Magnet 210 is crimped into magnet holder 206 . Nearer the proximal end of firing fork shaft 168 , firing main link pin 224 passes through firing fork shaft slot 225 to hold firing fork shaft 168 to carriage 220 . Firing main link pin 224 also captures curved firing levers 222 retaining them to the carriage 220 . Firing main link pin 224 is flanged on one end. The other end of firing main link pin 224 extends through carriage 220 to retain carriage 220 , firing fork shaft 168 , and curved firing levers 222 , where it is retained by welding to the lower curved firing lever.
[0070] Curved firing levers 222 and firing linkages 226 drive the arming of firing mechanism 160 . Curved firing levers 222 pin to firing linkages 226 using firing link pins 228 which are welded to firing levers 222 . Firing linkages 226 in turn pin to upper base shell 161 using frame link dowel pins 230 pressed into upper base shell 161 . Long clamp plate 174 retains firing linkages 226 using clamp plate mounting screws 176 . Each pinned joint of curved firing levers 222 , firing linkages 226 , and carriage 220 is rotatably movable about the axis of the pin.
[0071] Each curved firing lever 222 has a portion that extends laterally outwards through a slot located on either side of base shell 38 (See FIG. 2). A curved firing lever end 232 is attached to each curved firing lever 222 on the extension of curved firing lever 222 external to base shell 38 . Curved firing lever end 232 provides a convenient user interface for arming the firing mechanism. Arming the mechanism will be described later. The coil of torsion spring 234 surrounds each pinned joint of curved firing levers 222 and firing linkages 226 . The legs of link torsion springs 234 extend outwardly to hook into curved firing levers 222 and firing linkages 226 , applying a torque rotating them relative to each. other.
[0072] Locating firing linkages 226 and curved firing levers 222 at different distances from upper base shell 161 allows them clearance to pass by each other upon operation. Curved firing levers 222 have bends to offset them in a direction perpendicular to upper base shell 161 . The offset bends let them move within planes at different distances from upper base shell 161 while having the curved firing lever ends emerge from the slot created for that purpose in upper base shell 161 . Spacer 223 separates the links on the pin 230 . Having a curved firing lever 222 and firing linkage 226 on each side of the longitudinal centerline allows access by the user to operate firing mechanism 160 from either side of base shell 38 .
[0073] Fasteners secure a printed circuit board 262 to lower base shell 204 and latch block 242 . Printed circuit board 262 contains Hall-effect switch 264 for sensing the proximity of magnet 210 . A suitable Hall-effect switch 264 is Model No. A3142ELT available from Allegro Microsystems, Inc., Worcester, Mass. When firing fork 168 and associated magnet 210 are in the most proximal position (pre-fired position, as described later), magnet 210 is held in a position near Hall-effect switch 264 .
[0074] [0074]FIG. 11 is an exploded isometric view of triggering mechanism 235 , seen in FIG. 9. Triggering mechanism 235 safely latches and fires firing fork shaft 168 . Triggering mechanism 235 comprises firing latch 236 , firing latch block 242 , firing button shaft 244 and roller 241 , firing latch spring 246 , firing button shaft spring 247 , safety block 248 , safety latch 250 , safety latch torsion spring 251 , safety latch cover 252 , and firing button 254 .
[0075] Firing latch block 242 encloses the proximal portion of firing latch 236 and serves as a mounting platform for components of triggering mechanism 235 . Firing latch pin 237 and firing block pin 239 rigidly retain firing latch block 242 to upper base shell 161 . Firing latch pin 237 rotatably pins firing latch 236 to upper base shell 161 while passing through firing latch block 242 . Firing latch 236 pivots within a slot in upper base shell 161 . Firing latch spring 246 is compressed between firing latch block 242 and firing latch 236 , thereby forcing the distal end of firing latch 236 towards firing fork shaft 168 . Firing latch 236 possesses a firing latch hook 238 at its distal end, which removably latches into a firing fork shaft retainer 240 located at the proximal end of firing fork shaft 168 . Firing button shaft 244 slidably moves proximally and distally within a bore in firing latch block 242 and has roller 241 rotatably pinned to its distal portion to engage firing latch 236 to cause rotation of firing latch 236 . Firing button shaft spring 247 forces firing button shaft 244 proximally. Firing button shaft 244 is retained by safety block 248 , which is mounted to the proximal side of firing latch block 242 . Safety latch 250 resides within a counter bore on the proximal side of safety block 248 and is retained by safety latch cover 252 . Fasteners such as screws hold safety latch cover 252 in place.
[0076] Safety latch 250 is designed to facilitate locking and unlocking of the firing mechanism. Safety latch 250 can be rotated within the counter bore on safety block 248 through a rotation angle, while safety latch torsion spring 251 has extending legs hooked into safety block 248 and safety latch 250 to apply torque to safety latch 250 . Safety block 248 defines a locked position safety latch stop 245 and an unlocked position safety latch stop 243 separated by the rotation angle. Safety latch handle 249 extends radially from safety latch 250 to facilitate grasping and rotating of safety latch 250 by the user. Safety latch handle 249 also forms surfaces to abut safety latch stops 245 and 243 to limit the rotation angle. In the locked position, safety latch torsion spring 251 forces safety latch handle 249 against the locked position safety latch stop 245 , while in the unlocked position, the user forces safety latch handle 249 against unlocked position safety latch stop 243 . In the illustrated embodiment of the invention, the rotation angle through which safety latch 250 can be rotated is about thirty-five degrees. FIG. 12 shows that safety latch 250 contains two firing button stops 256 with one firing button stop 256 on each side of the longitudinal axis of firing button 254 at assembly. The firing button stops 256 interact with firing button 254 to effect locking (preventing lateral movement) and unlocking (allowing lateral movement) of firing button 254 .
[0077] [0077]FIG. 13 shows an isometric view of firing button 254 . Firing button 254 fixedly attaches to firing button shaft 244 (see FIG. 11), extends proximally through the center of safety latch 250 (see FIG. 12), and presents a proximal, flattened, cylindrical thumb pad 257 located at its most proximal end to the user. Firing button 254 comprises a smaller firing button outer diameter 258 having narrow flats 259 and wide flats 261 angularly offset from each other by the rotation angle traveled by safety latch 250 . Larger firing button outer diameter 260 is free of flats. A distal contact surface 255 exists proximally of narrow flats 259 and is substantially perpendicular to the longitudinal axis of firing button 254 . Firing button stops 256 , located on safety latch 250 , are separated by a distance slightly larger than the distance between wide flats 261 and less than the smaller firing button outer diameter 258 . Firing button stops 256 can flex in the radial direction, but resist flexing in the axial direction. The difference in stiffness in different directions can be accomplished by, for example, different thicknesses of the firing button stops 256 in the axial direction and in the radial direction.
[0078] When safety latch 250 is in the locked position, pushing firing button 254 will force distal contact surface 255 against firing button stops 256 . Firing button stops 256 prevent further proximal axial movement of firing button 254 because of rigidity in the axial direction.
[0079] Following is a functional description of the operation of the firing mechanism of the present invention:
[0080] A user arms and fires the firing mechanism during use of the probe assembly 42 in a surgical procedure. The user begins in the fired position depicted in FIGS. 14 and 15, grasps one of the curved firing lever ends 232 , and moves outboard end of curved firing lever 222 proximally. This begins action wherein each grasped curved firing lever 222 , each firing linkage 226 , carriage 220 , and upper base shell 161 act as four-bar linkage systems with upper base shell 161 being the stationary link and carriage 220 being a translational link. Motion can be described of all three movable links relative to the upper base shell 161 . Either curved firing lever end 232 can be moved by the user. Duplicity exists in the illustrated embodiment of the invention to facilitate user access from either side of base 44 .
[0081] Rotating either curved firing lever 222 in a direction that moves the curved firing lever end 232 proximally effects motion of the two members pinned to curved firing member 222 . Curved firing member 222 transfers motion through one pinned joint to carriage 220 to move it proximally along firing fork shaft 168 . Curved firing member 222 also transfers motion through a second pinned joint to firing linkage 226 , rotating the pinned joint towards firing fork shaft 168 . Firing linkage 226 is pinned to stationary upper base shell 161 and rotates about the pinned joint located on upper base shell 161 .
[0082] Carriage 220 , driven by curved firing member 222 , translates proximally along firing fork shaft 168 carrying main link pin 224 within firing fork shaft slot 225 until firing main link pin 224 reaches the proximal end of firing fork shaft slot 225 . Further proximal motion of carriage 220 and firing main link pin 224 begins to drive proximal motion of firing fork shaft 168 . Firing fork shaft 168 translates proximally through small firing bushings 170 .
[0083] As firing fork shaft 168 translates proximally, it carries with it attached firing fork assembly 164 . Firing fork shaft 168 also carries proximally attached spring collar 214 , decreasing the distance between spring collar 214 and distal saddle support 173 . Main spring 217 , located between spring collar 214 and distal saddle support 173 , becomes more compressed exerting more force against spring collar 214 . Firing fork shaft 168 continues to move proximally and continues to compress main spring 217 until the proximal end of firing fork shaft 168 reaches firing latch 236 (see FIG. 15). The proximal end of firing fork shaft 168 contacts firing latch 236 and exerts a force rotating it out of the path of proximally advancing firing fork shaft 168 . The proximal end of firing fork shaft 168 and the distal end of firing latch 236 have contoured surfaces to act as cams to assist in lifting firing latch 236 . Rotating firing latch 236 compresses firing latch spring 246 , exerting a force to hold firing latch 236 onto the proximal end of firing fork shaft 168 . Once the firing fork shaft retainer 240 has proceeded proximally to a position under firing latch hook 238 , firing latch spring 246 urges firing latch hook 238 into firing fork shaft retainer 240 by rotating firing latch 236 towards firing fork 168 . Firing assembly 160 is now in the pre-fire position shown in FIGS. 16 and 17.
[0084] The user can now release curved firing lever end 232 . Once the user releases curved firing lever end 232 , main spring 217 applies force urging firing fork 168 distally along its axis. The distal force moves firing fork shaft retainer 240 towards firing latch hook 238 extending down into firing fork shaft retainer 240 (see FIG. 19). The proximal wall of firing fork shaft retainer 240 is angled so that the reactive force of the proximal wall of firing fork shaft retainer 240 against firing latch hook 238 rotates firing latch hook 238 further into the firing fork shaft retainer 240 , preventing inadvertent release. The proximal wall of firing latch hook 238 is angled to mate with the angle of the proximal wall of firing fork shaft retainer 240 . After the user has released curved firing lever end 232 , link torsion springs 234 apply torque to curved firing levers 222 and firing linkages 226 rotating them towards each other. Rotating curved firing levers 222 and firing linkages 226 towards each other initiates motion that returns carriage 220 to its distal position. With firing fork 168 held by firing latch 236 while firing levers 222 and firing linkages 226 are in the most distal position, firing mechanism 160 is in the relaxed position shown in FIGS. 18 and 19. When carriage 220 returns to its distal position, curved firing levers 222 contact stops on the sides of raised bosses on upper base shell 161 .
[0085] Firing fork shaft 168 has now carried magnet 210 (see FIG. 9) which is located within magnet holder 206 proximally into a position near Hall-effect switch 264 on printed circuit board 262 . Hall-effect switch 264 senses the presence of magnet 210 and communicates with control unit 100 that firing fork 168 is in a proximal position and ready to fire.
[0086] Safety latch 250 “guards” firing button 254 . In the locked position shown in FIG. 20, firing button stops 256 on the safety latch 250 are located distally of distal contact surface 255 on firing button 254 . Firing button stops 256 on safety latch 250 are also located on either side of narrow flats 259 (see FIG. 13). Smaller firing button outer diameter 258 is larger than the distance between firing button stops 256 . Attempting to push firing button 254 distally will cause distal contact surface 255 to contact firing button stops 256 . The rigidity of the firing button stops 256 in the axial direction prevents further distal movement of the firing button and prevents inadvertent firing of the mechanism.
[0087] After the user has determined the proper location in which to insert the piercer 70 of biopsy device 40 into a surgical patient, the user can now unlock and fire firing mechanism 160 . Unlocking and firing the mechanism requires two separate actions, rotating the safety latch 250 and pressing the firing button 254 . The operator first grasps safety latch handle 249 to rotate safety latch 250 against the torque applied to it by safety latch torsion spring 251 (not visible). FIG. 21 shows rotating safety latch 250 so that safety latch handle 249 travels from locked position safety latch stop 245 to unlocked position safety latch stop 243 which aligns firing button stops 256 with wide flats 261 on smaller firing button outer diameter 258 . Since the distance between firing button stops 256 is larger than the distance between wide flats 261 , clearance now exists for wide flats 261 to pass between firing button stops 256 . Safety latch 250 is now in the “firing” position.
[0088] In the next step, the operator presses firing button 254 by placing force on cylindrical thumb pad 257 to urge firing button 254 distally. When firing button 254 is pressed, wide flats 261 move between firing button stops 256 allowing firing button 254 to proceed distally. Firing button 254 , attached to firing button shaft 244 , pushes firing button shaft 244 distally. The roller 241 on firing button shaft 244 contacts the cam surface on firing latch 236 to rotate firing latch 236 so that firing latch hook 238 lifts out of firing fork shaft retainer 240 (see FIG. 19). Once firing latch hook 238 is clear of firing fork shaft retainer 240 , main spring 217 drives firing fork shaft 168 distally carrying firing fork assembly 164 and piercer 70 of probe assembly 42 towards the target. Distal motion of firing fork shaft 168 continues until shock pad 216 contacts distal interior wall 218 of base shell 38 (see FIG. 14). Hall-effect switch 264 senses the departure of magnet 210 distally and communicates the departure to control unit 100 .
[0089] After firing the firing mechanism 160 the user releases firing button 254 , then releases safety latch handle 249 . When the user releases firing button 254 , firing button shaft spring 247 forces firing button shaft 244 proximally. Firing button 254 moves proximally as well, returning distal contact surface 255 and firing button smaller diameter 258 proximal of firing button stops 256 . The proximal movement of firing button 254 also places narrow flats 259 between firing button stops 256 . Releasing safety latch handle 249 allows safety latch torsion spring 251 to rotate safety latch 250 back towards the locked position with safety latch handle 249 forced against locked position safety latch stop 245 . With only narrow flats 259 and wide flats 261 between firing button stops 256 , safety latch 250 can freely rotate without interference from firing button stops 256 .
[0090] When firing button shaft 244 travels proximally, the roller 241 of firing button shaft 244 and cammed surface of firing latch 236 separate (see FIG. 15). Firing latch spring 246 then rotates firing latch 236 into a position where firing latch hook 238 is moved towards firing fork shaft 168 . An arming and firing cycle is now complete. Firing assembly 160 has returned to the post-fired position depicted in FIGS. 14 and 15.
[0091] It should be noted that if, after firing, the user of the firing mechanism 160 does not release firing button 254 before releasing safety latch handle 249 , the mechanism still operates properly because of incorporated unique design features. When firing button 254 is in the distal, pressed position, smaller firing button outer diameter 258 is between firing button stops 256 . Clearance for firing button stops 256 is made by alignment of firing button stops 256 with wide flats 261 . Releasing safety latch handle 249 before releasing firing button 254 causes safety latch torsion spring 251 to rotate safety latch 250 back towards the locked position and causes firing button stops 256 to rotate out of alignment with wide flats 261 . When the firing button stops 256 rotate out of alignment with wide flats 261 smaller firing button outer diameter 258 comes between firing button stops 256 . Smaller firing button outer diameter 258 is larger than the distance between firing button stops 256 . However, firing button stops 256 , designed to flex in the radial direction, separate by bending away from each other in the center when forced apart by smaller firing button outer diameter 258 . Because of the radial flexibility of firing stops 256 , firing button stops 256 apply little force to smaller firing button outer diameter 258 . With little force applied, firing button 254 slides easily through firing button stops 256 while returning to the proximal position. Firing button 254 returning to its proximal position brings smaller firing button outer diameter 258 between firing button stops 256 to allow safety latch 250 to continue to rotate back to the locked position. The difference in flexibility of the firing button stops radially and axially allows latching and release of triggering mechanism 235 regardless of order of operation of the components. Rigidity in the axial direction stops inadvertent operation of firing button 254 and flexibility in the radial direction allows interference with smaller firing button outer diameter 258 while still maintaining smooth release operation.
[0092] If desired, firing fork assembly 164 can be disassembled without tools from the rest of firing mechanism 160 and cleaned. Before a subsequent firing, an operator can attach a clean firing fork assembly 164 by mating proximal spade end 196 with spade slot 198 and threading firing spacer 188 onto end fitting 166 . When assembling firing fork assembly 164 with the firing mechanism in the post-fired position, an assembler can use depth marker line 189 to ensure proper assembly. The assembler can check alignment of depth marker line 189 with the outside surface of base shell 38 . A depth marker line 189 aligned with base shell 38 denotes a proper assembly. A depth marker line 189 that is misaligned with base shell 38 could indicate an improper assembly such as cross threading of firing spacer 188 or incomplete tightening of firing spacer 188 .
[0093] [0093]FIG. 22 shows an alternate embodiment of firing fork assembly 164 . Thumbscrew 191 threads into a threaded hole 187 on firing fork 62 , Threaded hole 187 on firing fork 62 passes through to a larger counter bore hole with flats on either side, commonly called a double-D hole 213 . Firing fork assembly 164 comprises thumbscrew 191 threaded onto firing fork 62 . Undercut 195 has ail outer diameter less than the minor diameter of threaded hole 187 on firing fork 62 and thus maintains clearance between threaded hole 187 and undercut 195 . Thumbscrew 191 , after assembly to firing fork 62 , can thus turn freely on firing fork 62 utilizing the clearance between threaded hole 187 and undercut 195 . An alternate embodiment of firing fork shaft end fitting 166 , shown in FIG. 22, has end fitting flats 211 machined on either side of the second embodiment of end fitting 166 . End fitting 166 is welded to the distal end of firing fork shaft 168 . The configuration of end fitting 166 with end fitting flats 211 will accept double-D hole 213 of the alternate embodiment of firing fork 62 . Use of end fitting flats 211 with double-d hole 213 prevents rotation of firing fork 62 relative to end fitting 166 and firing fork shaft 168 . The alternate embodiment of firing fork assembly 164 threads into alternate embodiment of end fitting 166 which is welded onto firing fork shaft 168 . The alternate embodiment end fitting 166 has a threaded internal diameter 193 to accept the threaded proximal end of thumbscrew 191 . Thumbscrew 191 has a knurled, easily grasped surface so that the alternate embodiment of firing fork assembly 164 can be assembled and disassembled without the use of tools.
[0094] Dual four-bar mechanisms have been utilized in the present embodiment of the invention to facilitate ease of use by providing access by the user from either side of base 44 . A variation that would become evident to one skilled in the art after reading the description would be a single four-bar mechanism to create the firing mechanism.
[0095] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. Accordingly, it is intended that the invention be limited only by the spirit and scope of the appended claims. | 1a
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CROSS-REFERENCE TO RELATED APPLICATIONS
This is a division of application Ser. No. 633,481, filed Nov. 19, 1975, now U.S. Pat. No. 4,060,998; which was a continuation-in-part of patent application Ser. No. 526,146, filed Nov. 22, 1974 entitled "PORTION CONTROLLED FROZEN FOOD", now abandoned.
FIELD OF THE INVENTION
This invention relates to the preparation of discrete frozen products, and more particularly relates to a system and method for producing frozen foods in individual discrete portions.
DESCRIPTION OF THE PRIOR ART
A wide variety of products, such as explosives, rubber devices, food products and building materials are commonly formed from a semi-fluid material. When the semi-fluid material is not sufficiently rigid to maintain its shape after extrusion, it has been heretofore quite difficult to form discrete products having a predetermined shape and having a desired weight. It has thus been common to prepare discrete products from semi-fluid material by filling individual containers or molds and then freezing or otherwise treating the individual containers. Such processes requiring the filling of individual containers have been found to be relatively slow and expensive.
With respect to food products, it has become desirable in the home, restaurants and other places to utilize food portioned in predetermined serving sizes or portions. For example, it has become desirable to provide serving portions of sausage such as a one-ounce sausage link or a two-ounce sausage patty. However, it has not heretofore been practical to provide such close controlled portion sizes of foods such as skinless pork sausage with conventional packaging techniques.
It has heretofore been known to produce skinless sausage of various types by stuffing comminuted meat into a casing, setting the meat by chilling or cooking and then stripping the casing from the meat. The requirement of stuffing the casing and then stripping the casing is time consuming and of course wasteful. It has also reportedly been heretofore attempted to extrude pork for various processing techniques, but the resulting friction along the sides of the extruding tube have caused fat to come to the surface of the pork, thereby producing a product which appears to consist of all fat or excessive fat, and it is therefore unpleasing to the consumer.
A need has thus developed for a system and process to enable the continuous forming of a plurality of discrete solid products from semi-fluid material. The system and process must not only be fast and cost effective, but must enable the formation of a plurality of different shapes and sizes of discrete products with very close weight tolerances.
SUMMARY OF THE INVENTION
The present invention has reduced or eliminated the problems associated with the prior art previously described. In accordance with the present invention, a plurality of discrete products having a predetermined weight may be formed by a system which pumps a semi-fluid mixture along a distribution path. An extrusion manifold receives the semi-fluid mixture and extrudes the mixture at a selected rate to form a continuous sheet of mixture having a predetermined uniform cross-section. A conveyor directs the continuous sheet through a chilling station in order to chill and firm the sheet such that the sheet maintains its extruded cross-sectional configuration. Structure severs the continuous sheet into a plurality of discrete products having predetermined weights.
In accordance with another aspect of the invention, a system is provided for forming a plurality of discrete products having preselected weights which includes a hopper for receiving a quantity of warm semi-fluid material. A pump pumps the material through a feed line at a selected rate and pressure. An extrusion manifold has an inlet connected at the end of the feed line and includes an outlet with a smaller dimension than the inlet. A flexible conduit extends from the manifold outlet and includes an end nozzle to form a continuous extruded sheet of material. A chilling chamber is mounted adjacent the end nozzle. A conveyor receives the continuous sheet from the end nozzle and carries the continuous sheet through the chilling chamber where it is chilled and firmed. A plurality of cutting disks are mounted at the outlet of the chilling chamber and continuously slice the sheet into continuous lengths of material. A cutting blade is movable in synchronism with the conveyor for severing the continuous lengths to form a plurality of discrete products having the selected weight.
In accordance with a more specific aspect of the invention, a cutting system is provided to periodically sever the sliced continuous lengths of material and includes structure for receiving a plurality of parallel lengths of material traveling in a direction parallel to the axes of the lengths. An elongated cutting blade is disposed above and normal to the direction of travel of the lengths of material. Structure moves the blade downwardly for simultaneously severing all of the lengths of material while moving the blade in the direction of travel of the lengths of material and at the same rate of speed as the lengths of material.
In accordance with another embodiment of the invention, a plurality of cutting molds are provided for stamping the continuous sheet as it is extruded from the end nozzle onto the conveyor to form a plurality of discrete products. Each cutting mold has a cutting edge for severing a predetermined shape of chilled mixture from the continuous sheet. A vacuum is drawn above the severed shapes of mixture to permit withdrawal of the severed shapes from the continuous sheet. A second conveyor is operable with the cutting molds whereupon the severed shapes of mixture are deposited and carried to a packaging station.
In accordance with still another embodiment of the invention, a rotatable drum is provided for severing the continuous sheet into predetermined discrete products. The drum is adapted with equally spaced sharpened circumferential blades for slicing the sheet into continuous lengths and sharpened longitudinal blades for severing the lengths to form the predetermined shapes from the chilled mixture. The drum is positioned to sever the continuous sheet by the action of the circumferential and longitudinal blades against the continuous sheet as it is moved on the conveyor. The drum is rotated so that the circumferential blades move at the same speed of travel as the linear conveyor on which the continuous sheet moves. The linear conveyor is adapted with indentions for receiving the sharpened edges of the circumferential and longitudinal blades to facilitate cutting of the continuous sheet.
In accordance with yet another aspect of the invention, a process for producing pork sausage includes boning warm prerigor pork. The boned pork is then comminuted to form a semifluid mixture which is pumped to an extrusion location. The semi-fluid mixture is then extruded into a continuous sheet having uniform cross-sections. The extruded continuous sheet is chilled such that it maintains the desired cross-sectional configuration. The sheet is periodically severed to form a plurality of chilled discrete sausage portions having the same weight and consistency.
DESCRIPTION OF THE DRAWINGS
For a more detailed description of the present invention and for further objects and advantages thereof, reference is now made to the following description, taken in conjunction with the accompanying drawings, in which:
FIG. 1 is a block diagram of the present portion controlled forming system;
FIG. 2 is a perspective view of the extruding portion of the system;
FIG. 3 is a partially broken away view of the extrusion manifold of the invention;
FIG. 4 is a sectional view of the extrusion manifold shown in FIG. 3 taken along line 4--4;
FIG. 5 is a sectional view of the extrusion manifold shown in FIG. 3 taken along line 5--5;
FIG. 6 is a perspective, partially broken away view of the extrusion nozzle assembly of the invention;
FIG. 7 is a perspective enlarged view of the nozzle connections assembly;
FIG. 8 is a sectional view of the extrusion material form shown in FIG. 6 with a continuous sausage sheet disposed therein;
FIG. 9 is a side view of the parallelogram lift linkage for the nozzle assembly;
FIG. 10 is a perspective view of the slicing disks of the invention;
FIG. 11 is a sectional view taken along line 11--11 of FIG. 10;
FIG. 12 is a perspective, partially broken away view of the cutting table of the invention;
FIGS. 13a-13d illustrate the cutting operation of the blade and bed of the cutting table;
FIG. 14 is a perspective view of the outlet of the cutting table;
FIG. 15 is a perspective view of a second embodiment of a cutting device for use with the present invention;
FIG. 16 is a sectional view taken along line 16--16 of the cutting device shown in FIG. 15;
FIG. 17 is a perspective view of a third embodiment of a cutting device for forming preselected shapes of sausage products;
FIG. 18 is a sectional view taken along line 18--18 of the cutting device shown in FIG. 17; and
FIGS. 19a-19c illustrate the cutting operation of the cutting device shown in FIGS. 17 and 18.
DESCRIPTION OF THE PREFERRED EMBODIMENT
FIG. 1 is a top flow plan illustrating the use of the present product forming invention to make fresh pork sausage. It has been found that the present invention is particularly adaptable to making fresh pork sausage and a detailed description of the invention will be made with respect to production of pork sausage from warm semi-fluid pre-rigor pork. However, it will be apparent that the present invention may also be utilized to form discrete products from other semi-fluid materials. For the purposes of this invention, the term semi-fluid is defined as material which is pumpable through conduits. The present system may thus be utilized to extrude hot or chilled ground meat, or other types of pumpable material.
Referring to FIG. 1, freshly killed hogs are dressed, skinned and cut shortly after slaughter. The still warm pre-rigor pork is cut on a boning table 10 and all cuts including the ham, loins and the like of the hogs are utilized in making the sausage. The hot boned meat coming off the boning table 10 is fed into a grinder 12 and is checked for fat content to maintain the fat content at 35%. A fat analysis unit, not shown, is maintained near the grinder 12 in order to make rapid fat checks regarding the fat content of the sausage being ground. The output of the grinder 12 is applied to two blenders 14a and 14b which form the sausage into a semi-fluid fluent material which will not retain its shape after being extruded.
In the preferred embodiment of the invention, it is necessary that the hogs be boned and ground within about four hours from slaughter before rigor mortis, and the temperatures of the boned meat be maintained at as near body temperature as possible, and at any rate above 80° F., such that the rended pork output from the blenders 14a and 14b is semi-fluid so as to freely flow. The process should be carried out in a room having an ambient temperature of not under 50° F. In the preferred embodiment, it is preferable to bone, grind, chill and sever the pork sausage within 90 minutes after slaughter. Alternatively, the present system may utilize chilled raw material which becomes semi-fluid after blending in the blenders 14a and 14b.
In the preferred embodiment, the blenders 14a and 14b may comprise, for example, two 3,000 pound Rietz blenders. The semi-fluid material output from the blenders moves through conduit 15 and is applied through a pump 16, which may comprise, for example, an auger feed pump including a de-aerating head. Pump 16 applies semi-fluid pork sausage through a distribution line 18 at a predetermined flow rate to an extrusion manifold 20. Although only a single manifold 20 is illustrated, it will be understood that two or more manifolds may be utilized, depending upon the desired quantity of material to be handled. The manifold 20 extrudes a continuous sheet of semi-fluid material which is applied through flexible conduit 22.
Flexible conduit 22 includes a nozzle on the end thereof to form and extrude a continuous sheet 23 of pork sausage having a predetermined uniform cross-section, the continuous sheet being moved through a freezer 24. The continuous sheet moves at 15-feet per minute through freezer 24, whereupon the continuous sheet is quickly chilled to an extent that it maintains its extruded cross-sectional shape. Freezer 24 may comprise any suitable type of freezer, but in the preferred embodiment comprises a liquid nitrogen freezer such as the Cyro-Quick freezer manufactured and sold by Air Products Corporation. In some cases, it may be desirable to spray a refrigerant such as nitrogen or fluorocarbon upon the sausage or on the underside of the moving conveyor belt in order to quickly chill the sausage.
The chilled pork sausage exits freezer 24 at an internal temperature of -10° F. The chilled sausage is continuously sliced into equal width continuous lengths by a slicer 25 and periodically severed into desired lengths by a cutter 26 to form a plurality of discrete sausage products each having a predetermined weight and volume. For example, the width and length of the final product may be controlled to produce a product having a weight of one-ounce. Sausage patties may be produced by the system having a weight of from 11/2 to 5-ounces. If desired, the present device may be utilized to produce square sausage patties having any desired width to generate a specific weight. An important aspect of the present invention is that a very high degree of portion control may be achieved by the present system to provide products of uniform size, shape and weight. The emulsion density, emulsion flow speed, freezer belt speed, the slicer operation and cutoff blade operation may be varied in order to maintain the exact desired weight, or to change to a different desired weight or size. If desired, the width of one of the continuous lengths may be increased in order to produce one lane of heavier lengths which may then be used to increase the weight of light sausage packages.
The severed sausages formed by the cutter 26 unit are applied to a loader 28 which accumulates predetermined numbers of sausages and applies them to a fill and seal station 30. The station 30 fills cartons with predetermined numbers of frozen sausages and seals the cartons. The cartons are then directed to a weighing station 32 and then to a metal detector station 34. A plurality of cartons are loaded into cases at stations 36 and the cases are then sealed for transport.
The present hot molding process, in combination with the present extrusion system, enables the production of packages of frozen pork lengths or sausage patties within 70 to 90 minutes after live hogs enter the restrainer in the slaughtering department. The present system can thus produce over 3,000 pounds an hour of sausage in a nonstop process which requires only a few workers for maintaining operation of the machine. With the addition of additional extruders, greater yields may, of course, be provided.
The present process is extremely economical, in that no storage space is necessary, as the sausages may be packaged and loaded onto a truck within several hours of the time the hogs are slaughtered. The present system is extremely accurate in the control of portions, as sixteen one-ounce lengths may be packaged to a package to provide a very close tolerance to a one-pound meat package. The present system provides very low waste, as there is no discard of bits and pieces, which occurs with prior techniques. The present system provides an increased yield, as the meat is not continuously handled after slaughter.
FIG. 2 illustrates in detail the extrusion system of the invention. The semi-fluid sausage material is applied from pump 16 through the distribution line 18 to extrusion manifold 20. The extrusion manifold has a generally conical configuration at inlet 38 connected to distribution line 18. The manifold gradually flattens to a rectangular outlet 40 which is joined to flexible conduit 22 having an identical rectangular configuration for maintaining the semi-fluid material in the shape generated by passage of the fluid through the extrusion manifold. The cross-sectional area of the rectangular outlet of extrusion manifold 20 is slightly smaller than that of the inlet end 38 connected to distribution line 18. In this way, a rectangular sheet 23 of semi-fluid material extruded from manifold 20 is continuous without voids which would otherwise occur.
A metering pump 42 is interconnected between extrusion manifold 20 and flexible conduit 22 and is mounted on support brackets 44. Metering pump 42 maintains the flow rate of material from extrusion manifold 20 into conduit 22. Extrusion manifold 20 is supported by support 46. A base 47 supports the support 46 and support brackets 44. Base 47 includes the drive motor (not shown) for the metering pump 42.
An extrusion nozzle 48 is attached to the outlet end of conduit 22 and is received in a nozzle support housing 50. Nozzle support housing 50 is mounted on a parallelogram linkage including arms 52 and 54 which are pivotally joined by the horizontal bars 56. The parallelogram linkage may be moved from the illustrated lower position to an upper position, to be subsequently described, in order to move nozzle 48 into and out of contact with a material conveyor 58. Conveyor 58 comprises a metal mesh conveyor belt which conveys the extruded semi-fluid material into nitrogen freezer 24.
FIG. 2 further illustrates the pump of the present extruder. Semi-fluid material is applied through a conduit 15 from the blenders 14a and 14b (FIG. 1) to pump 16. Pump 16 may comprise any suitable type of pump, such as a Crepaco auger feed pump with a de-aerating head, which may be operated to force the semi-fluid material through the distribution line 18 at a prescribed flow rate. A pressure gauge 59 communicates with the distribution line 18 in order to enable pump 16 to be manually adjusted to maintain the desired pressure and flow rate. Semi-fluid material flows through the distribution line 18 to extrusion manifold 20 in the manner previously described.
As previously described, rectangular outlet 40 is smaller in diameter than inlet 38 to the manifold 20. Outlet 40 is connected to flexible conduit 22 which leads to metering pump 42. Pump 16, distribution line 18, extrusion manifold 20 and pump 42 are preferably comprised of stainless steel for cleanliness of operation. Metering pump 42 is commonly driven from a DC motor (not shown). The metering pump operates to provide equal pressure, flow rate speed and consistency of the semi-fluid material across extrusion nozzle 48. The head pressure applied to metering pump 42 is greater than the output from the pump in order to enable constant extrusion and to enable control of the density and weight of the resulting emulsion extruded. For example, the head pressure applied to pump 42 may be 40 PSI, with the output pressure from the pump being 10 PSI. Nozzle 48 is particularly designed to provide even extrusion distribution and to prevent uneven density throughout the extruded product.
FIG. 3 illustrates in greater detail extrusion manifold 20 used to mold the semi-fluid material from the configuration defined by distribution line 18 to the continuous rectangular sheet of material extruded from outlet 40 of the manifold. Manifold 20 is provided with a generally conical cross-sectional configuration at inlet 38. Inlet 38 includes thread 62 for threadedly receiving distribution line 18. The conical end of manifold 20 gradually flattens to become rectangular outlet 40 opposite inlet 38. As previously noted, outlet 40 is connected to flexible conduit 22 by way of metering pump 42 as shown in FIG. 2.
Referring to FIG. 3, guide ribs 64 are provided on the inner surface of manifold 20 to guide the sausage material evenly from inlet 38 to rectangular outlet 40 opposite thereto. These ribs assure the movement of the semi-fluid material to the full length of rectangular outlet 40 of the manifold and eliminate any voids which might otherwise result from the passage of the material through the manifold.
FIG. 4 shows a sectional view of manifold 20 in the intermediate transition area between inlet 38 and outlet 40. Ribs 64 are shown extending from both the upper and lower walls of the manifold.
FIG. 5 illustrates the configuration of the extrusion manifold near outlet 40. At this point, ribs 64 are tapered away so as not to interfere with the rectangular configuration discharged from the manifold. Thus, as the semi-fluid material passes out of the manifold, it takes the form of a relatively thin evenly distributed rectangular sheet of material.
FIG. 6 illustrates extrusion nozzle 48 which forms the continuous sheet of semi-fluid material to be delivered into freezer 24. Flexible conduit 22 has been eliminated from FIG. 6 for clarity of illustration. Referring to FIG. 6, it will be seen that nozzle 48 slants downwardly toward the metal mesh, endless belt conveyor 58 which travels into freezer 24. Nozzle 48 is removably mounted in a housing 72, mounted on rod 74 (FIG. 7) to form the previously described nozzle support housing 50.
FIG. 7 illustrates in greater detail the interconnection of nozzle 48 to rod 74. Rod 74 extends horizontally across the belt conveyor 58 and is attached at opposite ends to the parallel linkages comprising arms 52, 54 and bar 56 (FIG. 6) previously described. Housing 72 is rigidly mounted along the rod 74.
Housing 72 includes two mating sections 72a and 72b interconnected by suitable means such as bolts 80. The lower section 72a of housing 72 is provided with a rectangular cutout along its entire upper length for receiving nozzle 48 therein. Nozzle 48 includes an enlarged front portion 48a for abutting with the front edge of lower section 72a and upper section 72b. Nozzle 48 includes a rearwardly extending portion 48b for connection to flexible conduit 22. This rearwardly extending portion also includes an enlarged section in order to facilitate a fluid-tight connection to the flexible conduit. Therefore, by positioning nozzle 48 within the rectangular cutout of housing 72 and assembling the upper section 72b thereabove, nozzle 48 is securely attached within housing 72.
Lower section 72a is further adapted with a circular bore 82 extending along its entire longitudinal length and below the rectangular cutout provided for nozzle 48. Bore 82 is adapted to receive rod 74 into frictional engagement. In addition thereto, set screws 84 may be provided for insertion through the lower side of housing 72 to engage rod 74 to maintain rod 74 fixed within housing 72 during operation.
When it is desired to clean the system, the upper portion of housing 72 is simply removed by removing bolts 80 and releasing nozzle 48 for cleaning. All of the elements shown in FIG. 7 are made of stainless steel to facilitate cleaning.
As shown in FIG. 6, in operation of the invention, continuous sheet 23 of semi-fluid material is extruded from nozzle 48. A stainless steel extrusion form 90 may be attached to conveyor 58 in order to guide continuous sheet 23 into the freezer while maintaining the sheet in the configuration in which it is extruded. Form 90 has a flat lower surface 90a and upright side members 90b to prevent the semi-fluid material from spreading out of its extruded configuration prior to chilling. Form 90 also facilitates the subsequent step of slicing the material as will hereinafter be described.
Alternatively, conveyor 58 may be adapted with vertical side members corresponding to the edges of the extruded continuous sheet of material. In this embodiment, the extruded material is deposited directly on the belt conveyor and carried into freezer 24.
Referring to FIG. 6, conveyor 58 is moving at the same speed as continuous sheet 23 is being extruded or in the preferred embodiment, at approximately 15 feet per minute. Similarly, form 90, where used, moves at the same speed as belt conveyor 58. The extruded continuous sheet 23 is promptly moved by conveyor belt 58 into the nitrogen freezer 24 (FIG. 1) whereupon the continuous sheet is immediately chilled to an extent that it maintains its cross-sectional shape. The present process is carried out in a room having an ambient room temperature of approximately 50° F. The freezer is provided with a temperature of approximately -170° F. in order to chill the interior of continuous sheet 23 to approximately -10° F. Nitrogen or fluorocarbon liquid may be sprayed on the sausage or underneath the conveyor in order to quickly chill the sausage.
When the system is initially turned on for operation, continuous sheet 23 initially extruded may not be of a desired consistency or at the desired flow rate. Thus, a handle 98 is provided on the parallelogram linkage comprised of arms 52, 54 and bar 56 in order to enable nozzle 48 to be raised away from contact with conveyor 58. Referring to FIG. 9, the dotted line position illustrates the upward position of nozzle 48 when in the raised position. In this position, the extruded material may be extruded into a dump bucket (not shown), until the material reaches the desired consistency or flow rate. At such time, the dump bucket may be removed and the parallelogram linkage moved downwardly by grasping handle 98 and pushing downwardly until nozzle 48 is again oriented at the desired angle to the conveyor as shown in FIG. 6.
Referring to FIG. 10, slicer 25 and cutter unit 26 of the invention are illustrated in detail. As previously noted, cutter unit 26 is located at the output of freezer 24 which delivers the continuous sheet 23 of chilled pork sausage to the cutter unit. Chilled sheet 23 is directed to extrusion form 90 which includes base 90a and vertical sides 90b corresponding to the width of the continuous sheet. The sheet is thus guided past a plurality of vertically suspended rotatable cutting disks 102 where the sheet is sliced into a plurality of equal width continuous lengths 104 of chilled material. Lengths 104 are then carried by conveyor 58 to an elongated vertical knife blade 106 which is reciprocated in a manner to be subsequently described in synchronism with a horizontal bed 108. A hold-down roller 110 is disposed in front of blade 106 in order to hold the continuous links down during the severing operation by knife blade 106. A back board 112 is disposed over blade 106.
As indicated above, slicing of the continuous sheet 23 into a plurality of equal width continuous lengths 104 is accomplished by the action of rotatable cutting disks 102. As shown in FIG. 11, disks 102 are rotatably assembled along horizontal bar 116. The ends of bar 116 are fixedly supported by a sleeve support member 118 which slidingly engages upper rod 120. Sleeve member 118 is adapted with a collar 122 and rod 120 is adapted with a corresponding flange 124 to permit limited translation of sleeve 118 along rod 120. A compression spring 126 is assembled between the lower end of rod 120 and a seat 118a provided at the lower end of sleeve support member 118. Compression spring 126 acts against rod 120 to apply a downward force upon rod bar 116 and thus engage cutting disks 102 against the chilled sausage material passing below disk 102. Rod 120 is rigidly supported from arms 130 which extend from a suitable frame structure 132. An identical connection exists between bar 116 and frame structure 132 on the opposite end of bar 116. In this way, the cutting disks 102 are kept in proper slicing engagement against the chilled sausage material moving on conveyor 58.
As is seen in FIG. 11, form 90 is adapted with longitudinal indentions 134 which correspond with the cutting edge of cutting disk 102. These small indentions facilitate severing of the chilled sausage material into continuous lengths. Vertical sides 90b of form 90 can also be seen to prohibit the lateral flow of sausage material during cutting. FIG. 11 further illustrates the action of compression springs 126 against bar 116 in order to engage cutting disks 102 against the sausage material. Likewise, the compression springs may be adapted with an adjustment for selectively increasing or decreasing the force applied to cutting disks 102 as necessary to effect a proper cut.
Referring to FIG. 12, bed 108 reciprocates in a horizontal plane over rollers 142 and 144. The cutting assembly is mounted on a horizontal platform 146 supported by legs 148. The reciprocating movement of knife blade 106 and bed 108 is provided by an electrical motor 150 which operates a drive motor 152. The output shaft of motor 152 rotates a gear 154 which operates a timing belt 156. Belt 156 operates a gear 158 of a linear displacement cam 160.
The output shaft of the motor 152 also rotates a gear 162 which operates a timing belt 164. Belt 164 rotates a gear 166 attached to a second linear displacement cam 168. The output of motor 152 also rotates a gear 170 which moves a timing belt 172 which rotates a gear 174 of a third linear displacement cam 176. The three linear displacement cams 160, 168 and 176 operate in the known manner to translate rotary motion to linear motion. Suitable linear displacement cams are manufactured and sold by the Stelron Corporation.
A block 180 is mounted above the linear displacement cam 168, while a block 182 is mounted above the cam 176. A vertical post 184 is pivotally mounted at pivot point 186 to block 180. Similarly, a vertical post 188 is pivotally mounted at pivot point 190 to block 182. The tops of posts 184 and 188 are connected to blade 106. Operation of the linear displacement cams 168 and 176 thus serve to provide vertical movement to blade 106. Operation of the linear displacement cam 160 operates to provide horizontal reciprocational movement to the cutting blade 106 and bed 108.
The back board 112 is shown interconnected with knife blade 106. Posts 188 and 184 operate to provide vertical movement to knife blade 106 in order to sever the continuous lengths of sausage in the manner to be subsequently described. The bed 108 rides upon rollers 142 and 144 in the manner previously described. A rod 200 includes a plurality of rollers 202 thereon in order to hold the continuous lengths down during the cutting operation.
As previously noted, the linear displacement cams 168 and 176 operate to cause reciprocating vertical motion to the posts 184 and 188. Knife blade 106 is attached to the top of posts 184 and 188 by bolts 220 (not shown) and 222 such that blade 106 is moved up and down in order to cut the continuous lengths. Inasmuch as the continuous lengths are traveling perpendicular to the orientation of blade 106, blade 106 cuts each of the continuous lengths simultaneously.
Linear displacement cam 160 reciprocates a block 224 in a horizontal plane. Block 224 is attached by arms 226 and 228 to posts 184 and 188. Thus, arms 226 and 228 are moved horizontally, thereby causing the posts 184 and 188 to pivot about pivot points 186 and 190. The posts 184 and 188 thus swing back and forth in a limited arc in order to move knife blade 106 in a horizontal plane. This mechanism also causes the movement of the bed 108 on a horizontal plane.
It will be seen from FIG. 12 that the posts 184 and 188 and the arms 226 and 228 may be selectively adjusted to any of several desired positions in order to allow the movement of blade 106 and bed 108 to be selectively adjusted. In this manner, the length of cuts made by the cutting blade may be selectively adjusted in order to enable the weight of the final discrete product to be selectively adjusted.
FIGS. 13a-13d illustrate the cutting operation of blade 106 and bed 108. Referring to FIG. 13a, blade 106 is shown in its initial starting position just behind roller 142 which operates to maintain continuous length 104 against bed 108. During operation of the device, knife blade 106 covers a reciprocating path indicated by the dotted line 234. That is, knife 106 moves along with length 104 for a short distance and is then moved downwardly in order to sever length 104. Subsequently, knife blade 106 is moved upwardly and is then raised and moved to the original starting position shown in FIG. 13a. Roller 142 rotates in the direction illustrated during operation of blade 106.
FIG. 13b illustrates how the knife blade 106 has been moved to the right in synchronism with movement of bed 108 and then moves downwardly in order to sever length 104. Inasmuch as blade 106 and bed 108 are traveling at the same rate as the length 104, the lengths do not have to be stopped to enable severing thereof.
FIG. 13c illustrates the final severing of length 104. As shown in FIG. 13c, bed 108 includes a depression 236 which receives the foremost edge of blade 106 in order to insure that the blade passes completely through length 104. Moreover, FIG. 13c illustrates the particular shape of knife blade 106. The lower-most portion 238 of the blade is relatively narrow and is maintained with a very sharp lower point. The upper portion 240 of the blade is wider than the lower portion. The two portions are separated by a beveled portion 242. The lower portion 238 is thus utilized to make the initial cut through length 104. The upper and wider portion 242 acts to push the severed portion of length 104 away from the uncut portion, and thus tends to break and completely sever any fibers which would tend to prevent clean cutting.
After the blade has made its downward descent as shown in FIG. 13c, the blade is raised while still traveling in the direction and at the same rate as length 104 until it reaches the position shown in FIG. 13d. At this position, blade 106 and bed 108 change horizontal direction as shown by arrow 246 (FIG. 13d) and move back to the original starting point as shown in FIG. 13a. Continuous length 104 has thus been severed by the knife blade 106. The blade 106 is continuously moved in the path shown by the dotted line 234 in order to periodically cut off identical lengths of product. In this way, products of exact weight, volume and consistency may be maintained. If desired, the volume, consistency, flow rate or length of cutting path of blade 106 may be varied in order to change the volume or weight or consistency of the final product. For a more detailed description of the operation of knife blade 106 and bed 108, during severing of continuous length 104, reference can be made to copending application, Ser. No. 610,301, filed Sept. 4, 1975, which is incorporated herein by reference.
FIG. 14 illustrates the output at cutter unit 26 which operates in the manner previously described. A downwardly sloping dispensing surface 260 extends from the output of the cutter unit and a plurality of discrete sausage lengths 262 may be seen to be dispensed from cutter unit 26. The products 262 roll and slide downwardly to a conveyor 264 whereupon products are conveyed to loading station 28.
As previously noted, a particular advantage to the present invention is that very accurate portion control may be provided for the present products. Thus, each of the products 262 may be formed with the same volume and size and weight so that a discrete number of the products may be packaged in individual cartons. For example, each of the products 262 may be cut in weigh one-ounce, and thus sixteen one-ounce products may be packaged together to provide a one-pound package. With the use of the present invention, a very accurate weight is maintained with each product. However, if the weight is desired to be changed, the system may be easily varied to change the weight. The product 262 is already frozen when packaged, and thus additional hard freezing is not required after packing.
FIG. 15 illustrates another embodiment of the cutter unit. A continuous sheet 270, having a rectangular cross-section, is illustrated as having been extruded and then chilled as previously described. The sheet is applied through a cutting station which includes a rotating cutting drum 272 including a cylindrical drum 273 having a plurality of slicing disks 274 equally spaced along a longitudinal length thereof and a plurality of equally spaced cutting blades 276 along the longitudinal length thereof. The cutting drum 272 is rotatably supported on axis rod 278 which is supported in a fashion similar to the support and spring structure defined with respect to the cutting disks illustrate and described with respect to FIG. 10. Thus, cutting drum 272 is engaged against the continuous sheet of chilled material which passes beneath the cutting drum as it is carried by the belt conveyor 58. The pressure of the cutting drum against the sheet of chilled material results in the severing of a plurality of rectangular products 280 which are then carried on the conveyor to a packaging station.
FIG. 16 illustrates a cross-sectional view taken along a vertical plane through the longitudinal axis of cutting drum 272. In this embodiment of the invention, belt conveyor 58 is provided with a plurality of longitudinal indentions 282 corresponding to the cutting edges of the slicing disks 274 in order to facilitate the complete severing of the chilled pork sausage. Similarly, the conveyor surface may likewise be adapted with transverse indentions 284 corresponding to the longitudinal cutting blades 276 extending longitudinally along cutting drum 272 (FIG. 15). In this case, the rotation of the cutting drum must be synchronized with the movement of conveyor 58 in order that longitudinal blades 276 mate with transverse indentions 284.
FIG. 17 illustrates another embodiment of the severing device used in the present invention. Again, a continuous sheet 270 of chilled sausage material is illustrated as it moves on conveyor 58 from freezer 24. The continuous sheet of chilled material is carried on conveyor 58 through a cutting station which includes a dual conveyor system for stamping discrete predetermined shapes of sausage material and carrying the severed shapes to an appropriate packaging station.
The first conveyor system includes an endless conveyor 300 entrained for continuous movement around drums 302 and 304 which are powered by an appropriate power means, such as an electric motor (not shown). Conveyor 300 has its longitudinal axis aligned with the longitudinal axis of material conveyor 58 and is positioned for rotation directly above conveyor 58, but having an opposite rotational direction. Conveyor 300 is adapted with a plurality of annular chambers extending the full width of the conveyor, such as chamber 300a, between its inner and outer surfaces. A plurality of stamping modules 306 extending perpendicularly from the outer surface of conveyor 300 and communicate with one of the annular chambers as hereinafter described.
Stamping modules 306 are adapted with a cutting configuration having a cylindrical or other desired shaped face 308 and corresponding cutting sidewall 309 extending therefrom to form a cup-like cutting unit 310. A tubular shaft 312 is connected to the outer surface of face 308 and is joined to conveyor 300 by way of an actuator valve 314 which is capable of extending the cutting module in response to a predetermined signal applied thereto. Tubular shaft 312 also communicates with one of the annular chambers between the inner and outer surfaces of conveyor 300. A second conveyor 320 is rotatable about motorized drums 322 and 324 (not shown). Conveyor 320 has its longitudinal axis transverse to the axes of conveyors 58 and 300 with its upper path of travel between conveyors 58 and 300.
FIG. 18 illustrates a cross-sectional view taken along the longitudinal axis of conveyor 320 and showing the relationship of the stamping modules 306 with respect to the material conveyor 58 and conveyor 320. In operation of the unit, belt conveyor 300 is moved at a rate of speed equal to the speed of travel of conveyor 58 on which the continuous sheet of chilled pork sausage is carried. A predetermined signal is applied to selected rows of actuator valves 314 attached to each of the cutting units 310 as conveyor 300 moves over a predetermined point of its course. While not so limited, the signal may be an electrical signal communicated to a selected number of rows of stamping modules 306 by way of electrical leads 325 pass an electrical connection 327 supplying electrical current from a power source 329.
Referring to FIGS. 19a-19c, in response to the signal, tubular shaft 312 is extended, forcing the stamping module 306 against the chilled sausage material. The action of the cutting sidewall 309 against the chilled material results in the severence of a discrete portion of the material in the configuration defined by the cutting unit 310 (FIG. 19b). Simultaneously therewith, an opening 323 in annular chamber 300a moves into communication with a vacuum line 316 connected to an appropriate vacuum drawing system 317 for applying suction through each cutting unit 310 communicating with annular chamber 300a. This suction creates a vacuum to facilitate the withdrawal of the sausage material with the cutting unit. The cutting units 310 are withdrawn from the sheet of sausage (FIG. 19c) as conveyor 300 moves past the point at which the predetermined signal is communicated to actuator valves 314. It will be understood that the extension of the cutting units is carried out by simultaneously actuating a group of cutting units such that one area of the continuous sheet is stamped at one time. The cycle is repeated sequentially with respect to successive groups of units as they pass over the sheet of sausage material.
After withdrawal of the cutting units 310, the cutting units pass above transverse conveyor 320 which is continuously rotating therebelow. It will be noted that the cutting heads normal retracted position is a sufficient distance above material conveyor 58 such that the heads are above transverse conveyor 320 which passes above material conveyor 58. As the cutting units pass above transverse conveyor 320, annular chamber 300a moves out of communication with the vacuum source. Thus, the vacuum drawn above the severed material is removed and the discrete sausage products contained therein are ejected onto belt conveyor 320. It may be found benefical in some instances to apply air pressure against the back side of the severed material retained in the cutting units by applying a positive pressure through annular chamber 300a in order to assure the discharge of the discrete sausage products contained therein onto conveyor 320. The discharge of the discrete products onto the transverse conveyor 320 is accomplished without the interruption of the movement of the cutting units on conveyor 300. The cutting units continue to move about conveyor belt 300 and the process of stamping discrete sausage products from the continuous chilled material sheet 270 is continued on an uninterrupted basis.
It will be noticed that the cutting units 310 are closely positioned so as to minimize materials which are not severed in the stamping process. Where rectangular configurations are stamped from the continuous sheet of chilled material, the sausage material not cut by the stamping units will be minimized or eliminated altogether. Where a circular or other irregular design is desired, the sausage material not stamped by the cutting units 310 is recycled and fed back through extrusion manifold 20 (FIG. 1).
The discrete sausage products discharged onto conveyor 320 are carried on the conveyor to an appropriate packaging station where the products are packaged in desired quantities. It will be appreciated that in the above described embodiment, the severing and discharge steps are carried out without interrupting the movement of the cutter units on conveyor 300 or the conveyors 58 or 320.
As previously mentioned, although the present invention has been described with respect to preparing chilled pork sausage, it will be understood that the present apparatus and method may be utilized to produce a wide variety of products when it is desired to form a plurality of discrete products having the same weight, size and characteristics from a semi-fluid material.
Whereas the present invention has been described with respect to specific embodiments thereof, it will be understood that various changes and modifications will be suggested to one skilled in the art, and it is intended to encompass such changes and modifications as fall within the scope of the appended claims. | 1a
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CROSS-REFERENCE TO RELATED APPLICATION
[0001] N/A
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT
[0002] N/A
BACKGROUND OF THE INVENTION
[0003] 1. Field of the Invention
[0004] The invention relates to shoes, more specifically to a mechanism wherein a low heel shoe converts into a stable shoe structure with a higher heel wherein the shoe's heel can be removed or replaced to change the style or comfort of the shoe.
[0005] 2. Discussion of the Background
[0006] It is well known that women enjoy the use of high-heeled shoes. High-heeled shoes represent a number of benefits for women, including style, increased height and improved posture. Women tend to feel more confident and poised when wearing high-heeled shoes. High-heeled shoes are considered to add style and elegance to a woman's outfit and are a staple of modern fashion.
[0007] Despite the many benefits, high-heeled shoes have proven detrimental to women's health. The use of heels is often painful, resulting in blisters, calluses and corns. Their use has also been linked to long-term problems such as foot pain, back pain, varicosity, edema, and infertility. High-heeled shoes concentrate the entire weight of the body on the ball of the foot, which often results in painful conditions such as metatarsalgia. When wearing high-heeled shoes, the shape of the foot conforms to a shape which counters the natural functionality of the foot, creating odd pressure points and often resulting in permanent damage. High-heeled shoes can create difficulties when walking, resulting in injuries such as sprained ankles.
[0008] For occasions that require that women dress elegantly and/or professionally, modern women tend to prefer the use of high-heeled shoes. However, it is possible that high-heeled shoes will not be suitable for certain moments of a particular day. For example, a woman may prefer high-heeled shoes for the office, in order to look elegant and professional during meetings or when receiving clients. However, if the same woman walks to work, the woman may prefer the use of flats or shoes with smaller heels to avoid a painful walk. In this case, the woman would have to use two separate pairs of shoes in the same day. This creates the inconvenience of having to carry the additional pair of shoes or having to keep additional pairs of shoes in different places. There is also the added cost of purchasing more than one pair of shoes.
[0009] Several shoes had been created to provide interchangeable heels, however most of the interchangeable shoes structures, more particularly in women shoes failed to provide an interchangeable stable structure easy to assemble without compromising the style.
[0010] Further a woman may also prefer to change the style of a particular shoe. For example, a woman may prefer “stiletto” type heels that match the color of the shoe's upper for a formal occasion. For a more casual occasion, a woman may prefer the same shoe, but with thicker, cork wedges. Also, a woman may prefer to use an all black shoe for the office, but may decide to add color to the outfit by changing to a colored heel for a social activity after work.
[0011] There is a need for shoes that can be adjusted for the changing needs of a woman during a particular day while providing a stable structure easy to assemble.
SUMMARY OF THE INVENTION
[0012] In light of the above shortcomings of the methods available to adjust the height of women's shoes, the present invention discloses a replaceable heel mechanism that is used to adjust the height of women's shoes. The mechanism comprises a shoe sole, a removable heel comprising a heel connector and an interchangeable heel, and a locking key to secure the removable heel to the shoe sole. The present invention is useful for adjusting the comfort or style of a particular pair of shoes during the course of a day.
[0013] Another object of the present invention is to provide a shoe that can be worn with or without the removable heel.
[0014] Another object of the present invention is to provide a mechanism wherein a removable heel can be easily attached or removed.
[0015] Another object of the present invention is to provide a more stable removable heel wherein the arrangement of part assists the shoe structure to withstand several unwanted movement.
[0016] Yet another object of the present invention is to provide a mechanism wherein a heel can be easily removed and replaced with a heel with different style.
[0017] To enable a better understanding of the objectives and features of the present invention, a brief description of the drawing below will be followed with a detailed description of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] FIG. 1A is an isometric view of the preferred embodiment of the invention.
[0019] FIG. 1B is a view of the preferred embodiment of the invention assembled.
[0020] FIG. 2 is an isometric view of the shoe sole of the preferred embodiment.
[0021] FIG. 3 is a side view of the foresole of the preferred invention.
[0022] FIG. 4 is an isometric view of the foresole of the preferred embodiment.
[0023] FIG. 5 is a top view of the foresole of the preferred embodiment.
[0024] FIG. 6 is a top view of the midsole of the preferred embodiment.
[0025] FIG. 7 is a bottom view of the midsole of the preferred embodiment.
[0026] FIG. 8 is an isometric view of the midsole of the preferred embodiment.
[0027] FIG. 9 is a side view of the hindsole of the preferred embodiment.
[0028] FIG. 10 is an isometric view of the hindsole of the preferred embodiment.
[0029] FIG. 11 is a top view of the hindsole of the preferred embodiment.
[0030] FIG. 12 is a front view of the heel connector of the preferred embodiment.
[0031] FIG. 13 is a top view of the heel connector of the preferred embodiment.
[0032] FIG. 14 is an isometric view of the heel connector of the preferred embodiment.
[0033] FIG. 15 is a side view of the interchangeable heel of the preferred embodiment.
[0034] FIG. 16 is a top view of the interchangeable heel of the preferred embodiment.
[0035] FIG. 17 is an isometric view of the interchangeable heel of the preferred embodiment.
[0036] FIG. 18 is an isometric view of a screw.
[0037] FIG. 19 is an isometric view of the removable heel assembly of the preferred embodiment,
[0038] FIG. 20 is an isometric view of the locking key of the preferred embodiment.
[0039] FIG. 21 is a top view of the locking key of the preferred embodiment.
[0040] FIG. 22 is an isometric view of the locking key nut of the preferred embodiment.
[0041] FIG. 23 is top view of the locking key screw of the preferred embodiment.
[0042] FIG. 24 is an isometric view of the locking key nut of the preferred embodiment.
[0043] FIG. 25 vectors force distribution for the preferred embodiment.
DETAILED DESCRIPTION OF THE INVENTION
[0044] The present invention discloses the preferred embodiment of the invention wherein the embodiment can be made of different materials, wherein the material selection depends on the type of shoes, the weather in which the shoes will most likely be used, the size of the shoes and the cost.
[0045] FIG. 1A and FIG. 1B show the present invention as it is assembled. The present invention comprises a shoe sole 1 , a removable heel R, a locking key 4 and a shoe upper 5 . The removable heel R comprises a heel connector 2 and an interchangeable heel 3 wherein said removable heel is mechanically connected to said shoe sole 1 in order to convert a low heel shoe in to a high heel shoe. As illustrated in FIG. 1B the shoe upper 5 is attached to the shoe sole an it may be anything from a few thin straps to totally enclosing the foot.
[0046] FIG. 2 shows an isometric view of the assembled shoe sole 1 . It has to be understood that the shoe upper 5 is not showed in order to clearly show the shoe sole 1 . The shoe sole 1 comprises an adjustable platform on the bottom of the shoe. The platform comprises three separate flat sections, named foresole 11 , midsole 12 and hindsole 13 . The sections are mechanically attached and are fixed to the bottom of the shoe.
[0047] FIG. 3 , FIG. 4 and FIG. 5 show the foresole 11 component of the preferred embodiment of the invention. The foresole 11 comprises a flat elongated component with at least one even edge 111 . The foresole's even edge 111 comprises a fixing means to attach the part to another part that allows rotational motion. The fixing means of the preferred embodiment comprises several semi-circular protrusions 112 along the even edge 111 , each comprising a hole 113 . Several spaces 114 or clear areas having a pre-determinated are interpose between each semi-circular protrusion 112 in order to separates each semi-circular protrusion 112 from each other. The holes 113 at the semi-circular protrusions 112 are centrally aligned in order to be easily mechanically coupled to the midsole 12 . The geometry of the remaining edges of the foresole 11 depends on the style of the shoe and the shoe upper 5 . The foresole 11 supports the forefoot, which comprises the ball of the foot and the toes.
[0048] FIG. 6 , FIG. 7 and FIG. 8 show different views of the midsole 12 of the preferred embodiment of the invention. The midsole 12 comprises a flat elongated body with a first short edge 121 , second short edge 122 and a middle body, such as a rectangular component, which extends across the length of the shoe. The midsole 12 comprises a first short edge 121 and a second short edge 122 , opposite to one another, and a middle body between said first short edge and said second short edge define by a first long edge 123 and a second long edge 124 . In the instant case the angles between the first short edge 121 and the first long edge 123 , the first long edge 123 and the second short edge 122 , the second short edge 122 and the second long 124 ; and the second long edge 124 and the first short edge 121 are all right angles. The first short edge 121 and the second short edge 122 are equipped with a first short edge attaching mechanism and a second short edge attaching mechanism respectively to attach the midsole to another part allowing rotational motion at the midsole edges. Similar to foresole attaching mechanisms, the first short edge attaching mechanism and a second short edge attaching mechanism of the preferred embodiment comprises semi-circular protrusions 126 along their length, each semi-circular protrusion 126 comprising a hole 127 . Several spaces 128 of a pre-determinated width separate each semi-circular protrusion 126 from the next semi-circular protrusion 126 . The holes 127 in the semi-circular protrusions 126 are centrally aligned. The position of the semi-circular protrusions 126 of the first short edge 121 of the midsole 12 coincides with the spaces 114 between the semi-circular protrusions 112 of the foresole 11 . The position of the semi-circular protrusions 126 of the second short edge 121 of the midsole 12 coincides with the position of the semi-circular protrusions 126 of the first short edge 121 . The midsole 12 lies below the arch of the foot, and provides support to the midfoot. The width of the midsole 12 corresponds to the width of the foresole 11 . The length of the midsole 12 depends on the style and size of the shoe.
[0049] Further the midsole 12 comprises a first attaching mean, such as a orifice 129 , positioned at the middle body inside a groove. In the instant case the preferred embodiment of the orifice 129 comprises inner threads. The groove is deep enough to enclose the attaching mean avoiding it contact with the floor.
[0050] FIG. 9 , FIG. 10 and FIG. 11 show different views of the hindsole 13 component of the preferred embodiment of the invention. The hindsole 13 elongated body comprises a foundation 131 , a spacer 132 and a brim 133 . The hindsole 13 supports the hindfoot, which comprises the heel of the foot.
[0051] The foundation 131 comprises a flat elongated component with at least one rounded edge 1311 and at least one foundation even edge 1312 . The foundation 131 comprises a attaching means at said foundation even edge 1312 to attach the hindsole to another part, such as the midsole, allowing rotational motion at the mechanically connection between the hindsole and the midsole. The attaching means of the preferred embodiment comprises several semi-circular protrusions 1313 along the even edge 1312 , each comprising a hole 1314 . A space 1315 of the equal or greater width than the semi-circular protrusion 1313 separates each semi-circular protrusion 1313 from the next semi-circular protrusion 1313 . The holes 1314 in the semi-circular protrusions 1313 are centrally aligned. The size and position of the semi-circular protrusions 1313 of the foundation 131 depends on the size and position of the semi-circular protrusions 126 of the second short edge 122 of the midsole 12 . The position of the semi-circular protrusions 1313 of the even edge 1312 of the foundation 131 coincides with the spaces 128 between the semi-circular protrusions 126 of the second short edge 122 of the midsole 12 . The semi-circular protrusions 1313 of the hindsole 13 must fit between the semi-circular protrusions 126 of the second short edge 122 of the midsole 12 . The center of the holes 1313 of the semi-circular protrusions 13 must fit be aligned with the holes 127 of the semi-circular protrusions 126 of the midsole 12 . Although the geometry of the foundation 131 may vary slightly depending on the style of the shoe, the shape of the foundation 131 will most likely comprise a semi-circular geometry.
[0052] Further the spacer 132 comprises a second flat component with geometry similar to the geometry of the foundation 131 . Like the foundation 131 , the spacer 132 comprises at least one spacer even edge 1321 . The length, radius and overall dimensions of the spacer 132 is smaller than the dimensions of the foundation 131 . The spacer 132 is integrally made or attached to the foundation 131 by a fixing means such as glue, nails, or screws and extends from the foundation 131 toward the brim 133 .
[0053] The brim 133 comprises a third flat component with geometry similar to the geometry of the foundation 131 . Like the foundation 131 , the brim 133 comprises at least one brim even edge 1331 . In the instant case the length, radius and overall dimensions of the brim 131 are smaller than the dimensions of the foundation 131 , but greater that the dimensions of the spacer 132 . The brim 133 is integrally made or attached to the spacer 132 by a fixing means such as glue, nails, or screws.
[0054] The foundation even edge 1312 of the foundation 131 is aligned with the spacer even edge 1321 and the brim even edge 1331 . When assembled, the hindsole 13 comprises a part with at least one even edge, at least one rounded edge, several semi-circular protrusions 1313 and a groove created by the differences in dimension of the foundation 131 , the spacer 132 and the brim 133 .
[0055] The foresole even edge 111 is mechanically attached to a first short edge 121 of the midsole 12 . The semi-circular protrusions 126 of the first short edge 121 of the midsole 12 are positioned in the spaces 114 between the semi-circular protrusions 112 of the foresole 11 . The holes 113 of the semi-circular protrusions 112 of the foresole 11 are centrally aligned with the holes 127 of the semi-circular protrusions 126 of the first short edge 121 of the midsole 12 . A first pin is inserted through the holes 113 , 127 , keeping the foresole 11 attached to the midsole 12 . The foresole 11 and the midsole 12 is able to move with respect to one another about the axis of the first pin. Alternatively, the parts can be manufactured without the semi-circular protrusions 112 , 126 and attached to each other by a fixing means such as hinges.
[0056] The foresole even edge 111 of the hindsole 13 is mechanically attached to a second short edge 121 of the midsole 12 . The semi-circular protrusions 126 of the second short edge 122 of the midsole 12 is positioned in the spaces 1315 between the semi-circular protrusions of the foundation 131 of the hindsole 13 . The holes 1314 of the semi-circular protrusions 1313 of the foundation 131 of the hindsole 13 is centrally aligned with the holes 127 of the semi-circular protrusions 126 of the second short edge 122 of the midsole 12 . A second pin is inserted through the holes 1314 , 127 of the semi-circular protrusions 1313 , 126 , keeping the hindsole 13 attached to the midsole 12 . The hindsole 13 and the midsole 12 is able to move with respect to one another about the axis of the pin. Alternatively, the parts can be manufactured without the semi-circular protrusions 126 , 1313 and attached to each other by a fixing means such as hinges.
[0057] When assembled, the shoe sole 1 comprises an elongated mechanism with two points of inflection. The upper side of the shoe sole 1 comprises the inner section of the shoe. The upper side of the shoe sole 1 is covered with a soft material in order to provide comfort for the user. The bottom side of the shoe sole 1 may be covered with a non-slip material, such as rubber.
[0058] FIG. 12 , FIG. 13 and FIG. 14 show different views of the removable heel R, more particularly the heel connector 2 component of the preferred embodiment of the invention. The heel connector 2 comprises an elongated flat portion with a geometry that matches the geometry and dimensions of the hindsole 13 . The heel connector 2 comprises at least one heel connector even edge 21 , and at least one rounded heel connector edge 22 . The heel connector 2 also comprises a raised rim 23 extending upwards throughout the entire perimeter of the geometry, with exception of the heel connector even edge 21 . The raised rim 23 has an extended rim 24 facing the inner portion of the heel connector 2 . The length of the extended rim 23 must be less than the difference between the brim 133 and the spacer 132 of the hindsole 13 .
[0059] The extended rim 24 of the heel connector 2 slides between the foundation 131 and the brim 133 of the hindsole 13 , keeping the hindsole 13 and the heel connector 2 attached to one another. Further the heel connector comprises a heel attaching mean 25 .
[0060] FIG. 15 , FIG. 16 and FIG. 17 show different views of the interchangeable heel 3 of the preferred embodiment of the invention. The interchangeable heel 3 comprises an elongated component comprising an angled proximal end 31 and a distal end 32 . The geometry of the angled proximal end 31 of the interchangeable heel 3 resembles the geometry of the heel connector 2 . The angle of the angled proximal end 31 depends on the difference in height between the foresole 11 and the hindsole 13 , that is, the angle depends on the overall length of the interchangeable heel 3 . The cross-sectional geometry of the interchangeable heel 3 can vary throughout the length, for example the elongated body may have a constant cross-sectional area throughout its length, or a variable cross-sectional area, with greater width at the angled proximal end 31 and a smaller geometry at the distal end 32 . Other geometries can also be found, including wedges that extends all the way towards the foresole 11 , covering the entire area below the shoe sole 1 . Each interchangeable heel 3 comprises a hole 34 at a pre-determinated position wherein said position is directly related to the position of the orifice 129 in the midsole 12 , wherein said orifice 129 coincides with the height of the hole 34 in the interchangeable heel 3 .
[0061] Further the interchangeable heel 3 comprises a hole 33 aligned in accordance with the heel attaching mean 25 . The hole 33 on the interchangeable heel 3 comprises an inner thread placed in a position such that the holes 25 , 33 such as a screw 35 is inserted through the hole 25 in the heel connector 2 and is held in place by the inner thread in the hole 33 in the interchangeable heel 3 , holding the heel connector 2 and the interchangeable heel 3 in place. An example of the screw 35 is shown in FIG. 18 . FIG. 19 shows an isometric view of the assembly for the removable heel R composed by the heel connector 2 and the interchangeable heel 3 .
[0062] FIG. 20 , FIG. 21 , FIG. 22 and FIG. 23 show different views of the locking key 4 component of the preferred embodiment of the invention. The locking key 4 mechanically attaches the interchangeable heel 3 to the midsole 12 wherein said locking key comprises an elongated body with a first locking key attachment, such as a bolt with a first threaded distal end 47 . The locking key 4 is meant to be inserted into the hole 34 of the interchangeable heel 3 and fix inside the orifice 129 of the midsole 12 . The locking key 4 further comprises a second threaded distal end 46 , wherein said second threaded distal end is fixed at said interchangeable heel 3 . Providing two threaded distal ends at said locking key 4 assists with the assembling process of the interchangeable heel 3 for a stable structure. It is important to understand that a nut may be included in a first recess 48 at the interchangeable heel 3 , as shown in FIG. 24 , wherein said recess support a nut which is fixed to said interchangeable heel. The shape of the recess 48 assists with the assembling process by holding the nut 44 in position.
[0063] When in use, the bottom surface of the foresole 11 rests flat above the floor. The midsole 12 is attached to the foresole 11 and is positioned at an angle with respect to the floor. The angle between the floor and the midsole 12 depends on the height of the interchangeable heel 3 . The hindsole 13 is attached to the midsole 12 , and is also positioned at an angle with respect to the floor. The angle between the hindsole 13 and the floor is less than the angle between the midsole 12 and the floor. The heel connector 2 and the interchangeable heel 3 are attached by a fixing means, such as a screw 34 . The heel connector 2 slides into the groove between the foundation 131 and the brim 133 of the hindsole 13 . When correctly assembled, the distal end 32 of the interchangeable heel 3 comes into contact with the floor.
[0064] The locking key 4 is positioned in parallel with respect to a line that connects the distal end 32 of the interchangeable heel 3 and the foresole 11 . When in use, the bottom surface of the foresole 11 and the distal end 32 of the interchangeable heel 3 comes into contact with the floor. The user inserts her feet into the shoe, with the ball of the foot resting on the upper surface of the foresole 11 and the heels resting on the upper surface of the hindsole 13 . The user's weight is distributed between the ball of the foot and the interchangeable heel. The position of the locking key 4 lies between both pressure points and distributes the user's weight more evenly among the different areas of the shoe.
[0065] The heel connector 2 principally restricts vertical movement between the shoe sole 1 and the interchangeable heel 3 . The locking key 4 principally restrict horizontal motion between the interchangeable heel 3 and the shoe sole 1 , completing the structure. However due to the positioning of the locking key with respect to the heel connector a more stable structure is acquired. For example, as shown in FIG. 25 , the resulting force due to the person's weight wearing the removable heel 3 is distributed over the whole structure providing a more stable structure. The triangular shape created due to the arrangement of parts, such as having at least approximately a 90 degrees angle between the interchangeable heel 3 and the midsole 12 increases the supporting force of the shoe structure when using a removable heel R. Further the locking key 4 avoids the unwanted rotational motion of the interchangeable heel 3 and simultaneously the unwanted distance displacement of the midsole 12 with respect to the interchangeable heel 3 . The present structure arrangement provides a stronger support for the ankle due to the connection, more particularly to the connection of the interchangeable heel 3 with the midsole 12 .
[0066] Alternatively, the shoe can be worn without the heel connector 2 or the interchangeable heel 3 . The locking key 4 is removed and the heel connector 2 slides from behind the hindsole 13 . The attacing means that attach the foresole 11 to the midsole 12 and the midsole 12 to the hindsole 13 allows the rotational motion of each part, therefore the angles between the foresole 11 and the midsole 12 and the midsole 12 and the hindsole 13 can be adjusted. The shoe sole 1 is adjusted such that the brim 133 of the hindsole 13 comes into contact with the floor.
[0067] The interchangeable heel 3 may vary is style and shape different style with an easy assembling procedure such as removing or disconnecting the heel connector attaching mean 25 from the heel attaching mean 33 . The screw 35 is removed, separating the interchangeable heel 3 from the heel connector 2 . A different interchangeable heel 3 is attached to the heel connector 2 and the screw 35 is replaced. The heel connector 2 slides onto the hindsole 13 , and the locking key 4 is inserted through the hole 34 of the interchangeable heel and into the orifice 129 of the midsole 12 to complete the structure.
[0068] Further the interchangeable heel 3 can be replaced with a interchangeable heel 3 with a different height. For this feature, the midsole 12 must comprise more than one orifice 129 and additional locking keys 4 with different lengths will be needed. The position of each orifice 129 depends on the height of the interchangeable heel 3 . The screw 35 is removed, separating the interchangeable heel 3 from the heel connector 2 . A different interchangeable heel 3 is attached to the heel connector 2 and the screw 35 is replaced. The heel connector 2 slides onto the hindsole 13 , and the locking key 4 is inserted through the hole 34 of the interchangeable heel 2 and into the correct orifice 129 of the midsole 12 to complete the structure. When inserted into the correct orifice 129 , the locking key 4 will be positioned parallel to the floor.
[0069] The shoe upper comprises all materials above the shoe sole. The shoe upper depends on the style of the shoe. The shoe upper can comprise straps to attach the show sole to the foot, or can comprise a more elaborated covering to protect the foot. The material used for the upper can also vary depending on the style of the shoe and the weather it is used in.
[0070] In summary of the previous sections, the invention presented here is structurally innovative, presents advantages not available at the moment with existing shoes, complies with all new patent application requirements and is hereby lawfully submitted to the patent bureau for review and the granting of the commensurate patent rights.
[0071] While the invention has been described as having a preferred design, it is understood that many changes, modifications, variations and other uses and applications of the subject invention will, however, become apparent to those skilled in the art without materially departing from the novel teachings and advantages of this invention after considering this specification together with the accompanying drawings. Accordingly, all such changes, modifications, variations and other uses and applications which do not depart from the spirit and scope of the invention are deemed to be covered by this invention as defined in the following claims and their legal equivalents. In the claims, means-plus-function clauses, if any, are intended to cover the structures described herein as performing the recited function and not only structural equivalents but also equivalent structures.
[0072] All of the patents, patent applications, and publications recited herein, and in the Declaration attached hereto, if any, are hereby incorporated by reference as if set forth in their entirety herein, All, or substantially all, the components disclosed in such patents may be used in the embodiments of the present invention, as well as equivalents thereof. The details in the patents, patent applications, and publications incorporated by reference herein may be considered to be incorporable at applicant's option, into the claims during prosecution as further limitations in the claims to patentable distinguish any amended claims from any applied prior art. | 1a
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CROSS REFERENCE
This is a continuation of application Ser. No. 07/974,863, filed Nov. 10, 1992, now abandoned, which is a continuation-in-part of Ser. No. 07/785,137, filed Oct. 30, 1991, now abandoned.
BACKGROUND OF THE INVENTION
U.S. Pat. No. 3,652,589 discloses a class of analgesic cycloalkanol-substituted phenol esters having a basic amine group in the cycloalkyl ring. The compound (1R, 2R or 1S, 2S)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)-cyclohexanol, commonly known as tramadol, is specifically disclosed therein. A series of articles pertaining to the pharmacology, toxicology and clinical studies of tramadol are found in Arzneim, Forsch. (Drug Res.), 28(I), 114 (1978). Driessen et al., Arch. Pharmacol., 341, R104 (1990) disclose that tramadol produces its analgesic effect through a mechanism that is neither fully opioid-like nor non-opioid-like. The Abstracts of the Vlth World Congress on Pain, Apr. 1-6 (1990), disclose that tramadol hydrochloride is an orally active pure agonist opioid analgesic. However, clinical experience indicates that tramadol lacks many of the typical side effects of opioid agonists, e.g., respiratory depression (W. Vogel et al., Arzneim Forsch. (Drug Res.), 28(I), 183 (1978)), constipation (I. Arend et al., Arzneim. Forsch. ( Drug Res.), 28(I), 199 (1978)), tolerance (L. Flohe et, al., Arzneim. Forsch. (Drug Res.), 28(I), 213 (1978)), and abuse liability ( T. Yanagita, Arzneim. Forsch. (Drug Res.), 28(I), 158 (1978)). When given at a dose of 50 mg by rapid i.v. injection, tramadol may produce certain side effects unique to tramadol including hot flushes and sweating. Despite these side effects, tramadol's combination of non-opioid and opioid activity makes tramadol a very unique drug. Tramadol is currently being marketed by Grunenthal GMBH as an analgesic.
Opioids have for many years been used as analgesics to treat severe pain. They, however, produce undesirable side effects and as a result cannot always be given repeatedly or at high doses. The side effect problems are well documented in the literature. See, for example, J. Jaffe in "Goodman and Gilman's, The Pharmacological Basis of Therapeutics", 8th edition; Gilman et al.; Pergamon Press, New York, 1990; Chapter 22; pages 522-573 wherein it is disclosed that morphine and its congeners, e.g., codeine, hydrocodone and oxycodone, are opioid agonist analgesics that exhibit side effects such as respiratory depression, constipation, tolerance and abuse liability.
As alternatives to using opioids, non-opioids such as acetaminophen, aspirin and ibuprofen are used as analgesics. Ibuprofen, like aspirin, is not subject to the tolerance, addiction and toxicity of the opioid analgesics. However, ibuprofen, aspirin and other nonsteroidal antiinflammatory drugs (commonly referred to as NSAIDs) are only useful in relieving pain of moderate intensity, whereas the opioid analgesics are useful in relieving more intense pain; See Woodbury, D. and Fingl, E. in "The Pharmacological Basis of Therapeutics", 5th Ed.; Goodman, L. and Gilman, A., Chapter 15, (1975).
To reduce the side effect problems of opioids, opioids have been combined with other drugs including non-opioid analgesic agents, which lower the amount of opioid needed to produce an equivalent degree of analgesia. It has been claimed that some of these combination products also have the advantage of producing a synergistic analgesic effect. For example, A. Takemori, Annals New York Acad. Sci., 281,262 (1976) discloses that compositions including combinations of opioid analgesics with drugs other than analgesics exhibit a variety of effects, i.e., subadditive (inhibitory), additive or superadditive. R. Taber et al., J. Pharm. Expt. Thera., 169(1), 29 (1969) disclose that the combination of morphine and methadone, another opioid analgesic, exhibits an additive effect. U.S. Pat. No. 4,571,400 discloses that the combination of dihydrocodeine, an opioid analgesic, and ibuprofen, a non-opioid analgesic, provides superadditive effects when the components are within certain ratios. See also U.S. Pat. Nos. 4,587,252 and 4,569,937 which disclose other ibuprofen opioid combinations. A. Pircio et al., Arch. Int. Pharmacodyn., 235, 116 (1978) report superadditive analgesia with a 1:125 mixture of butorphanol, another opioid analgesic, and acetaminophen, a non-opioid analgesic, whereas a 1:10 mixture did not show any statistically significant superadditive analgesia.
Combinations of non-opioid analgesics have also been prepared to avoid the side effects associated with opioids, and the combinations are noted to have the benefit of requiring less of each ingredient and producing superadditive effects. G. Stacher et. al., Int. J. Clin. Pharmacol. Biopharmacy, 17, 250 (1979) report that the combination of non-opioid analgesics, i.e., tolmetin (another NSAID) and acetaminophen, allows for a marked reduction in the amount of tolmetin required to produce analgesia. In addition, U.S. Pat. No. 4,260,629 discloses that an orally administered composition of acetaminophen and zomepirac, a non-opioid analgesic, in a particular weight ratio range produces a superadditive relief of pain in mammals. Furthermore, U.S. Pat. No. 4,132,788 discloses that 5-aroyl-1-(lower)alkylpyrrole-2-acetic acid derivatives, non-opioid analgesics, when combined with acetaminophen or aspirin exhibit superadditive antiarthritic activity. However, there have been warnings against the daily consumption of non-opioid analgesic mixtures and of the consumption of a single non-opioid analgesic in large amounts or over long periods (see, D. Woodbury and E. Fingl at page 349). In addition, ibuprofen, aspirin and some other NSAIDs may cause gastrointestinal side effects especially if used repeatedly. See, for example, M. J. S. Langman, Am. J. Med. 84 (Suppl. 2A): 15-19, 1988; P. A. Insel in "The Pharmacological Basis of Therapeutics" 8th Ed.; Gilman, A.G. et al., Chapter 26, pp. 664-668, 1990.
The prior art, however, does not disclose that tramadol, an `atypical` opioid analgesic, can or should be combined with another analgesic to lessen the side effects of each or to yield a composition comprising a tramadol material and another analgesic that exhibits superadditive analgesia.
SUMMARY OF THE INVENTION
It has now been found that a tramadol material which includes various forms of tramadol as defined hereinafter can be combined with nonsteroidal antiinflammatory drugs (hereinafter NSAIDs) to produce analgesia. The combination employs lesser amounts of both the tramadol material and the NSAID than would be necessary to produce the same amount of analgesia if either was used alone. By using lesser amounts of both drugs the side effects associated with each are reduced in number and degree. Surprisingly, the compositions comprising the tramadol material and one or more NSAIDs have been found to exhibit synergistic analgesic effects when combined in certain ratios. Particularly preferred compositions are those comprising a tramadol material and ibuprofen. The compositions according to this invention may also be useful in treating tussive conditions.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 is an isobologram showing the analgesic effect of tramadol hydrochloride and ibuprofen composition on the acetylcholine-induced abdominal constriction in mice.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is generally directed to compositions comprising a tramadol material and an NSAID. The tramadol material is any one of (1R, 2R or 1S, 2S)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol (tramadol), its N-oxide derivative ("tramadol N-oxide"), and its O-desmethyl derivative ("O-desmethyl tramadol") or mixtures thereof. It also includes the individual stereoisomers, mixtures of stereoisomers, including the racemates, pharmaceutically acceptable salts of the amines, such as the hydrochloride salt, solvates and polymorphs of the tramadol material. Tramadol is commercially available from Grunenthal or may be made by the process described in U.S. Pat. No. 3,652,589, which is herein incorporated by reference.
Tramadol N-oxide is prepared by treating tramadol as a free base with an oxidizing agent, e.g., hydrogen peroxide (30%), in an organic solvent, e.g., methanol or isopropanol, with, but preferably without heating. See, "Reagents For Organic Synthesis", 1,471, Fieser & Fieser eds., Wiley N.Y.; (1987), B. Kelentey et al., Arzneim. Forsch., 7, 594 (1957). With heating, the reaction takes about 1 hour, whereas without heating the reaction takes about 3 days. Following the oxidation, the mixture is treated with an agent, e.g. PtO 2 or preferably Pt/C, for about a day, to destroy the excess hydrogen peroxide. The mixture is filtered, followed by the evaporation of the flitrate and then the residue is recrystallized from an organic solvent mixture, e.g., methylene chloride/ethyl acetate.
O-desmethyl tramadol is prepared by treating tramadol as a free base under O-demethylating reaction conditions, e.g., reacting it with a strong base such as NaH or KH, thiophenol and diethylene glycol (DEG) with heating to reflux. See, Wildes et al., J. Org. Chem., 36, 721 (1971 ). The reaction takes about an hour, followed by cooling and then quenching in water of the reaction mixture. The quenched mixture is acidified, extracted with an organic solvent such as ethyl ether, basified and then extracted with a halogenated organic solvent such as methylene chloride. The extract is then dried and the solvent evaporated to yield the O-desmethyl product, which may then be short-path distilled, converted to its corresponding salt, e.g., treated with an acidified (HCI/ethanol) solution, and recrystallized from an organic solvent mixture, e.g., ethanol/ethyl ether.
NSAIDs according to the present invention are non-opioid analgesics characterized in that they are nonsteroidal drugs which act as antiinflammatory, analgesic and anti-pyretic agents. This class of drugs is well known in the art. See for example, Goodman, L. and Gilman, A., supra, in Chapter 26 (1990). These drugs share certain therapeutic actions and side effects. Within this broad class of drugs are salicylates, such as aspirin; pyrazolone derivatives such as phenylbutazone, onyphenbutazone, antipyrine, aminopyrine, dipyrone and apazone; indomethacin; sulindac; fenamates such as mefenamic, meclofenamic, flufenamic, tolfenamic and etofenamice acids; aryl acetic acid and propionic acid compounds such as 2-(p-isobutylphenyl)propionic acid (generic name ibuprofen); alphamethyl-4-(2-thienylcarbonyl) benzene acetic acid (generic name suprofen); 4,5-diphenyl-2-oxazole propionic acid (generic name oxprozin); rac-6-chloro-alphamethyl-carbazole-2-acetic acid (generic name carprofen); 2-(3-phenyloxyphenyl)-propionic acid, particularly the calcium salt dihydrate thereof (these compounds being referred to generically as fenoprofen and fenoprofen calcium); 2-(6-methoxy-2-naphthyl) propionic acid (generic name naproxen; the generic name of the sodium salt is naproxen sodium); 4-(1,3-dihydro- 1-oxo-2H-isoindol-2-yl)-α-methylbenzene acetic acid (generic name indoprofen); 2-(3-benzoylphenyl)propionic acid (generic name ketoprofen); and 2-(2-fluoro-4-biphenylyl) propionic acid (generic name flurbiprofen) and 1-5-(4-methylbenzoyl)-1H-pyrrole-2-acetic acid (generic name tolmetin). Also included within NSAIDs are compounds within the class including sodium 5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetate dihydrate (generically referred to as zomepirac sodium); 4-hydroxy-2-methyl-N-(2-pyridyl-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide (generic name piroxicam); 2', 4'-difluoro-4-hydroxy-3-biphenylcarboxylic acid (generic name diflunisal) or 1-isopropyl-7-methyl-4-phenyl-2(1H)-quinozolinone (generic name proquazone), phenylacetic acid derivatives such as diclofenac; etodolac and nabumetone. For the purposes of this invention, para-aminophenol derivatives such as acetaminophen are not considered NSAIDs because of their general lack of antiinflammatory activity. All of the NSAIDs are commercially available materials. A particularly preferred class of NSAIDs for use in the composition of the present invention are the propionic acid derivatives. Within this class of compounds ibuprofen is the most preferred.
In the compositions of the present invention, the NSAID portion of the composition may either be a single NSAID or a combination of one or more NSAIDs. Accordingly, as used herein, NSAID includes all of these possibilities.
The NSAID and the tramadol material are generally present in a weight ratio of tramadol material to NSAID from about 1:1 to 1:200. Certain ratios result in a composition which exhibits synergistic analgesic effects. For example, in a composition comprising a tramadol material and an NSAID, the ratio of the tramadol material: NSAID is preferably from about 1:1 to 1:200; and, more preferably, from about 1:2 to 1:200. The most preferred ratios are from about 1:2 to 1:20. Compositions of a tramadol material and an NSAID within these weight ratios have been shown to exhibit synergistic analgesic effects.
A particularly preferred composition according to the present invention is a tramadol material and ibuprofen. The ratio of the tramadol material to ibuprofen in this preferred combination is from about 1:1 to 1:200, more preferably from about 1:2 to 1:200 and most preferably from about 1:2 to 1:20.
The tramadol/NSAID formulations according to the present invention may also contain therapeutically effective amounts of one or more other pharmaceutical actives including but not limited to decongestants or bronchodilators (such as pseudoephedrine, phenylpropanolamine, phenylephrine and pharmaceutically acceptable salts thereof), antitussives (such as caraminophen, dextromethorphan and pharmaceutically acceptable salts thereof), antihistamines (such as chlorpheniramine, brompheniramine, dexchlorpheniramine, dexbromphreniramine, triprolidine, doxylamine, tripelennamine, cyproheptadine, hydroxyzine, pyrilamine, azatadine, promethazine and pharmaceutically acceptable salts thereof), non-sedating antihistamines (such as acrivastine, astemizole, cetirizine, ketotifen, Ioratidine, temelastine, terfenadine (including the metabolites disclosed in U.S Pat. Nos. 4,254,129 and 4,284,957 hereby incorporated by reference) and pharamceutically acceptable salts thereof), muscle relaxants (such as glycerylmonether SMRS, methocarbamol, mephenesin, mephenesin carbamate, mephenesin acid succinate, cyclobenzaprine, chlorphenesin carbamate, chlorzoxazone or pharmceutically acceptable salts thereof) and suspected adjuvants (such as diphenhyhdramine, caffeine, xanthine derivatives (including those disclosed in U.S. Pat. No. 4,558,051, hereby incorporated by reference) and pharmaceutically acceptable salts thereof) and combinations of any of the aforesaid pharmaceuticals. The aforesaid pharmaceuticals may be combined with a tramadol/acetaminophen formulation for the treatment of such ailments as allergies, sleep disorders, cough, colds, cold-like and/or flu symptoms in mammals including humans.
Pharmaceutical compositions comprising the tramadol material and the NSAID and when desired other pharmaceutical actives in an intimate admixture with a pharmaceutical carrier can be prepared according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., intravenous, oral or parenteral. The composition may also be administered by means of an aerosol. In preparing the compositions in an oral dosage form, any of the usual pharmaceutical media may be employed. For example, in the case of oral liquid preparations (such as suspensions, elixirs and solution), water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like may be used. In the case of oral solid preparations (such as, for example, powders, capsules and tablets), carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like, may be used. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar-coated or enteric-coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, though other ingredients, for example, to aid solubility or for preservative purposes, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions will generally be in the form of a dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, containing from 0.1 to about 800 mg/kg, and preferably from about 0.3 mg to 200 mg/kg of the active ingredients. The dosage unit is calculated based on the amount of active which may be given to a 70 kg human subject in a single dose. The pharmaceutical compositions may be given at a daily dosage of from about 10 to 6000 mg/kg/day. However, it will be appreciated that the precise dose of the active ingredients will vary depending upon the particular NSAID and tramadol material being used. In the case wherein one or more other pharmaceutical components are added to the tramadol/NSAID composition those components may be added in therapeutically effective amounts known in the art and may be given at dosages conventional for such components. For example, decongestants and bronchodilators may be given in a single dosage of from about 12.5 to 75 mg/kg and at a daily dosage of from about 60 to 150 mg/kg/day. Antitussives may be given in a single dosage of from about 2.5 to 30 mg/kg and at a daily dosage of from about 20 to 120 mg/kg/day. Antihistamines may be given in a single dosage of from about 1 to 50 mg/kg and at a daily dosage of from about 4 to 600 mg/kg/day. Non-sedating antihistamines may be given in a single dosage of from about 8 to 30 mg/kg and at a daily dosage of from about 30 to 120 mg/kg/day. Muscle relaxants may be given at a single dosage of from about 10 to 1500 mg/kg and at a daily dosage of from about 60 to 8000 mg/kg/day. Adjuvants may be given in a single dosage of from about 1 to 25 mg/kg and at a daily dosage of from about 1 to 100 mg/kg/day.
The following experimental examples describe the invention in greater particularity and are intended to be a way of illustrating but not limiting the invention.
EXAMPLE 1
Preparation of the Combined Doses of Tramadol and Ibuprofen
The preparation of different ratios of a tramadol/ibuprofen combination was effected by preparing solutions having concentrations expressed in mg drugs per 10 mL of distilled water. For example, 40 mg of tramadol as the free base and 40 mg of ibuprofen as the free base were added to 10 mL of water with 2 drops of TWEEN 80, a pharmacological dispersant, manufactured by Fisher Scientific Company, to yield the highest concentration of the tramadol/ibuprofen 1:1 (40mg:40mg) ratio. Each concentration of the ratio was prepared separately in a similar manner and injected in a volume of 10 mL/kg per mouse. Similarly, the other ratios of tramadol/ibuprofen listed in Table 1 were prepared at the various concentrations.
EXAMPLE 2
Preparation of the Combined Doses of Tramadol N-oxide and Ibuprofen
First, tramadol N-oxide was prepared as set forth hereinafter. Tramadol hydrochloride (0.5 mol) was converted to its free base in basified water (pH>9) and then extracted with ether. The ether was evaporated to yield the crystalline hydrate of tramadol. The solid was then heated with steam under a high vacuum to remove as much water as possible to yield 131.5 g of material. The material was dissolved in methanol (500 mL) and 65 g of 30% H 2 O 2 was added. The solution was stirred for 3 hours and then an additional 65 g of the 30% H 2 O 2 was added. The reaction was stirred for 2.5 days at room temperature. Approximately 10 mg of PtO 2 on carbon (use of Pt/C is suggested for its ease of removal) was added to the reaction mixture, and very gentle foaming took place. An additional 10 mg of PtO 2 was added and the reaction mixture was stirred overnight and then filtered thru a filter aid. The flitrate was concentrated under vacuum while being heated to a temperature of <40° C. The residue was taken up in methylene chloride. Since the methylene chloride solution contained some colloidial platinum, the solution was diluted with ethyl acetate to 1 L and filtered through a nylon filter membrane (0.45 μ pore size) to yield a clear colorless flitrate. The flitrate was concentrated to 600 mL, and then ethyl acetate was added continuously to maintain a volume of 800 mL while the solution was heated until a vapor temperature of 74° C. was reached. The solution was then cooled to room temperature. The solid was collected by filtration, washed with ethyl acetate and dried in vacuo to yield 126.6 g of the tramadol N-oxide (mp. 159.5°-160° C.).
C16H25NO3 Theor.: C, 68.78; H, 9.27; N, 5.01 Found: C, 68.65; H, 9.22; N, 4.99
The preparation of different ratios of a tramadol N-oxide/ibuprofen combination is effected by preparing solutions having concentrations expressed in mg drugs per 10 mL of distilled water. For example, 40 mg of tramadol as the free base and 40 mg of ibuprofen as the free base is added to 10 mL of water with 2 drops of TWEEN 80, a pharmacological dispersant, manufactured by Fisher Scientific Company, to yield the highest concentration of the tramadol N-oxide/ibuprofen 1:1 (40mg:40mg) ratio. Each concentration of the ratio is prepared separately in a similar manner.
EXAMPLE 3
(-) and (+) Enantiomers of O-Desmethyl Tramadol: Their Syntheses and the Preparation of Doses of O-Desmethyl Tramadol with Ibuprofen
First, O-desmethyl tramadol was prepared as set forth hereinafter. Diethylene glycol (125 mL) was added with cooling to potassium hydride (9.5 g) with the temperature being maintained at <50° C. To the solution was added thiophenol (10 mL) dissolved in diethylene glycol (25 mL), and then (-)-tramadol as the free base (9.3 g) in diethylene glycol (50 mL) was added. The final reaction mixture was heated slowly to reflux for 45 minutes. The mixture was cooled and then quenched into water. The pH was adjusted to about 3, and the mixture was extracted with ethyl ether. The pH was readjusted to about 8 and the resulting mixture was extracted 5 more times with methylene chloride. The extract was dried and the methylene chloride was evaporated to yield 4.6 g of the title compound as an oil. The oil was distilled (Kugelrohr), dissolved in tetrahydrofuran and treated with an ethanol/HCI solution to give 2.3 g of the salt. The salt was recrystallized from ethanol/ethyl ether and dried to yield 1.80 g of the salt of the (-) enantiomer of O-desmethyl tramadol (mp. 242°-3° C.), [α] D 25 =-32.9 (C=1, EtOH).
C15H23NO2.HCI Theor.: C, 63.04; H, 8.46; N, 4.90 Found: C, 63.00; H, 8.51; N, 4.94
To prepare the (+) enantiomer of the title compound, the reaction was run under the same conditions except that (+)-tramadol as the free base was used instead of the (-)-tramadol to yield 2.8 g of the (+) enantiomer of O-desmethyl tramadol (mp. 242°-3° C.) [α] D 25 =+32.2 (C=1, EtOH).
C15H23NO2.HCI Theor.: C, 63.04; H, 8.46; N, 4.90 Found: C, 63.14; H, 8.49; N, 4.86
The preparation of different ratios of a O-desmethyl/ibuprofen combination is effected by preparing solutions having concentrations expressed in mg drugs per 10 mL of distilled water. For example, 40 mg of O-desmethyl as the free base and 40 mg of ibuprofen as the free base were added to 10 mL of water with 2 drops of TWEEN 80, a pharmacological dispersant, manufactured by Fisher Scientific Company, to yield the highest concentration of the O-desmethyl tramadol/ibuprofen 1:1 (40mg:40mg) ratio. Each concentration of the ratio is prepared separately in a similar manner and injected in a volume of 10 mL/kg per mouse.
EXAMPLE 4
Analgesic Activity
Male CD1 mice (weighing from 18-24 g) were utilized in determining the analgesic effects associated with the compositions of the invention. The mice were all dosed orally with tramadol hydrochloride (calculated as the base), which was completely dissolved in distilled water, and ibuprofen (calculated as the base), which was completely dissolved in distilled water or in distilled water containing 2% by volume of Tween 80 containing 100% polysorbate 80. The dosing volume was 10 mL/kg.
The procedure used in detecting and comparing the analgesic activity of different classes of analgesic drugs for which there is a good correlation with human efficacy is the prevention of acetylcholine-induced abdominal constriction in mice (H. Collier et al., Br. J. Pharmacol., 32, 295 (1968)).
Mice, incubated with various doses of tramadol hydrochloride alone, ibuprofen alone, combined doses of tramadol hydrochloride and ibuprofen, or vehicle such as distilled water, or distilled water containing 2% by volume of Tween 80, were injected intraperitoneally with a challenge dose of acetylcholine bromide. The acetylcholine was completely dissolved in distilled water at a concentration of 5.5 mg/kg and injected at the rate of 0.20 mL/20 g. For scoring purposes an "abdominal constriction" was defined as a contraction of the abdominal musculature accompanied by arching of the back and extension of the limbs. The mice were observed 10 minutes for the presence or absence of the abdominal constriction response beginning immediately after receiving the acetylcholine dose, which was 30 minutes after receiving the oral administration of tramadol hydrochloride, ibuprofen, combined doses of tramadol hydrochloride and ibuprofen, or vehicle. Each mouse was used only once.
The analysis of possible superadditivity for the compositions at each fixed ratio was determined as disclosed by R. J. Tallarida et al., Life Sci., 45, 947 (1989). This procedure involved the determination of the total amount in the mixture that is required to produce a specified level of effect, such as 50% (ED50 mix ), and the corresponding total amount that would be expected under simple additivity (ED50 add ). Where it was established that ED50 mix <ED50 add for a specific fixed-ratio, then that composition ratio was superadditive. Both the quantities ED50 mix and ED50 add were random variables; ED50 mix was estimated from the dose-response curve for a specific fixed-ratio; ED50 add was obtained by combining the ED50 estimates for the two drugs under additivity. ED50 mix was then compared to ED50 add via a Student's t-test. The ED50 value for tramadol hydrochloride alone was 5.5(4.8-6.4) mg/kg. The ED50 value for ibuprofen alone was 33.5 (24.1-46.5) mg/kg.
The interaction between tramadol and ibuprofen was determined at precise dosage ratios of tramadol hydrochloride and ibuprofen. Multiple (typically 4-6) coded doses of each selected combination were studied for analgesic effectiveness after 30 minutes using an experimental design which permitted the complete randomization of the separate dosage forms tested.
The interaction of tramadol hydrochloride and ibuprofen on the acetylcholine-induced abdominal constriction in mice was demonstrated by the data in Table I and is shown in the Loewe isobologram, FIG. I, (see, S. Loewe, Pharm. Rev., 9; 237 (1957) regarding the preparation and basis of an isobologram). In FIG. 1, the diagonal line joining the ED50 values of the two drugs given separately represents the simple additivity of effects at different component ratios. The dotted lines adjacent to the diagonal line define the 95% confidence interval. ED50 values falling under the curve (between the line and the origin) indicate superadditivity, i.e., unexpected enhancement of effects. The diagonal dashed lines radiating from the origin represent the dose ratios of ibuprofen to tramadol hydrochloride used in mice receiving the combined drug dosages. The bars through the ED50 points for the tramadol and ibuprofen composition represent the 95% confidence intervals of the ED50 value. The experimental data as represented in FIG. I establish that compositions having a ratio of tramadol to ibuprofen from about 1:1 to 1:200 (represented by the curved line) give unexpectedly enhanced activity since ED50 mix is less than ED50 add .
It is expected that based on these results, other NSAIDs, and particularly the propionic acid derivatives, when combined with a tramadol material, will produce similar synergistic results.
TABLE I__________________________________________________________________________TRAMADOL:IBUPROFENDRUG COMBINATIONS DOSE (mg/kg, p.o.) ED.sub.50 at 30 min (95% Cl's)(Tramadol:Ibuprofen) Tramadol Ibuprofen analgesia Tramadol Ibuprofen__________________________________________________________________________tramadol only 2 0 3/15 5.5 -- 3 0 4/15 (4.8-6.4) 4 0 14/45 6 0 20/45 8 0 40/60 10 0 15/15 16 0 14/152:1 2.5 1.25 2/15 4.8 2.4 5 2.5 7/15 (3.8-6.2) (1.9-3.1) 10 5 14/151:1 1.25 1.25 2/15 4.4 4.4 2.5 2.5 3/15 (3.3-5.9) (3.3-5.9) 5 5 6/15 10 10 15/151:2 1.25 2.5 1/15 2.5 5.1 2.5 5 7/15 (2.1-3.1) (4.1-6.3) 5 10 14/15 10 20 15/151:20 0.15625 3.125 2/15 0.4 9.0 0.3125 6.25 7/15 (0.3-0.6) (6.3-12.8) 0.625 12.5 8/15 1.25 25 26/30 2.5 50 13/15 5 100 15/151:200 0.05 10 3/15 0.1 25.8 0.1 20 6/15 (0.1-0.2) (18.4-36.2) 0.2 40 9/15 0.4 80 13/15 0.8 160 15/15ibuprofen only 0 10 2/15 0 20 4/15 0 40 8/15 -- 33.5 0 80 13/15 (24.1-46.5) 0 160 14/15__________________________________________________________________________ | 1a
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This invention relates generally to improvements in surgical devices and more particularly to aids in the prevention of the rubbing or catching of incision sutures on other objects, such as clothing, bed sheets or covers, and other articles.
The cover of this invention is particularly adapted for use with suture bridges designed to secure sutures above and out of contact with the incision closure and suture exit points while maintaining the sutures laterally fixed at the points where they exit to the skin. Several forms of suture bridges are disclosed in our prior U.S. Pat. No. 3,831,608, others being disclosed in such U.S. Pat. Nos. as Chambers, 815,264; Anderson, 1,852,098; McCarthy 3,014,483; Edwards et al, 3,650,274; and Chodorow, 3,695,271. While many of the suture bridges of these patents hold sutures against collateral displacement at their skin exit points, they do not have portions that project outwardly, or portions wherein the sutures or knots therein are exposed in such manner as to be caught or otherwise engaged by clothing, bed sheets or other covering, and possibly disturbed thereby to an extent as to cause irritation or pain to the patient. The protective cover of this invention, in its several forms herein disclosed, is highly effective in enclosing exposed portions of a suture, and is quickly and easily placed and releasably held in suture enclosing relationship on a suture bridge.
The protective cover is made from flexible resilient material to provide wall structure that is adapted to enclose the suture engaging portion of a bridge in outwardly spaced relation to those foot portions of the bridge that engage the skin of the patient laterally outwardly of the incision. The cover has smooth outer surfaces and snap fastener elements for releasably holding the cover in enclosing relationship to the suture engaging portion of the bridge.
DESCRIPTION OF THE DRAWINGS
FIG. 1 is a view in plan of a protective cover produced in accordance with this invention, and applied to a suture bridge;
FIG. 2 is a view in side elevation;
FIG. 3 is an enlarged transverse section taken on the line 3--3 of FIG. 2;
FIG. 4 is a view in perspective of a modified form of cover;
FIG. 5 is a fragmentary transverse section taken generally on the line 5--5 of FIG. 4;
FIG. 6 is a view corresponding to FIG. 1 but showing a further modification;
FIG. 7 is a view in side elevation of the structure of FIG. 6, some parts being broken away and some parts being shown in section;
FIG. 8 is a fragmentary section taken on the line 8--8 of FIG. 7;
FIG. 9 is a view corresponding to FIG. 1 but showing a still further modified form of cover;
FIG. 10 is a view in side elevation of the structure of FIG. 9;
FIG. 11 is a enlarged transverse section taken on the line 11--11 of FIG. 10;
FIG. 12 is a further enlarged transverse section corresponding to FIG. 11, but showing a further modified arrangement.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
In FIGS. 1-8, a suture bridge is shown as comprising a lower bridge member 21 and an upper bridge member 22, the former including foot portions 23 interconnected by a bridge portion 24. Each foot portion 23 is provided with a slot 25 extending longitudinally of the bridge for passage therethrough of a suture. The bridge portion 24 includes a generally flat top section 26 and angular sections 27 that converge from the foot portions 23 toward the top portion 26. The top and angular portions 26 and 27 are formed to provide a dove tail channel or recess 28 for reception of the intermediate portion of the upper bridge member 22.
The upper bridge member 22 is formed to provide cantilevered arms or end portions 29 having longitudinal slots 30 which overlie respective ones of the slots 25 and are adapted to receive and have tied therein opposite end portions of a suture, not shown. Preferably, the arms 29 are resilient so as to maintain a suture under predetermined tension.
The suture bridge, above described, does not in and of itself comprise the instant invention. The suture bridge is more specifically disclosed and claimed in our copending application filed Aug. 6, 1974, Ser. No. 500,689 and entitled "Improved Suture Bridges".
A preferred embodiment of our protective cover is illustrated in FIGS. 1-3 and indicated generally at 31, the same comprising wall structure including an outer or top wall 32, opposite end walls 33, and laterally spaced generally parallel side walls 34, the cover having an open inner side or bottom. The several walls 32-34 are disposed to closely encompass the bridge members 21 and 22 above the foot portions 23 thereof, and to enclose the upper portions of sutures tied to the arms 29 of the upper bridge member 22. The cover 31 may be made from any suitable material having flexibility and resilience, such as polyethylene or other suitable synthetic plastic material. As shown in FIGS. 1-3, the cover 31 is formed to provide opposed snap fastener elements in the nature of detents 35 that are adapted to engage under the opposite sides thereof, the top ridge portion 26 to releasably hold the cover 31 in place on the bridge. Preferably, and as shown in FIGS. 1-3, the cover 31 has smooth outer surfaces and rounded corners, so as to slide smoothly over clothing, bed coverings, or other material which might come in contact therewith. The lower edges of the side walls 34 are upwardly arched, as indicated at 36 to avoid any contact with an underlying incision, should swelling occur at the incision. Further, the arched portions 36 provide clearance between the incision and the lower edge of the cover for the tips of an operator's fingers, for the purpose of spreading the side walls 34 to disengage the dentents 35 from the bridge and remove the cover therefrom when the incision has healed to the point where removal of the suture is desired.
MODIFICATIONS OF THE PREFERRED EMBODIMENT
In the modified form illustrated in FIGS. 4 and 5, a cover 37 is substantially identical in shape to the cover 31, having a top wall 38, opposite end walls 39, one of which is shown, and opposite side walls 40 provided with opposed detents 41. Like the cover 31, the cover 37, when mounted on a suture bridge, is disposed to extend transversely of an underlying incision. In the form of cover illustrated in FIGS. 4 and 5, the side walls 40 are formed to provide foot portions 42 that extend transversely outwardly from the walls 40 to overlie and protect portions of an incision at opposite sides of the bridge on which the cover 37 is mounted. Preferably, the foot portions 42 are cross sectionally curved, and the corners and edges thereof are rounded so as to provide smooth outer surface portions that do not catch on clothing, bed sheets and the like.
A pair of covers are illustrated in FIGS. 6-8, these being identical in construction, and used in pairs, each cover being indicated generally at 43. As shown, each cover 43 comprises top and bottom walls 44 and 45 respectively, opposite flat side walls 46 and outer end walls 47, the inner ends of the covers 43 being open. The bottom walls 45 are provided with slot like openings 48, each of which is adapted to overlie the slot 25 in an underlying foot portion 23 of the bridge, see particularly FIG. 8. Like the covers 31 and 37, the covers 43 are preferably made from flexible resilient material and have smooth outer surfaces and rounded edges and corners, the inner ends of the covers 43 having marginal edges. The side walls 46 have portions extending longitudinally beyond the marginal edges to provide snap fastener elements in the nature of latch hooks 49 that have latching engagement with the inner side surfaces of the angular portions 27 of the lower bridge member 21.
In the form of the invention illustrated in FIGS. 9-11, a cover, indicated generally at 50, comprises a pair of cooperating cover sections 51 and 52 each having an outer or top wall portion 53, opposite end wall portions 54 and a side wall 55. Each side wall 55 has integrally formed therewith, adjacent its inner marginal edge 56, a pair of spaced foot portions 57 that extend laterally outwardly and downwardly from the marginal edge 56 and decreasing in thickness to provide relatively thin flexible hinge portions 58 integrally formed with or anchored to foot portions 23a of a lower bridge member 21a. With the exception of the hinge portions 58 attached to the foot portions 23a, the lower bridge member 21a is identical to the bridge member 21. As shown in FIG. 11, the cover sections 51 and 52 are movable on their hinge portions 58 between cover open positions shown by dotted lines in FIG. 11, and longitudinally abutting cover closed positions shown by full lines in FIG. 11. The cover sections 51 and 52 are releasably held in their cover closed positions by snap fastener buttons 59 integrally formed with the outer or top wall portions 53 of respective cover sections 51 and 52. The snap fastener buttons 59 are preferably of the type found on the hinged closure portions of coin purses and ladies hand bags.
In the modified arrangement illustrated in FIG. 12, a cover 60 is similar to the cover 50 differing therefrom only in the manner of hinging the same to the foot portions of the suture bridge, and in the design of the snap fastener. The cover 60 comprises cooperating cover sections 61 and 62 the side walls 63 of which are provided with downwardly projecting foot portions 64 that are mounted in socket forming heel and toe elements 65 and 66 respectively, integrally formed with foot portions 23b, one of which is shown, of a lower bridge member 21b, that is otherwise identical to the lower bridge member 21. Although only one foot portion 64 is shown as being associated with each side wall 63 and but one foot portion 23b is shown in FIG. 12, it will be understood that each side wall 63 is provided with a pair of foot portions 64 each associated with heel and toe elements 65 and 66 of both foot portions 23b of the suture bridge member 21b. The cover sections 61 and 62 have top wall portions 67 and 68 respectively, these being provided with cooperating snap fastener hooks 69 and 70 for releasably holding the cover sections 61 and 62 in cover closed positions shown by full lines in FIG. 12. The foot portions 64 are so disposed, relative to their respective side walls 63 that, when the hooks 69 and 70 are disengaged, the cover sections 61 and 62 assume a normally spread apart relationship as indicated by dotted lines in FIG. 12. When the cover sections 61 and 62 are moved in to cover closed relationship, as shown by full lines in FIG. 12, the sections are under yielding bias toward a cover open relationship. After the cover sections 61 and 62 are unlatched, they may be manually moved away from each other beyond their normally spread apart portions and the foot portions 64 pivotally moved out of engagement with their respective heel and toe portions 65 and 66. Thus, the cover sections 61 and 62 can be entirely disassociated from the suture bridge during the suturing operation, and can be thereafter quickly and easily applied to the suture bridge.
While we have shown and described a preferred embodiment and several modified forms of protective cover for suture bridges, it will be understood that the same is capable of further modification without departure from the spirit and scope of the invention, as defined in the claims. | 1a
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This is a continuation of application Ser. No. 552,776, filed Nov. 17, 1983, now abandoned.
BACKGROUND OF THE INVENTION
The present invention is directed to a method and device for providing respiration to a pateint which respiration is synchronized with the heart rhythm and which device and method promote the blood circulation.
In conventional respirator treatments, breathing gas is supplied to the lungs under pressure. This pressure is also partly propagated outside of the lungs into the body cavities in the thorax. It is known that this pressure essentially has a negative influence on the blood circulation. This negative influence is mainly based on the fact that the supply of blood to the heart and the filling of the chambers of the heart during the relaxation phase or expansion of the heart which is known as the diastole is impeded. An inadequate filling of the heart chambers, however, means that the heart cannot generate an adequate beat volume during the following contraction phase which is known as systole. When the heart activity of the blood circulation are already inadequate due to a disease, the negative influences caused by the respiration treatment can have serious consequences.
A series of proposals have already been made in order to reduce these harmful effects on the circulation. It is thus known that an adequate respiration can be achieved with a very high breathing rate, for example, several breaths per second. The volume of each breath is thus decreased and thus the pressure increases which disturb the blood circulation are reduced. This procedure is disclosed in an article in Proc. Am. Soc. Exp. Biol. Vol. 38, 1979, p. 951 and a prospectus Aga Bronchovent, 318.002 Sv, November 1978: Klain Jet Ventilator.
An additional known improvement can be achieved when the ventilation occurs synchronously with the heart activity so that one breath occurs at every heartbeat or at every second heartbeat. When the inhalation phase is thereby chronologically placed such that it coincides with the systole, an advantageous pressure increase around the heart can be achieved. At the same time, the pressure influence on the heart during the diastole is entirely or at least partially avoided so that the heart's activity is improved overall.
It is also known that the heart chambers can be emptied by means of external compression of the thorax and the heart chambers will again fill up upon removal of this compression. As a result thereof, a certain blood circulation can also be maintained even when the heart does not independently contract or when it is greatly diminished in this function of contraction.
A described possibility for reducing harmful effects on the blood circulation and for promoting the circulation are, however, limited. Given the high frequency ventilation in the heart rhythm, a low breath volume already produces a sufficient respiratioin so that only a slight intrathoracic pressure increase results. Even when this pressure increase is synchronized with the heart rhythm so that it appears during systole, only a slight positive effect is achieved.
Given an increase in the volume of each breath in order to achieve a more effective pressure increase, there exists a risk that the lungs may be damaged by the higher gas pressure to which they have been exposed. In addition, the lungs cannot be emptied fast enough given such a high volume for each breath.
An external compression of the thorax has the disadvantage that this can cause injury to the thorax itself or to internal organs. In addition, the external compression of the thorax may be painful to the patient.
SUMMARY OF THE INVENTION
The present invention is directed to providing a specific method for respiration and ventilation of a patient which respiration is synchronized with the heart rhythm so that the pressure exerted on the heart can be adjustably increased to such a degree that the contraction of the heart can be significantly increased without injury occurring to the lungs and/or to the thorax walls. Another object of the invention consists of providing a respirator with which the desired method can be implemented in a simple and reliable manner.
The objects are inventively achieved in a method comprising the steps of applying a respiratory gas to the lungs of the patient, applying a uniform pressure opposing the expansion of the chest and the abdomen, and synchronizing the step of applying the respiratory gas and applying the uniform force at a particular point of time in the heartbeat cycle so that the pressure rise of the respiratory gas around the heart coincides with the contraction phase of the heart. In addition, the step of synchronizing includes sensing the electrical signals of the heart and utilizing the sensed signals to synchronize the step of applying the respiratory gas and the uniform pressure.
The invention thus proceeds on the basis of the perception that the desired pressure increase around the heart by means of synchronizing the ventilation with the heart rhythm is at least partially cancelled thereby the chest and the abdomen are allowed to expand during the step of respiration. The invention therefore provides that the expansion is restricted in that a uniform force is exerted on the chest and/or on the abdomen. Upon respiration, thus, the lungs can be partially expanded toward the inside so that the pressure increase around the heart is achieved to the desired degree. The respiration of the patient should thereby occur at a particular point of time in the heart rhythm. That means that one breath should be present per heart cycle or on the other hand, that the breath respectively appears only on every second heartbeat or even more infrequently but synchronous with the heart activity in each case.
It is provided in a further development of the invention in order to optimize the respiration and/or the support of the blood circulation that the point of time and/or the duration of the application of the breathing gas feed and/or pressure are adjustable. Further, the point in time, the duration and the magnitude of the uniform force exerted on the thorax and/or the abdomen is also adjustable.
To accomplish the method, the invention also is directed to a respirator having a first valve control arrangement for controlling the flow of the respiratory gas from a source to and from the patient, means for generating and exerting a uniform pressure on the chest and/or the abdomen, means for sensing the parameters of the heart activity and control means which actuate at least the valves of the first arrangement as a function of the sensed signal.
An advantageously simple embodiment of the respirator provides that the means for applying uniform pressure consist of a rigid hollow body which surrounds at least a part of the chest and/or the abdomen of the patient. This hollow body surrounds the thorax similar to rigid armor. The inside dimension of the hollow body is selected so that a certain amount of expansion of the chest and/or the abdomen is possible before the hollow body is tightly engaged by the patient and prevents further expansion. In order to increase the adaptability in particular to likewise enable possibilities of applying one and the same hollow body for different patients, it is provided in a further development of the invention that the hollow body contains a series of closed chambers consisting of flexible material which are positioned between the thorax and the abdomen of the patient and the hollow body and are filled with a fluid or gas. The inside dimensions, i.e., the size of the hollow body, can thus be practically defined depending on the amount of filling of the series of closed chambers. Means for filling and also emptying the chambers are provided in order to be able to increase the influence on the blood circulation. As a result thereof, the force exerted on the chest and/or the abdomen can be exactly chronologically limited to the systole and be quickly cancelled thereafter by means of emptying the chambers. Significant pressure is no longer exerted on the heart even though the lungs are then, for example, in a more or less filled condition because the thorax can again expand.
A possibility of further pressure increases inventively consist therein that the respirator is provided with a variable dead space or clearance volume. What is meant by a dead space is a quasi-buffer in the breathing gas line that stores a certain volume of CO 2 upon exhalation and resupplies it to the lungs during the following inhalation phase. In a simple case, this can be a matter of an elongation of the hose between the tracheal cannula and the respirator. Breathing gas can be supplied to the patient under higher pressures in a manner so that the emptying of the heart during the systole is further enhanced without the CO 2 content in the lungs sinking below a disturbing level.
BRIEF DESCRIPTION OF THE DRAWING
The FIGURE is a schematic illustration of a respirator in accordance with the present invention.
DESCRIPTION OF THE PREFERRED EMBODIMENT
The principles of the present invention are particularly useful in a respirator generally indicated at 1 in the FIGURE. The respirator 1 receives respiratory gas on a line 2, which is connected to an external gas source 40. Instead of the single gas line 2, a plurality of such lines of various components of the gas can be provided. The respiratory gas is supplied to the patient 6 through a valve arrangement 3 as well as a tracheal cannula 4 connected thereto and the tracheal cannula 4 terminates tightly in the trachea 5 of the patient 6. A cuff 7 can, for example, be provided for the termination of the trachea cannula 4 in the trachea 5. An eduction or ejection valve 8 is also connected to the tracheal cannula 4. The valve arrangement 3, which produces a metered feed of respiratory gas received in the line 2 from the pressurized source 40 can, for example, be of a known type such as disclosed in the International patent application No. PCT/SE82/00063 (W082/03014).
However, it is possible to utilize an open cannula for spontaneous breathing. The open cannula has a thin additional cannula for the feed of the respiratory gas instead of a tracheal cannula terminating in the trachea and the eduction or ejection valve 8. The emptying of the lungs then occurs directly over the open cannula. Further, it is also possible to insert a thin cannula directly into the trachea in a surgical manner. The expiration then occurs over the natural breathing organs. In the two latter instances, a HFPPV respiration method (a high frequency positive pressure ventilation) is then advantageously employed.
The respirator 1 also includes a valve 9 which receives gas from an additional pressurized source 50 on a line 10. Compressed air is usually employed in the simplest case as the pressurized gas from the source 50. A line 11 leads from the valve 9 to a plurality of closed chambers 12 consisting of flexible material. The closed chambers 12 are disposed around the chest and/or partially around the abdomen of the patient 6. A hollow body 13 consisting of a rigid material which is matched to the shape of the thorax is situated around these chambers. A fluid can also be utilized for filling the chambers instead of pressurized gas. The eduction valve or ventilation valve 14 is again connected to the line 11 to enable exhaust or venting these chambers.
The ventilator or respirator 1 further contains an amplifier 15 to which the signals of a sensor are supplied. In the embodiment which is illustrated, two ECG electrodes 36 and 37 are applied to the patient's body and register the electrical heart signals and act as the sensor. These heart signals are processed by the amplifier and then applied to a detector 16 which detects the high electrical heart voltage during the systole and emit a pulse to an electronic circuit 17 or, respectively, a circuit 18. The circuits 17 and 18 each contain means for setting a selectable delay of the pulse coming from the detector 16. The valve arrangement 3 as well as the valves 8, 9 and 14 are driven by pulse-shaping circuits 19, 20 and 21, respectively. The pulse-shaping circuits 19-21 can, for example, by one-shot multivibrators with different pulse widths. In addition, the pulse-shaping circuits should contain means for setting the pulse width.
As illustrated, the output of the electronic circuit 17 goes to the pulse-shaper 20 whose output goes to both the pulse-shaper 21 and also to the valve 9. From the pulse-shaper 21, pulses go to the eduction valve 8 and also to the exhaust or eduction valve 14. In a similar manner, the signal from the detector 16 is applied to the electronic circuit 18, which has the time delay, and the output of the circuit 18 goes to the pulse-shaper 19, which applies a pulse to the valve arrangement 3.
The schematic illustration of the FIGURE also shows that the lungs 25 and 26 of the patient surround a large part of the heart of which the left ventricle 27 is shown. Pressure on the heart will occur due to the expansion of the lungs 25 and 26. Under normal conditions, however, this pressure increase is slight since the volume of the thorax easily enlarges particularly due to the outwardly directed movement of the thorax wall 28 and partially due to the downward directing movement of the diaphragm 29 into the abdomen cavity.
According to the invention, the thorax and the upper part of the abdomen are surrounded by a hollow body 13 which consists of a shapable envelope consisting of rigid material. This envelope is positioned around the body so that a certain expansion of the respiratory organs, i.e., the lungs and the chest and/or the abdomen, is possible without the envelope significantly impeding this expansion. When due to the application of the respiratory gas, this expansion has reached a certain amplitude, further expansion is prevented by the envelope as a result of which an increased pressure will occur inside the envelope and thus inside the thorax and around the heart.
The function of the respirator ventilator 1 and thus of the method utilizing the respirator is described in greater detail hereinbelow. The electrical activity of the heart at the beginning of the systole is registered by the electrodes 36 and 37 and initiates the feed of respiratory gas through the valve arrangement 3. The psychological delay between the electrical heart signal for the systole (the QRS complex) and the mechanical contraction of the heart is exploited in order to fill the lungs in one breath through the fast action of the valve arrangement 3. However, it is also possible to set a delay in the electrical circuits 17 and 18 so that the feed of the respiratory gas will occur during the systole that is related to the next following heartbeat.
At the same time as the feed of the respiratory gas or nearly simultaneously therewith, the elastic chamber 12 is filled with pressurized gas through the valve 9 and the line 11. The amount of gas supplied can also be regulated. An excess pressure will occur when the lungs expand because of the flow of the respiratory gas and this excess pressure is then amplified by the movement when the outwardly directed movement of the thorax wall 28 and/or downwardly directed movement of the diaphragm 29, respectively, is partially arrested by the hollow body 13 and by the filled chambers 12. This excess pressure is propagated through the cardiac wall so that the pressure on the blood enclosed in the heart will rise. By the correct setting of the electrical circuits such as 17, 18, 19, 20 and 21, the pressure increase on the heart will occur chronologically and synchronously with the pumping of the blood from the left ventricle into the large systemic aorta of the body. The blood in the systemic aorta 30 will then proceed to the important organs such as through additional artery 31 to the brain.
The various delay times and pulse durations are set according to the following principle. The amount of respiratory gas supplied to the patient at each respiration is defined by means of setting the valve arrangement 3 and/or the pressure in the line 2 so that the ventilation of the lungs suffices for a good gas exchange. The hollow body 13 is applied around the patient so that it adapts to the external contour of the body without exerting high pressure on the body at the beginning of each respiration cycle. The supply of air to the closed chambers 12 is likewise controlled so that the movement of the walls of the thorax and the diaphragm 29 during the feeding of the respiratory gas are restricted to such a degree that a suitable intensification of the pressure around the heart is generated during its pumping process.
The thorax itself is not compressed by the flexible chambers 12 to such a degree that the force exerted produces an inwardly directed movement on the thorax wall 28. The flexible chambers 12 only fill out the cavity between the body surface and the hollow body 13. The flexible chambers 12 serve to limit the outwardly directed movement of the body surface in a definable and controllable manner. Moreover, they also serve to balance out certain inequities of the pressure on the body surface that could, for example, be produced by a rigid hollow body.
The pressure on the lungs 25 and 26 which occurs due to the supplying of the respiratory gas is composed of the pressure required for the expansion of the lungs and of the thorax walls and of the pressure arising in the thorax due to the hollow body 13 and the pressure chambers 12. The pressure gradient across the lung structure, however, does not exceed the gradient that occurs given a standard high-frequency ventilation in which experience has shown to be harmless. Any kind of deforming force that could damage the thorax wall is prevented by the pressure equalization of the air-filled, flexible chambers 12. An injurious effect on the blood circulation due to an impeded refilling of the heart ventricle is avoided in that every form of undesirable pressure on the thorax and in the thorax is prevented during the relaxation phase of the heart because the flexible chambers 12 are emptied through the exhaust valve 14 at the end of the systole. The lungs empty at the same time through the valve 8.
The electrical coupling according to the sample illustrated embodiment is as follows:
The output signal of the detector 16 proceeds over the two delay circuits 17 and 18, respectively, to the pulse-shaping circuits 19 and 20, respectively. The pulse-shaping circuit 19 determines the chronological duration during which the respiratory gas is supplied to the patient through the valve arrangement 3 and also determines the point in time to which this feed is to begin. Correspondingly, the circuit 20 determines when and how long the valve 9 should be opened. The point in time for opening the valves 14 and 8, respectively, is determined through a further circuit 21. At the same time it is presumed here that the valves 8 and 14, respectively, are closed when the arrangement 3 or, respectively, the valve 9 is opened.
The described sample embodiment is only of an explanatory nature. The support of the blood circulation strived for with the invention is also assured when the respirator is modified within the framework of the invention. For example, the sensors instead of being ECG electrodes could be connected to a heart pacemaker or a device which generates pulse to control the heart's activity. To provide a dead space or variable volume for receiving CO 2 exhaled from the lungs, the tube or cannula 4 may have an excess portion such as a loop 4a.
Although various minor modifications may be suggested by those versed in the art, it should be understood that we wish to embody within the scope of the patent granted hereon, all such modifications as reasonably and properly come within the scope of our contribution to the art. | 1a
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to German Patent Application No. DE 103 52 993 4, filed on Nov. 13, 2003, which is incorporated herein by reference in its entirety.
TECHNICAL FIELD
[0002] This invention relates to a brush attachment according to the prior-art portion of claim 1 , and to an electric toothbrush having a handle and a brush attachment of said type.
BACKGROUND
[0003] A replaceable brush attachment for an electric toothbrush is known from U.S. Pat. No. 3,369,265. On the brush attachment are bristles in a fixed arrangement. The end of the brush attachment intended for connecting to the handle has a cavity in which provision is made for two opposite lying detent notches, both of which are arranged in the same axial position. A connecting pin of a handle equipped with corresponding detent elevations engages in these detent notches. The end of the brush attachment intended for connecting to the handle is divided by two slots into two legs which are spread apart when the brush attachment is plugged onto the connecting pin, thus permitting a snap-action effect. The end of the connecting pin engages in the end of the cavity, which is conformably shaped in flush fashion.
[0004] WO 00 76420 describes an electric toothbrush with a brush attachment. The latter has a coupling means formed by a rubbery component with a sawtooth serration, which frictionally engages over an extension of the housing. A clamping ring is used to achieve high retaining forces without making it difficult to push on the brush attachment. This ring is rotatably held on the brush attachment and equipped with a run-on ramp that grips the housing extension. In addition, provision is made for an anti-rotation device using a coupling sleeve. This solution is relatively elaborate in its construction and hence expensive.
[0005] A brush attachment of the prior-art type is known from WO 99 20202. The brush attachment can be plugged onto a handle of an electric toothbrush that has a receiving socket from which a shaft projects. An axial securing element arranged in a brush shank of the brush attachment has a first spring element that is configured like a detent finger and engageable in a groove of the shaft. A second spring element in the form of a bending bar acts on the receiving socket on the handle and is part of a sleeve inserted in the brush shank. This plug-on mechanism is intended for a brush attachment on which a bristle carrier mounted on the brush shank is to be set in oscillatory rotational motion by the shaft of the handle.
[0006] It is an object of the present invention to construct a brush attachment of the prior-art type such that it can also be used on a toothbrush with which dental cleaning is supported by a fast vibratory motion of the bristles. The transmission of these vibrations from the handle to the brush attachment should take place without clattering noises in the attachment area, and it should still be easy to plug on and remove the brush attachment. The plug-on mechanism should also display these advantageous characteristics at comparatively high vibration frequencies of preferably 100 to 300 Hz.
[0007] This object of the invention is accomplished in that the brush attachment has a plug-on part on which a first and a second spring element are arranged in an axially offset relation to each other and which act on the shaft when the brush attachment is plugged onto the shaft.
[0008] This solution enables a connection without play between the shaft and the brush attachment, whereby relatively high forces and torques can be transmitted. The brush attachment is supported on the shaft under bias by in particular elastic shaped elements.
[0009] In an advantageous further configuration of the brush attachment of the invention the first and the second spring element are arranged in the same radial position. As a result, the pressure forces of the spring elements act in the same plane, or to be more exact in the same radial direction. This is advantageous with regard to the behavior of the brush attachment when plugged onto the shaft.
[0010] According to an advantageous embodiment, provision is made for the first spring element to be constructed as a detent finger that extends axially and engages in an approximately V-shaped detent groove of the shaft. This arrangement can be implemented at very little cost and tells the user of the brush attachment by means of an audible and tangible snap action that the brush attachment is securely seated on the handle.
[0011] When, in accordance with an advantageous arrangement, the second spring element is arranged on an area close to the bristle carrier while the first spring element is arranged at a location more remote from the bristles, the second spring element can then act on the free end of the shaft. This means that only the first spring element acts at the beginning of the plug-on operation and very little resistance can be felt when plugging on. The second spring element, which is preferably calculated to have a higher pressure force, does not come into play until at the end.
[0012] A preferred arrangement of the detent finger wherein the finger points in the direction of the handle, has the advantage of allowing the detent groove to be deeper and bigger, as the shaft generally has a larger diameter in the vicinity of the handle. The bigger detent groove and the bigger detent finger enable a better snap action to be provided.
[0013] A preferred embodiment of the brush attachment of the invention wherein the second spring element is an axially aligned spring bar with a bend curved in the direction of the shaft, whereby the spring bar is arranged between two axial slots of the plug-on part, has the advantage of being an economical and durable solution. A necessary pressure force is assured even after very frequent changing of the brush attachment.
[0014] An even better hold is afforded by a third spring element in accordance with another advantageous configuration of the brush attachment of the invention. The third spring element is arranged in an axially offset position relative to the first two spring elements. Conveniently, the plug-on part has several, in particular three, radially offset resilient fingers that urge against the shaft in the mounted state. Through this supporting of the shaft at least three axially offset points the brush attachment is seated particularly quietly and securely on the shaft. The radial support of the plug-on part is also effected preferably at three points of the shaft.
[0015] According to another preferred embodiment of the brush attachment of the invention, provision is made for the brush attachment to be constructed for mounting on a shaft having several cross sectional areas, the shaft having an essentially D-shaped cross section at its forward end close to the bristle carrier and a circular cross section at its rear end close to the handle, the forward end of the shaft preferably having a flattening against which a spring element rests. This enables user-friendly attachment and good guidance of the brush attachment. On the one hand, the shaft tip has a small cross section that is inserted in a relatively large receiving opening of the plug-on part. On the other hand, the brush attachment with its bristles has the correct radial alignment. In the first moment of the plug-on movement it is even possible for the bristles to be in any radial alignment. Using a practically automatic rotary movement of the brush attachment in an already partly inserted position, a precise alignment of the bristles is achieved by means of insertion bevels and/or curves running preferably transverse to the shaft on the shaft and/or the plug-on part. The plugging on operation is thus greatly facilitated. Incorrect plugging on is impossible.
[0016] When the plug-on part is constructed for mounting on a shaft having at least two circular cross sectional areas of various diameters, with different spring elements resting against the different cross sectional areas, then it is possible for third spring elements, for example, to rest against an enlarged cross sectional area. Preferably provision is made for a first diameter for the first spring element and for a second, bigger diameter for the third spring element. When the brush attachment is pushed on, very little force is required initially because the third spring element does not take support upon the shaft until at the end of the push-on movement. This makes it easy to insert the plug-on part.
[0017] It is an advantage for the brush attachment to be encompassed by a soft-elastic padding that extends over at least a section of the brush attachment in order to equip the brush attachment with a shock-absorber function. This padding is preferably arranged in a region proximate the bristles, with a soft-elastic component preferably encompassing a hard part at least in a region opposite the bristles. This shock absorber function enables the forces acting on the teeth on contact with the bristle carrier at high frequencies of vibration to be dampened and reduced. As the result, the user does not experience the contact as bothersome or indeed painful. Drive frequencies can lie above 100 Hz and particularly between 200 and 500 Hz, for example 260 Hz or higher. Without a suitable shock absorbing effect the high acceleration could cause damage to the teeth in extreme cases. It suffices for the padding to extend over a partial area, preferably about half of a circumference and/or only in the vicinity of the brush attachment. In particular, a soft-elastic component additionally covers side areas of the brush attachment in full or in part. The padding can have a structured, in particular studded or ribbed, surface. It is optimal for the soft-elastic component to have a Shore hardness of 30 to 60 A Shore.
[0018] An embodiment of a brush attachment of the invention, the present invention itself as well as further advantages thereof will be explained in the following with reference to the description of the accompanying drawing.
DESCRIPTION OF DRAWINGS
[0019] FIG. 1 is a side view of a section of a handle of an electric toothbrush, showing a shaft;
[0020] FIG. 2 is a sectional view of the shaft taken along the section line A-A of FIG. 1 ;
[0021] FIG. 3 is a view of a brush attachment of the invention;
[0022] FIG. 4 is a cross-sectional view taken along the section line B-B of FIG. 3 ;
[0023] FIG. 5 is a cross-sectional view taken along the section line C-C of FIG. 3 ;
[0024] FIG. 6 is a cross-sectional view taken along the section line D-D of FIG. 3 ;
[0025] FIG. 7 is a view of a brush attachment of the invention similar to FIG. 1 , but in attached condition;
[0026] FIG. 8 is a view of a first variant of the brush attachment of the invention, showing a partial soft-elastic padding;
[0027] FIG. 9 is a view of a second variant of the brush attachment of the invention, showing a partial soft-elastic padding; and
[0028] FIG. 10 is a view of another variant of the brush attachment of the invention, showing a complete soft-elastic padding.
[0029] In the Figures, like parts are assigned like reference characters.
DETAILED DESCRIPTION
[0030] FIG. 1 shows a connecting area of a handle 1 of an electric toothbrush for connecting to a brush attachment 13 of the invention shown in FIG. 3 .
[0031] The handle 1 is comprised of a plastic housing and all components required for operation such as an electric motor, a gear unit, batteries or storage batteries, a controller and the like. These components are in the interior of the housing and not shown.
[0032] As illustrated in FIG. 1 , a shaft 2 made in particular of metal projects directly out of the handle 1 and performs a small torsional oscillation about its longitudinal axis at a high frequency of 260 Hz, approximately. In other words, the shaft 2 executes a vibratory motion when driven by an electric drive mechanism. Other vibratory motions, such as those along the shaft axis 3 or a combination thereof for example, are also possible. This vibratory motion is directly transmitted to bristles 50 of the brush attachment 13 . The bristles 50 are fixedly secured to the brush attachment 13 either directly in a bristle area or by way of a replaceable bristle holder, not shown. However, the bristles 50 do not move relative to the brush attachment but only relative to the handle 1 . In other words, they move together with the brush attachment 13 . The vibratory motion of the bristles 50 is used for dental cleaning and dental care.
[0033] The brush attachment 13 has a brush shank 12 —preferably made of plastic—in which a plug-on part 11 —preferably also made of plastic—is fastened by positive and/or frictional engagement therewith, being in particular snap-locked in the brush shank 12 by detent means. Preferably, the brush shank 12 is shaped in an essentially tubular configuration and the plug-on part 11 is constructed as a sleeve. At one front face or end 21 of the brush attachment 13 or the plug-on part 11 is an approximately circular receiving opening in which the shaft 2 can be inserted.
[0034] The brush attachment 13 is thus constructed to be pluggable onto and detachable from the shaft 2 of the handle 1 .
[0035] The plug-on part 11 is equipped with a first spring element 35 acting directly on the shaft 2 , as shown in FIG. 3 . This element is constructed as a detent element to engage with a detent notch 8 of the shaft 2 with a snap action. The first spring element has preferably a detent finger with an approximately V-shaped detent lug 36 , which engages in a V-shaped detent groove 8 of the shaft 2 such that the brush attachment 13 is also axially located relative to the shaft 2 , with the detent finger transmitting axial forces. The first spring element extends preferably axially in relation to the shaft 2 . With its free end the detent finger adjoins a cavity 37 of the plug-on part 11 , with material recesses 38 situated to the side of the detent finger.
[0036] The brush attachment 13 is equipped in addition with a second spring element 30 arranged in an axially offset position relative to the first spring element 35 .
[0037] According to the invention the second spring element 30 is arranged on the plug-on part 11 and acts likewise directly on the shaft 2 . As the result, the brush attachment 13 , or to be more precise the plug-on part 11 , takes support upon two axially spaced points of the shaft 2 , thus permitting the use of high drive frequencies. The axial distance A 5 (cf. FIG. 7 ) between the first spring element 35 and the second spring element 30 amounts to preferably 5 to 20 mm, particularly around 8 to 14 mm, e.g., 12 mm, which is a good compromise between minimizing the sleeve dimensions and maximizing the noise damping.
[0038] As FIGS. 4 and 5 show, the first spring element 35 and the second spring element 30 are arranged preferably in the same radial position, the second spring element 30 being arranged on an area close to the bristle carrier or the bristles 50 while the first spring element 35 is arranged at a location more remote from the bristle carrier, as illustrated in FIG. 3 . The detent finger 35 points preferably in the direction of the handle 1 .
[0039] As FIGS. 3 and 7 show, the second spring element 30 is comprised of an axially aligned spring bar with a bend curved toward the shaft 2 . This spring bar is constructed in particular as a bending bar. The spring bar lies between two axial slots 51 , 52 or recesses 31 ( FIG. 4 ) of the plug-on part 11 . When the brush attachment 13 is plugged on, the spring bar 30 is bent slightly outwardly, its spring force operating to urge it directly against the shaft 2 , as shown in FIG. 7 . The detent finger 35 presses likewise with its spring bar and/or detent lug 36 against the shaft 2 . The distance A 3 ( FIG. 4 ) is smaller than the distance A 1 ( FIG. 2 ). The difference is equal in particular to less than 1 mm.
[0040] The spring action of the bent spring bar 30 is obtained necessarily by demolding when, after the plug-on part 11 is injection-molded, a core provided in the manufacturing process for this bent shape is withdrawn.
[0041] The plug-on part 11 is equipped with a third spring element 22 in an axially offset position relative to the first two spring elements 30 , 36 , which lies preferably in the vicinity of the receiving opening or is arranged on the end 21 close to the handle 1 . The first spring element 35 then lies between the second spring element 30 and the third spring element 22 .
[0042] As becomes apparent from FIG. 6 , the third spring element 22 is comprised of several, in particular three, radially offset resilient fingers 53 - 55 , which in the mounted state also urge against the shaft 2 . The fingers 53 - 55 extend axially and point preferably toward the handle 1 and are relatively short, preferably only 1 to 3 mm long. Free spaces 23 exist between the fingers 53 - 55 .
[0043] In the non-inserted state the free ends of the fingers 53 to 55 adjoin a(n only imaginary) circular line 24 ( FIG. 6 ) with a diameter D 3 . The diameter D 1 of the shaft 2 in this area is bigger than the diameter D 3 , thus producing a radial bias between a rear section 4 ( FIG. 1 ) of the shaft 2 and the fingers 53 - 55 of the plug-on part 11 .
[0044] As is shown in FIGS. 1 and 2 , the shaft 2 is constructed with several cross sectional areas, including one area with a circular cross section and a diameter D 1 in the vicinity of the handle 1 for the third spring element 22 , one area, which is roughly in the middle of the shaft 2 , with a likewise circular cross section and a somewhat smaller diameter D 2 for the first spring element 35 , and one forward area with a reduced cross section (cf. A 1 in FIG. 2 ) for the second spring element 30 on the free end of the shaft 2 . On this forward end close to the bristle carrier the shaft 2 has an essentially D-shaped cross section. In this region are two parallel surface areas 6 and 7 . The surface area 7 , which makes contact with the second spring element 30 , is smaller, for example ¼ to ¾, in particular approximately half the size of the opposite surface area 6 . The surface area 6 lies in the vicinity of the axis 3 , while the flattening 7 or surface area 7 lies close to the circumference of a forward section 5 . The distance A 2 can be smaller than 1 mm, for example. The surface area 6 can also meet exactly with the axis 3 or even be arranged above it. The distance A 1 between the two surface areas equals preferably about 1.5 to 2.5 mm or approximately half the diameter D 2 . The diameter D 2 equals preferably 80% to 97% of the diameter D 1 and in particular 3 mm to 5 mm, for example 4 mm. The distance A 4 between the second and the third spring element 30 , 22 is relatively large and equals preferably 20-40 mm, particularly 23-27 mm. This is favorable for the transmission of bending moments between the shaft 2 and the plug-on part 11 .
[0045] The third spring element 22 lies in the shaft area with the biggest diameter D 1 . The first spring element 35 lies in the area with the reduced diameter D 2 , and the second spring element 30 thus lies in the D-shaped forward area of the shaft. The plug-on part 11 encloses the D-shaped area such that the brush attachment 13 can be plugged onto the shaft 2 in a certain radial position only.
[0046] A plane area 29 ( FIG. 4 ) of the plug-on part 11 rests flush on the surface area 6 ( FIG. 2 ) such that high torques can be transmitted. The spring bar 30 can transmit lateral forces and bending moments between the shaft 2 and the plug-on part 11 .
[0047] A frontal insertion bevel 60 in the vicinity of the surface area 6 and a further insertion bevel 61 in the area of the diameter D 2 facilitate the plugging on such that the brush attachment 13 rotates into the correct position on its own.
[0048] FIG. 3 shows further that the plug-on part or the sleeve 11 is press-fitted into the brush shank or secured therein by frictional engagement, namely at points 14 and 15 at the ends respectively of the sleeve 11 . In axial direction the sleeve 11 is additionally fastened by positive engagement of an annular, outwardly extending fastening collar 16 with the brush shank 12 , for which a groove 17 is provided on the brush shank 12 . The sleeve 11 is thus held by in the brush shank 12 by both frictional and positive engagement therewith.
[0049] FIGS. 8 and 9 illustrate a very advantageous embodiment of the brush attachment 13 with soft-elastic areas. The soft-elastic construction is useful in combination with the spring element arrangement of the invention. This construction, which is shown in FIGS. 8 or 9 , can also be used in combination with a different plug-on solution.
[0050] The brush attachment 13 or the brush shank 12 has a soft-elastic padding 70 , 71 or 76 . This padding extends at least over a section of the brush attachment and covers preferably at least a rear side of the area set with bristles. In other words, this padding 70 or 71 is arranged preferably in a region proximate the bristles. A soft-elastic component, which forms the padding 70 or 71 , encompasses a hard part 72 or 73 , which lies in an area opposite the bristles 50 . The padding 71 extends preferably over a partial area, preferably about half of a circumference, and exists only in the vicinity of the bristles 50 .
[0051] The soft-elastic component can cover in addition side areas of the brush attachment in full or in part, as shown in FIG. 8 .
[0052] As illustrated in FIG. 10 , a soft-elastic padding 76 can also enclose the brush attachment 13 in full.
[0053] The soft-elastic, in particular rubbery plastic mass is injection-molded using a two-component plastic injection-molding process.
[0054] This elastic padding can have a structured, in particular studded or ribbed, surface, such that the brush shank is particularly good to grip.
[0055] If the bristles 50 are omitted or replaced by massage elements, such a vibrating device with a soft-elastic component can also be used as a massaging device.
[0056] A number of embodiments have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting of the invention described herein. The scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced herein.
[0000] List of Reference Characters
[0000]
1 handle
2 shaft
3 axis
4 section
5 section
6 , 7 surface areas
8 detent groove
11 plug-on part
12 brush shank
13 brush attachment
14 , 15 points
16 fastening collar
17 groove
21 end
22 third spring element
23 free spaces
24 circular line
30 second spring element
35 first spring element
36 detent lug
37 cavity
38 material recesses
50 bristles
51 , 52 slots
53 - 55 fingers
61 , 62 insertion bevels p 0 70 , 71 , 76 padding
72 , 73 hard part | 1a
|
FIELD OF THE INVENTION
This invention relates to a machine for the manufacture of brushes and, more particularly, to a machine wherein the bristle bunches are weldably secured to a brush head.
BACKGROUND OF THE INVENTION
in the classic brush construction (German AUS No. 1114463), the bristle bunches are fastened by pressing them into openings of the brush head member. The bristles are bent at 180° prior to the pressing in operation and have a thin wire around them at the bent area. Bunches which are prepared in this manner are then pressed into the holes of the brush head member. The holes were earlier prepared by a drilling operation.
Machines are used for these operations, with which brush head members can be rotated into any desired positions, so that openings of any desired direction can be provided in the brush head member and pushingin elements for pressing in of the bunches can each be aligned to the axis of the receiving opening. A machine of this type is illustrated in the aforesaid German AUS No. 1114463, in which a turret rotates about a vertical axis. Such machines can, however, also be built with turrets which are rotatable about horizontal axes. Any type of brush shapes can be manufactured with these machines, wherein the brush head can also have a curved bristle-lined surface and the bristle bunches can have any desired directions, so that any desired angular dispersion can be manufactured. This is an important advantage because for many brushes a lateral projection of the bristles beyond the lateral edges of the brush head is desired so that the bristles will reach into corners, which would otherwise be prevented by the brush head contacting a wall surface. At this point it is remarked that the term brushes is not only to include brushes in the more narrow sense, namely relatively short-bristle articles with relatively stiff bristles, but also other articles, as for example brooms and whisk brooms.
The classic brush construction requires a brush head, which is sufficiently thick that the openings which are needed for pressing in of the bunches can be manufactured with the necessary depth, for which reason the brush heads are relatively thick parts. The areas in which the bristles engage the holes are not accessible. Germs and other contaminants can settle therein, which raises doubt with respect to hygiene, for example, where brushes are to be used for creating conditions as sterile as possible, for example in hospitals.
Brushes have also become known lately in which bristles consisting of a thermoplastic plastic material are welded to a brush head which also consists of a thermoplastic material. For the manufacture of such brushes, machines are used (see for example U.S. Pat. No. 3,604,043) which have a bristle magazine, in which bristles, which are cut to length, are stacked. Holes are provided in the magazine wall for receiving small tubes therein, which small tubes are mounted on a bunch holder and are filled with bristles when inserted into the magazine. The ends of the bristle bunches are then pressed against a heating plate and are warmed up until the bristles melt together. The brush head which consists of thermoplastic material is also melted at each desired fastening point and several bristle bunches are simultaneously welded to the brush head. The brush head has a flat bristle-lined surface.
Such brushes have the advantage that openings for engagement by the bristle bunches are not required, so that the brush head can be constructed relatively thin. Also depressions do not exist for the collection of contaminants. It is disadvantageous that machines do not exist which permit the manufacture of brushes of any desired shape, thus for example of brushes with a fanned bristle bunch arrangement, in which the angle of inclination differs from bristle bunch to bristle bunch.
The basic purpose of the invention is to provide a machine which permits a manufacture of brushes with bristle bunches which are welded to the brush head, which have just like in the classic brush construction any desired shape, wherein also any desired direction of the bristle bunches is possible.
The attainment of this purpose is based on a conventional (German Pat. No. 1114463) machine for the manufacture of brushes wherein at least one brush head mounting structure for brush heads is provided, which mounting structure is pivotal about two axes, and furthermore is longitudinally movable. The machine includes a bristle bunch holder for gripping of bristle bunches and which is movable for supplying the bristle bunch to a brush head. Such a machine is characterized inventively by arranging at least two heating elements with contact heating surfaces thereon between the bunch holder and the brush head mounting structure, which are provided on a movable heating-element carrier movable between an engaging position in which one heating surface is adjacent to the brush head and the other adjacent to the bunch holder, and a rest position, which lies outside of the range of movement of the bunch holder.
The brush member can be swung with such a machine just like with the classic brush manufacturing machines into any desired position. The brush head is now melted at the desired location with a heating element, while at the same time the other heating element melts a bristle bunch at its end. After swinging out of the heating elements from the area between the brush head and bristle bunch, the bristle bunch is guided to the brush head and is welded to same. During the creation of the contact between the bristle bunch and the brush head, the places which had been warmed up earlier with the heating elements are still in a tacky condition. After welding of the bristle bunch to the brush head, the bunch holder returns into its initial position, the brush head is swung into a new position and the heating elements are swung between the bristle bunch holder and the brush head, after which the described operations are repeated.
The invention brings about the advantage that it is now also possible to manufacture brushes with bristle bunches weldably secured thereto in any desired overall shape so that the advantages of classic brushes, namely their advantageous overall shapes are related to the advantages of brushes with bristles welded to the brush head, namely thin brush heads can be used and the more advantageous hygienically maintainable brushes are obtained. Also the process of drilling bristle-fastening holes is no longer necessary.
It is preferable to arrange the two heating elements on one heating piece, because then only one movement device is needed for the heating elements. However, embodiments are also part of the invention in which two separate heating elements with separate movement devices are used. The movement devices for the heating-element carrier can be pivotally mounted on a frame for the aforesaid movement, even though other movement devices can also be used. Thus the movement and pulling back of the heating-element carrier could also take place along a rectilinear guideway.
It is also an object of this invention to provide an arrangement of a bristle magazine from which the bristles are inserted into small tubes, as this is actually known from the state of the art. However, it is also possible to weld bristles which are bent at 180° to a brush head. The removal of the bristles from the magazine can, as is actually known, occur by introducing the small tube into the magazine. However, it is also possible according to the invention to secure a small tube on the magazine, into which small tube bristles are pushed by a plunger.
Various other embodiments are possible for the invention. One embodiment includes a movably arranged bristle magazine. Of course, not all objectives need to be simultaneously realized in this embodiment. For example, in place of cam plate gearing driving the magazine carriage for movement, it would also be possible to use fluid pressure power cylinders for the movement thereof. The use of a magazine having several compartments provides a means of selection, namely, permitting the use of several bristle types on one brush, for example hard and soft bristles or bristles of differing colors. With this type of magazine, it is also possible to provide bristle bunches of differing thicknesses. The size of the bunch is determined by the plunger diameter and the small tube diameter. The plunger and the small tube can be easily exchanged.
A further embodiment in which bristles can be processed from a spool is also possible. Such an embodiment has naturally no bristle magazine with bristles stored therein and which are cut to length. This embodiment has the advantage that the operation of cutting to length away from the machine is omitted.
The parallel arrangement of several brush head mounting structures has the advantage that the output of the machine is increased, namely, by a factor which equals the number of the parallel arranged brush head mounting structures, etc. It must be remarked here, that the heating up and welding of a bristle bunch to a brush head takes more time than pushing a bristle bunch into a hole. This disadvantage is partly cancelled by the time it takes to drill the holes in the brush head, which step is deleted, however, the time for the drilling of a hole and the pushing in of a bristle bunch together is still shorter than the time for heating up and welding of a bristle bunch to the brush head. The output of an inventive machine can, however, be achieved in a desired degree by the described parallel arrangement of brush heads and bristle bunch holders.
The method of operation has the advantage that the heated-up locations on the brush head and on the bristle bunch can contact one another in as short a time as possible after the heating-up procedure. However, due to the material character a certain phase shifting between the heating up of the brush head and the heating up of the bristle bunch can also be preferable. It is also possible to use different time intervals for contact between the one heating element and the brush head and for contact between the other heating element and the bristle bunch.
BRIEF DESCRIPTION OF THE DRAWINGS
Exemplary embodiments of the invention are illustrated in the drawings, in which:
FIG. 1 is a partial side view and a partial vertical cross-sectional view of a machine having a movable bristle magazine;
FIG. 2 is a side view of a bristle magazine, which can be used in a machine according to FIG. 1;
FIG. 3 is a cross-sectional view taken along the line III--III of FIG. 2;
FIG. 4 is a side view of a machine having a stationarily arranged bristle magazine;
FIG. 5 is a top view corresponding with the line V of FIG. 4;
FIG. 6 is a side view of elements of a machine with the supply of bristles from a storage roll; and
FIG. 7 is a view of the elements according to FIG. 6 in direction of the arrow VII of FIG. 6.
DETAILED DESCRIPTION
The machine according to FIG. 1 has a frame 1, of which only the upper area is illustrated. A turret 2 with several brush head mounting structures thereon, a bristle magazine 3 and a drive mechanism identified as a whole by the reference numeral 4, are arranged on the machine frame 1. The turret 2 and the bristle magazine 3 are movable along a pair of parallel guide rods 5 which are secured to the frame 1. A further important element of the machine is a heating-element carrier 6 having heating elements 7 and 8. The mentioned main parts will be discussed individually hereinbelow.
The turret 2 is arranged on a carriage 9, on which all together four guide sleeves 10 are provided, which are slidable on the guide rods 5. Bearing blocks 11 extend upwardly from the carriage 9, in which bearing blocks is supported a shaft 12 of the turret 13.
A mounting structure or brush head holder 14, 15 for the brush heads 16 is provided on the turret. The mounting structure 14 and 15 can both be moved vertically and also can be pivoted about two axes which are at a right angle with respect to one another, which is illustrated in FIG. 5. We deal here with a technique which is actually known in brush making machines.
Several mountings 14 and 15 are preferably arranged side-by-side at a right angle with respect to the drawing plane for FIG. 1.
The brush magazine 3 is arranged on a carriage 17, on which four guide sleeves 18 are provided, which are also movable along the guide rods 5. A hopper 19 extends upwardly from the carriage 17 for receiving bristles 20 therein which have been cut to length. The width b of the hopper 19 equals the length of the bristles. The hopper has an enlarged portion 21 at the upper end, which portion makes the placement of the bristles into the hopper 19 easier.
An opening 22 exists in the wall 19a of the magazine hopper. A small tube 23 is secured on the opposite wall 19b, which small tube is in axial alignment with the opening 22. A plunger 24 is received in the opening 22, the axis of which plunger is in alignment with the axes of the small tube 23 and naturally the opening 22.
A further carriage 63 is movably supported by means of guide sleeves 64 on the rods 5. A pivot 65 is provided on the carriage 63 for the connection to a push rod which, however, is not illustrated in the drawings. A member 25 is rotatably supported on the carriage 63 about the axis 26. The rotatable driving device which is used to rotate the member 25 is not illustrated in the drawing. An arm 27 projects from the member 25 and has an upwardly projecting section 27a, at the end of which is secured a holder 28 for a heating rod 29. The ends of the heating rod 29 form the heating elements 7, 8. The axis of the heating rod 29 is axially aligned with respect to the axis 23a of the small tube 23.
A push rod 31 engages the wall 19c of the magazine hopper at 30, which push rod is pivotally connected at 32 to one arm 33a of a two-arm lever 33. The two-arm lever 33 is pivotally supported at 34 on a frame 35 supporting the elements of the drive mechanism 4. The other arm 33b has a feeler roll 36 thereon which engages a cam 39' rotatably supported on a shaft 38. The shaft 38 is rotatably supported in bearing blocks 39 which are secured to the frame 1.
An arm 40a of a two-arm lever 40 engages a further cam 37, which is positioned on the shaft 38, which two-arm lever 40 is also pivotally supported on the frame 35. A connecting plate 43 is pivotally connected as at 42 to the other arm 40b of the lever 40. The connecting plate extends to a carriage 44, to which it is pivotally connected at 45. The carriage 44 is slidable on guide rods 46 and is connected to a push rod 47, which is slidably supported in a guide sleeve 48. The already mentioned plunger 24 is secured to the front end of the push rod 47.
The machine operates as follows:
FIG. 1 illustrates a position in which the heating rod 29 is provided between the brush head 16 and the small tube 23. The small tube is filled with bristles 20, which are pushed into the small tube by the plunger 24 and a cyclical operation of the drive mechanism. The bristles project slightly beyond the left end (FIG. 1) of the small tube 23.
After the small tube 23 is filled with bristles, simultaneously the heated heating element 7, which is on the left side of the holder 28 (FIG. 1) contacts the brush head 16 caused by a moving of the carriage 63 by the drive mechanism 4 to the left to melt a small portion thereof and the bristle bunch which is provided in the small tube 23 contacts the heating element 8 caused by a moving of the magazine carriage to the left by the drive mechanism 4 to melt a small portion thereof.
The location to which the bristles are to be attached to the brush head 16, which consists of thermoplastic material, is melted by this procedure. The ends of the bristles 20, which project from the small tube 23, are at the same time melted by this procedure. The heating elements are thereafter slightly removed from the melted locations, which can be done in various ways, for example by slightly moving the bristle magazine and slightly moving the carriage 63. Alternatively, one could also slightly move the turret with the brush head mounting structure thereon. Also possible is a pulling back of the heating elements, which could then for example be telescopically constructed. After removing the heating elements from the melted locations, the member 25 and arm 27 is swung outwardly at a certain angle, for example at 90°, so that the two heating elements 7 and 8 come out of the area between the small tube 23 and the brush head 16. The bristle magazine 3 is now moved forwardly by the cam 39' through the lever 33 and the push rod 31 until the melted, still tacky ends of the bristle bunch contact the melted point on the brush head. The bristle bunch is hereby welded to the brush head 16. During the following pulling back of the bristle magazine 3, the bristle bunch remains adhered to the brush head 16, so that the small tube 23 can be pulled off from the bristle bunch.
The mounting structure 15 for the brush head carries now out such movements that the next fastening point for a bristle bunch is aligned with respect to the small tube 23. Simultaneously therewith or also thereafter, the arm 27 and the heating rod 29 thereon is again swung between brush head and the small tube 23. The plunger 24 moves a further bristle bunch into the small tube 23 and the described operation is repeated.
Since the melting procedure and the welding or attachment procedure does require a certain amount of time, it is preferable to simultaneously weld bristle bunches to several brush heads. The turret 13 can for this purpose be constructed relatively long, viewed at a right angle with respect to the drawing plane for FIG. 1, and several brush head mounting structures 15 can be arranged side-by-side. The movement of all of these mountings can be effected from the same drive mechanism 4.
When the brush head 16 is completely occupied with bristles, the turret 13 is swung 180°, after which a new bristleless brush head 16 reaches the welding station. The finished brush is then removed and is replaced with a new bristleless brush head.
A brush is illustrated in the drawing, in which the angle of inclination of the bristle bunch differs from bunch to bunch. This arrangement is possible with the inventive machine. The inclined position is also different in the rows which extend at a right angle with respect to the drawing plane for FIG. 1. This can be achieved also in flat brush heads. However, one will often use in this case arced brush heads. At any rate, the inventive machine permits the manufacture of any kind of brush shape.
In the modification illustrated in FIGS. 2 and 3, the brush magazine which is here identified as a whole by the reference numeral 3' is not only movable in a direction toward the brush head, but also at a right angle to said direction. A box 49 is for this purpose suspended on a swivel bearing 50. An axle 50A projects sidewardly from the swivel bearing 50. A suspended plate 51 is connected to the axle 50A and the box 49 is secured to the lower end of the suspended plate 51. A piston rod 53a of a power cylinder which is identified as a whole by the reference numeral 53 is pivotally connected at 52 to the sidewall 49a of the box, the cylinder portion 53b of which cylinder being pivotally connected at 54 to a bracket 55, which can be secured for example on the carriage 17 according to FIG. 1. The swivel bearing 50 could also be fixedly mounted on the carriage 17.
The suspended plate 51 forms at the same time a partition between two compartments 56 and 57 in the box 49. Various bristle types are supported in the compartments, for example hard bristles 58 and soft bristles 59. Various bristle colors are also often used.
An opening 60 or 61 is associated with each compartment 56 and 57, which opening corresponds with the opening 22 according to FIG. 1. A small tube is arranged opposite each opening. FIG. 3 shows the small tube 62 which is opposite the opening 60.
With the aid of the cylinder 23 the opening 60 or the opening 61 can be selectively axially aligned with a plunger 24', which corresponds with the plunger 24 of FIG. 1.
By suitably adjusting the box 49, either bristles 58 or bristles 59 can be welded to the brush head.
Alternative with respect to the shown exemplary embodiment, it is also possible for the plunger to slide in a guideway which is connected to the magazine. The plunger is then not fixedly connected to the plunger push rod, as this is illustrated in FIGS. 1 and 3. Instead, the pugh rod presses onto the plunger which is supported on the magazine, which is aligned with respect to the push rod.
The machine according to FIGS. 4 and 5 also has a turret which is here as a whole identified by the reference numeral 2' and which is constructed and is supported in the same manner as the turret 2 according to FIG. 1.
A heating-element holder having heating elements 7' and 8', which holder is identified as a whole by the reference numeral 6', exists also again. The heatingelement holder is again arranged on a rotatably supported member 25'. The member 25', however, is provided on a separate carriage 63, which is movably supported by means of four guide sleeves 64 on guide rods 5'. A pivot 65 for the connection to a push rod, which, however, is not illustrated in the drawings, is provided on the carriage 63.
A further carriage 66 having guide sleeves 67 thereon is movable along the guide rods 5'. A bearing block 68 extends upwardly from the carriage 66, on which bearing block is rotatably supported a turret which as a whole is identified by the reference numeral 69. The turret 69 includes a plate 70 thereon, on which all together four small tubes 71 are secured and project in direction of the brush head 16'. The small tubes 71 are angularly spaced at 90° with respect to one another.
The plate 70 is positioned on a shaft, with which is fixedly connected a ratchet wheel 72. A ratchet 73 cooperates with a ratchet wheel 72, which ratchet 73 is movable by means of a drive lever 74. The plate 70 can be rotated step-by-step through 90° intervals with the aid of the ratchet mechanism.
A push rod 78 engages at one end and at 75 the carriage 66, which push rod is pivotally connected at 79 to the arm 80a of a two-arm lever 80. The lever 80 is pivotally supported at 81 on the machine table 1'. The other arm 80b carries a feeler roll 82, which cooperates with a cam 83, which (see here also FIG. 5) is mounted on a shaft 84. The shaft 84 is driven for rotation by a V-belt, for example, connected to a V-belt pulley 85 on the shaft.
A bristle magazine 86 is stationarily arranged on the machine table 1' and is filled with bristles 87. The position of the magazine is side-by-side with the brush head supporting the turret 2'. The small tubes 71 on the plate 70 are angularly spaced so that simultaneously one small tube 71 is aligned with respect to the bristle magazine 87 and another small tube is aligned with respect to the brush head 16', when the plate 70 is in one of its locked positions. The two other small tubes 71 do not have any operating function in this stage. These two functionless small tubes reach after a further rotation of 90° the aforesaid operating position.
One will recognize from the view of FIG. 5, and as stated above, the mounting structure 14' and 15' for the brush heads 16' are swingably supported. A description of details for this is not required since such supports and drives are known in classic brush making machines, for example from German Pat. No. 1114463.
The machine according to FIGS. 4 and 5 operates as follows:
Starting out from the illustrated position, the heating elements 7' and 8' contact in the same manner the brush head 16' or the end of a bristle bunch 870, as this was described already with reference to FIG. 1. After the heating elements are swung out of the way about the axis of the member 25, the carriage 66 is moved forwardly, wherein at the same time welding of the earlier melted bristle bunch 870 to the brush head 16' and the removal of a bristle bunch from the magazine 86 occurs. In addition, and during movement of the carriage 66, the small pipe 71, which is aligned with a corresponding opening in the wall 86a of the magazine 86, also penetrates into the magazine and is thereby filled with bristles 87.
After welding of a bristle bunch to a brush head, the carriage 66 is pulled or retracted back, wherein the small tube 71 is pulled away from the welded bristle bunch and at the same time a small tube which is filled with bristles is pulled out of the magazine 86. After this a rotation of 90° of the turret 69 takes place and a small tube which is filled with bristles reaches the welding station. If one conceives that in FIG. 4, viewed from the right, the turret rotates clockwise, the lowermost small pipe 71 is filled with bristles, while the uppermost small pipe 71 is empty. If the movement would occur counterclockwise, then the uppermost small tube 71 would be filled with bristles, while the lowermost small tube would be empty.
The manufacture of any desired brush shape is possible also with the machine according to FIGS. 4 and 5.
The embodiment according to FIGS. 6 and 7 is only partly illustrated. Part of this machine also includes a turret with brush head mounting structure corresponding with the brush head mounting structure 14, 15 or 14', 15'. Such a mounting structure, which is identified by the reference numeral 15", is illustrated isolated in FIG. 6. The also isolated illustration of the heating-element holder 6" is supported in the same manner as is described with reference to FIGS. 4 and 5. In addition, the machine according to FIGS. 6 and 7 has a turret, which is here identified as a whole by the reference numeral 88. The turret 88 is supported on a bearing block 89, which is provided in turn on a carriage corresponding with the carriage 66 according to FIG. 4.
The turret 88 includes a stationary plate 90, on which is arranged an inlet nozzle 91. A plate 92 rests on the plate 90, which plate 92 is rotatable, and on which plate 92 are provided small tubes 93, namely four small tubes, which are angularly spaced from each other at 90° with respect to one another.
A tooth system consisting of saw-tooth-shaped teeth 94 is arranged on the periphery of the plate 92, which cooperates with a transport pawl 95. The transport pawl 95 ia pivotally supported at 96 on a lever arm 97a of a two-arm lever 97. The lever 97 is pivotally supported at 98. The bearing 98 is preferably rigidly connected to the bearing block 89. A pivot 99 for a rod which is not illustrated is provided on the other lever arm 97b for pivoting the lever 97.
A drive roller system 100 consisting of transport rollers 100a and 100b is arranged in front of the inlet nozzle 91. The transport roller pair 100 is fixedly arranged relative to the stationary plate 90.
A mounting for a storage spool 102, which mounting is identified as a whole by the reference numeral 101, is furthermore part of the machine. The storage spool is rotatably supported in bearings 103 and 104. Bristle material 105 is stored on the storage spool, preferably a strand of several parallel fibers.
The machine according to FIGS. 6 and 7 operates as follows:
The movement of the heating-element carrier 6" and of the turret 88 occurs as this has already been described with reference to FIGS. 4 and 5. The difference from the embodiment according to FIGS. 4 and 5 consists only in the filling of the small tube 93 with bristles. This filling is done by the transport rollers 100a and 100b being moved step-by-step and thereby moving the bristle strand 105 for the length of a bristle bunch. The bristle material strand is hereby moved forward through the inlet nozzle 91 and the respective small tube 93, which is aligned therewith, until the front end of the strand projects from the small tube.
The plate 92 is now rotated 90° in direction of the arrow 106 (see FIG. 7). The edges 107 of the opening of the inlet nozzle and 108 of the adjacent opening in the small tube 93 act as cutting edges, which cut off the strand 105. After two further rotary steps of the plate 92 the bristle bunch reaches the welding position and is welded to the brush head as this has already been described with reference to FIGS. 4 and 5.
Although particular preferred embodiments of the invention have been disclosed in detail for illustrative purposes, it will be recognized that variations or modifications of the disclosed apparatus, including the rearrangement of parts, lie within the scope of the present invention. | 1a
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[0001] This application is a continuation of Ser. No. 11/108,784 filed Apr. 19, 2005, which is a continuation of Ser. No. 09/904,568 filed Jul. 16, 2001, now abandoned, which claims priority to Canadian patent application No. 2,312,256 filed Jul. 14, 2000 and which is a continuation-in-part of Ser. No. 09/223,796 filed Dec. 31, 1998, now abandoned, which is a continuation-in-part of Ser. No. 08/667,495 filed Jun. 21, 1996, now abandoned.
FIELD OF THE INVENTION
[0002] The present invention relates to a novel gene that shows tissue specific expression and increased expression in a low calcium concentration medium and in hypertensive animals, and which is potentially involved in the regulation of cell proliferation.
BACKGROUND OF THE INVENTION
[0003] Calcium ion is an essential element of life with distinct extracellular and intracellular roles. Extracellular functions of calcium include its role in blood clotting, intercellular adhesion, bone metabolism, maintenance of plasma membrane integrity whereas its intracellular roles include protein secretion, cellular contraction and division. The free extracellular calcium concentration is maintained within a narrow range (−1 to 1.3 mM) and that of intracellular calcium is in the order of 100 nM; 10,000 fold lower than the extracellular free calcium concentration.
[0004] The first priority of the extracellular calcium homeostatic system is to maintain a normal extracellular ionized calcium concentration. This component represents approximately 45% of the total circulating calcium concentration. Another 45% of total circulating calcium is bound to proteins (primarily albumin) and about 10% is Pound to small organic anion. Therefore, ionized calcium concentration in plasma is maintained within a very narrow range. The major players maintaining extracellular calcium homeostasis are calciotropic hormones, parathyroid hormone (PTH), 1,25 dihydroxyvitamin P, calcitonin and calcium itself. Indeed, extracellular calcium regulates its own concentration as an extracellular messenger by acting on cells involved in the control of extracellular calcium homeostasis such as parathyroid. bone, intestine and kidney cells (56). For example, parathyroid cells are key sensors of extracellular calcium in vertebrates responding with increases in PTH secretion when there is a decrease in calcemia while high calcemia stimulates hormonal release of calcitonin from C cells of the thyroid gland
[0005] Cells of the parathyroid gland possess such a calcium sensor (6). Even slight reductions in extracellular ionized calcium concentration (in the order of 1-2% or less) elicit prompt increases in the rate of PTH secretion and mRNA levels. Renal responses to the increase in circulating levels of PTH relevant to mineral ion metabolism include phosphaturia and enhanced distal tubular reabsorption of calcium. The most rapid changes In calcium handling by the target tissues of PTH take place in the kidneys and skeleton
[0006] The parathyroid gland is particularly well positioned to respond to hypocalcemic stresses. The parathyroid cells (and probably few other cell types) are capable of sensing the changes in the extracellular calcium concentration. The process of calcium sensing (that Is a capacity to recognize and respond to physiologically meaningful changes in extracellular calcium), differs from simple calcium dependence. A parathyroid calcium receptor has been recently characterized. It is present on the cell surface and interacts not only with calcium but also with a variety of other divalent cations as well as with polycations. The receptor has probably at least two binding sites that confer positive cooperativity to it. The putative calcium receptor is linked to several intracellular second messenger systems via guanylyl nucleotide regulatory G proteins and activate a phosphoinositide specific phospholipase C leading to accumulation of inositol 1,4,5 triphosphate (IP3) and diacylglycerol (1-5). Such a receptor is also found in the proximal tubular cells consistent with a regulation of tubular function through a mechanism similar to that in parathyroid cells. Hypocalcemia promotes parathyroid cellular hypertrophy and increases levels of the mRNA for PTH. 1,25 dihydroxyvitamin D has a clear inhibitory effects on parathyroid cellular proliferation.
[0007] Historically, research on the parathyroid gland has focused on the chemistry, regulation, synthesis and secretion of PTH There is growing interest in other calcium-regulating proteins of this gland that are also negatively regulated by extracellular calcium, such as chromogranin A and Secretory Protein-I (7), as well as a hypertensive factor of parathyroid origin (PHF) (8, 9). This hypertensive factor of parathyroid origin has been recently documented with similarities to an Intracellular calmodulin-PDE activator, described in hypertensive tissues and organs (57, 58) This factor increases blood pressure when injected into anesthetized rats and has been shown to potentiate the action of pressor agents (norepinephrine) on the contraction of vascular smooth muscle (59).
[0008] Diseases associated with hypertension include arteriosclerosis. hypertensive renal failure, stroke, heart failure and myocardial infarction, to name a few. While methods to treat hypertension are available, the etiology of hypertension, for the most part, remains unknown.
[0009] A number of persons have attempted to purify the active component of parathyroid hypertensive factor in an attempt to improve methods of treating patients with diseases which involve extracellular calcium elevation, such as hypertension. In one patent application, PCT 93US5626, the inventors describe a purified and isolated parathyroid hypertensive factor component including a polypeptide linked to a phospholipid. This component produces a delayed onset of an increase in blood pressure of a normotensive rat to which it is administered. The increase in blood pressure is said to temporarily correlate with an increase in extracellular calcium uptake by vascular smooth muscle. However, this factor, when highly purified, is not greatly increased in hypertensive states
[0010] Similarly, other hypertensive factors derived from parathyroid gland are described in other patent applications, such as Japanese patent application 413-4098 and PCT 90US1577. The factors are obtained by culturing, dialyzing, ultrafiltering, refrigerating drying plasma component and separating the active fraction by gel filtration column chromatography. Again, these factors are not greatly increased in hypertensive states.
[0011] Despite the work that has been done in the area of hypertensive factors, a need still exists to identify a mammalian gene which is increased in hypertensive states. This gene could be used (1) to treat diseases related to modulation in calcium levels, (2) to screen pharmaceutical components which are effective in treating diseases related to modulation in calcium levels, or (3) for the diagnosis of the presence of diseases related to modulation in calcium levels. Diseases related to modulation in calcium levels include hypertension, hyperthyroidism, osteoporosis, osteopetrosis, heart failure, Insulin dependent and independent diabetes, cancer (including breast, thyroid, colon, kidney and leukemia), disorders of the central nervous system including stroke, atherosclerosis, gastrointestinal diseases, inflammatory bowel disease and asthma.
[0012] In particular, arterial hypertension is associated with numerous disturbances of calcium metabolism manifested not only in humans but also in genetic as well as acquired models of hypertension (10-14). Disturbances in renal and intestinal handling of calcium in hypertension have been reported by several investigators (15). Urinary calcium has generally been shown to be increased (so-called urinary leak) and intestinal calcium absorption diminished in genetically hypertensive or spontaneously hypertensive rats (SHR) (15, 16). Cytoplasmic free calcium concentration has most often been found to be elevated in circulating platelets, lymphocytes, erythrocytes, and vascular smooth muscle cells (VSMC) from hypertensive animals and humans (for review, see 17). In SHR as well as in low-renin hypertensive patients, there seems to be an inverse relationship between extracellular and intracellular calcium (18). It has been hypothesized that certain genetic abnormalities might be responsible for the link between some forms of hypertension, calcium homeostasis and the parathyroid gland. To identify new genes that might be abnormally regulated by extracellular calcium in the parathyroid gland of genetically hypertensive rats, the present inventors prepared a cDNA library from the parathyroids of SHR. In this study, the present inventors describe the isolation and characterization of a novel gene, designated HCaRG (for Hypertension-related, Calcium-regulated Gene), negatively regulated by extracellular calcium with higher mRNA levels in SHR. HCaRG is a nuclear protein with putative “leucine zipper” motifs and is potentially involved in the regulation of call proliferation.
SUMMARY OF THE INVENTION
[0013] The present inventors have identified a new gene expressed in the parathyroid gland. The expression of this gene is regulated in a way similar to that of PTH, that is hypocalcemia increases its mRNA levels. Experiments involved spontaneously hypertensive rats (SHR), models of low renin hypertension, and normotensive counterparts Wistar-Kyoto (WKY). The expression of this novel gene was higher in the SHR parathyroid cells than in cells from WKY. In situ hybridization studies showed that this gene has a specific pattern of expression. It is highly expressed in the tubular fraction of the renal cortex, in the medulla and the inner part of the adrenal cortex, in the intestine, In the heart and In the brain.
[0014] Therefore, the present invention relates to a nucleic acid molecule isolated from parathyroid of a mammal and whose expression is regulated by extracellular calcium concentration. In one case, the mammal is a human and the molecule encodes the amino acid sequence set out in FIG. 4 (bottom lines; SEQ ID NO:5). In another case, the mammal is a rat and the molecule encodes the amino acid sequence set out in FIG. 4 (top lines; SEQ ID NO:2). The invention includes a nucleotide molecule of a human, and having a homology of 60% or greater to all or part of the sequence set out in FIG. 1 (SEQ ID NO:3). The molecule may have a 60% or greater homology to the translated portion of the sequence.
[0015] The invention also includes a purified and isolated protein (HCaRG) encoded by the nucleic acid molecule of this invention. Mimetics of and antibodies to this protein are included within this Invention as are proteins having a homology of 60% or greater to the proteins encoded by the nucleic acid molecules of this invention.
[0016] The invention also suggests that HCaRG is a nuclear protein potentially involved in the control of cell proliferation, since HCaRG mRNA was significantly more expressed in adult than in fetal organs, and its levels were decreased in tumors and cancerous cell lines. In addition, the present inventors observed that after 60-min ischemia followed by reperfusion, HCaRG mRNA declined rapidly in contrast with an increase in c-myc mRNA. Its levels then rose steadily to exceed baseline at 48 h of reperfusion. As an evidence that HCaRG can be used to treat a disease inhibiting calcium, HEK293 cells stably transfected with HCaRG and overexpressing the same, exhibited much lower proliferation, as shown by cell count and 3H-thymidine incorporation.
[0017] A pharmaceutical composition of this invention would include at least a portion of the protein encoded by the nucleic acid molecules of this invention or in the alternative, a pharmaceutical composition could include a nucleic acid molecule of this invention, or a portion thereof, for use in gene therapy. The composition could be used to treat a patient suffering from a condition caused by the abnormal intracellular or extracellular modulation of calcium or abnormal proliferative disorders comprising administering an effective amount of a sense molecule hybridizing with the nucleic acid of FIG. 1 , for example, (to upregulate the molecule's expression) or an antisense molecule, for example, (to downregulate the molecule's expression) to the patient.
[0018] The molecule could be delivered as part of a recombinant vehicle, or in liposomes, for example. In one case, the molecule would include a sense or an antisense sequence to all or part of the nucleic acid sequence of a human gene sequence encoding the protein set out in FIG. 4 . The sense sequence would enhance the effect of the protein which sequence is set out in FIG. 4 . The antisense sequence would, on the contrary, suppress the effect of the same.
[0019] Included within this invention is a kit for the detection of a disease, disorder or abnormal physical state caused by abnormal modulation of calcium levels in a patient. The kit could include, as a target or as a marker, all or part of the nucleic acid molecule of this invention, for example, the sequence of a human gene encoding the protein set out in FIG. 4 . In another case, a kit could include as a marker or as a target all or part of a protein encoded by a nucleic acid molecule of this invention, a mimetic of such a protein or an antibody to such a protein. The kit could be used to help diagnose hypertension, hyperthyroidism, osteoporosis, heart failure, insulin dependent and independent diabetes, disorders of the central nervous system including stroke, cancer (including prostate, ovary, breast, thyroid, colon, kidney and leukemia), atherosclerosis, gastrointestinal diseases, inflammatory bowel disease and asthma. Once diagnosed, patients may wish to regulate extracellular calcium uptake by increasing dietary calcium levels or taking calcium supplements.
[0020] Also included within this invention is the use of the pharmaceutical compositions of this invention to treat a patient having a disease, disorder or abnormal physical state related to abnormal intracellular or extracellular calcium levels. Also included is the use of the protein of this invention or the mimetics of such protein to screen for inhibitors to such protein.
[0021] A method for assaying for abnormal intracellular or extracellular calcium levels would include (a) reacting a sample of a patient with a nucleic acid molecule of this invention, or a portion thereof, under conditions where the sample and the molecule, or a portion thereof, are capable of forming a complex; (b) assaying for complexes, free molecule, or a portion thereof, and (c) comparing with a control. In one case, the molecule is a sense or an antisense sequence to all or part of the human gene sequence encoding a protein as set out in FIG. 4 .
[0022] In another assay for abnormal intracellular or extracellular calcium levels, the assay includes (a) reacting a sample of a patient with a protein of this invention, or a portion or a mimetic thereof, or an antibody thereto, under conditions where the sample and the protein, or a portion or a mimetic thereof, or an antibody thereto, are capable of forming a complex; (b) assaying for complexes, free protein, or a portion or a mimetic thereof, or an antibody thereto, and (c) comparing with a control.
[0023] A method for differentiating normal cells and cells of a tissue exhibiting an abnormal intra-cellular or extra-cellular calcium level (such as “diseased tissue” includes but is not limited to cancer cells), is also within the scope of this invention. This method involves a step of contacting a diseased tissue with a detectable ligand which binds to HCaRG protein or nucleic acids. Examples of ligands are hybridizing probes, antagonists or antibodies. The binding of the ligand to a diseased tissue would provide boundaries that can be visualized by a therapist or surgeon, for differentiating normal tissue, not to be treated or excised, from diseased tissues to be treated (by radiotherapy or chemotherapy, for example) or excised (by surgery)
[0024] In yet another assay for screening for efficacy of products modulating (enhancing or inhibiting) abnormal calcium levels, the assay includes (a) reacting a sample of a patient with a protein of this invention, or a portion or a mimetic thereof, or an antibody thereto, under conditions where the sample and the protein, or a portion or a mimetic thereof, or an antibody thereto, are capable of forming a complex; (b) assaying for complexes, free protein, or a portion or a mimetic thereof, or an antibody thereto, and (c) comparing with a control.
[0025] Furthermore, another assay for screening for efficacy of a product for modulating (enhancing or inhibiting) abnormal intracellular or extracellular calcium levels could include (a) reacting the product with a protein of this invention, or a portion or a mimetic thereof, or an antibody thereto, under conditions where the product and the protein, or a portion or a mimetic thereof, or an antibody thereto, are capable of forming a complex; b) assaying for complexes, free protein, or a portion or a mimetic thereof, or an antibody thereto, and (c) comparing with a control.
[0026] This invention includes a method for screening for efficacy of a product for use in modulating (enhancing or inhibiting) abnormal intracellular or extracellular calcium levels, the assay includes (a) reacting the product with a nucleic acid molecule of this invention, or a portion thereof, under conditions where the product and the molecule, or a portion thereof, are capable of forming a complex; (b) assaying for complexes, free molecule, or a portion thereof, and (c) comparing with a control.
[0027] Other objects, features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples while indicating preferred embodiments of the invention are given by way of example only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
DESCRIPTION OF THE FIGURES
[0028] The invention will now be described in relation to the figures in which:
[0029] FIG. 1 . cDNA cloning of HCaRG. FIG. 1A . Reconstitution scheme of HCaRG cDNA. Overlapping fragments leading to the reconstitution of rat HCaRG 1100-bp cDNA (SEQ ID NO:1) are shown. cDNA fragments were initially obtained using 5′-RACE and 3′-RACE strategies as well as by screening a SHR parathyroid cDNA library. The first cDNA fragment was by 3′-RACE (3r 290). This initial fragment served to screen the SHR parathyroid cDNA library. Fragments HCaRG 2c-t3+2c-t7, HCaRG 825, HCaRG 10-ic, and HCaRG 10-174 were Isolated from the cDNA library. Fragments 5r 285 and 5r 260 were obtained by 5′-RACE This reconstitution was confirmed by sequencing a 860-bp PCR product with nested primers in 5r 260 and HCaRG 825 and containing the complete open reading frame. FIG. 1B . Nucleotide (SEQ ID NO:1) and deduced amino acid (SEQ ID NO:2) sequences of HCaRG. The translation initiation start site codon is at position 1 and the termination codon is at position 675 The deduced amino acids are indicated below the nucleotide sequence. The localization of a 482-bp intron is indicated at position-52 by a triangle.
[0030] FIG. 2 . Identification of a novel gene negatively regulated by extracellular calcium. FIG. 2A . Northern blot analysis of Poly A RNA isolated from parathyroid cells (PTC). HCaRG mRNA appears as a doublet of approximately 1.2 and 1.4 kb. The positions of ribosomal RNAs and GAPDH transcript are indicated. FIG. 2B . PTC Extracted from normotensive rats (WKY) (from passages 8 to 10) were incubated in low (0.3 mM) or normal (2 mM) calcium-containing medium for 2 and 48 h. Total RNA was extracted and analyzed by RT-PCR as described in the Experimental Procedures section. Incubation of PTC for 2 h in 0.3 mM (L) calcium significantly increased HCaRG mRNA compared to 2 mM (N) calcium; this increase lasted up to 48 h. FIG. 2C . Significantly higher basal HCaRG levels were found in PTC from hypertensive rats compared to the normotensive rat strain WKY (left panel). D. This was confirmed with RNA (right panel) and proteins extracted directly from the kidneys of SHR and BN./x, another normotensive strain. The figure represents the mean .+−.S.E.M. of 2 independent experiments performed in duplicate. ** indicates p<0.02, * indicates p<05 as evaluated by the unpaired t-test.
[0031] FIG. 3 . In vitro translation of HCaRG cDNA. cDNA was cloned into pSP72 vector and used for coupled transcription/translation in the presence of 35 S-methionine. Lane 1: molecular weight markers; lane 2: translation products of the control luciferase gene; lane 3: translation products without the insert; lane 4: translation product from HCaRG cDNA; lane 5: translation products of HCaRG cDNA The proteins were separated by 15% PAGE in the presence (lanes 1 to 4) or absence (lane 5) of β-mercaptoethanol. Transcription/translation of HCaRG cDNA yields a protein of 27 kDa (lane 4). In the absence of β-mercaptoethanol, a product of 43 kDa was also observed (lane 5), suggesting intramolecular or intermolecular disulfide bridges and the formation of homodimers or heterodimers with other protein(s) present in the lysate.
[0032] FIG. 4 . Sequence comparison between human HCaRG and rat HCaRG. The deduced amino acid sequences of rat HCaRG (rHCaRG, SEQ ID NO:2) and of human HCaRG (hHCaRG, SEQ ID NO:5) are aligned. Identical amino acids are boxed while homologous amino acids are shaded. We calculated 80% homology between these 2 sequences. Analysis revealed homology to the EF-hand motif, with 8 out of the 10 most conserved amino acids (dashed box). Further analysis using the PROSEARCH database revealed 4 overlapping putative “leucine zipper” consensus motifs (underlined). We also identified a nuclear receptor-binding domain (bold and italics).
[0033] FIG. 5 . Subcellular localization of HCaRG in cultured cells. COS-7 cells were transfected with GFP-HCaRG. 24 h later, the cells were fixed and observed. Cells transfected with pEGFP vector alone show diffuse fluorescence (A) while cells transfected with pEGFP-HCaRG present nuclear fluorescence (B). Nuclear localization was confirmed by immunofluorescence on COS-7 cells transfected with pcDNA1/Neo-HCaRG (C), and by electron microscopy (D) on pituitary.
[0034] FIG. 6 . Tissue distribution of HCaRG mRNA. FIG. 6A . Comparison of HCaRG expression in fetal versus adult human organs. HCaRG mRNA is expressed less in all fetal tissues compared, particularly in the heart, kidney and liver (adult; fetal). FIG. 6B . Northern blot containing 2 μg of polyA+ RNA from fetal and adult human hearts. HCaRG is more expressed in all regions of the adult heart (L: left, R: right). FIG. 6C . Comparison of HCaRG expression in adult human organs versus cancerous cell lines. HCaRG mRNA is expressed less in most cancerous cell lines compared. Lymphocyte (normal; Burkett's lymphoma Raji; Burkett's lymphoma Daudi). Leukocyte (normal; leukemia HL-60; leukemia K-562; leukemia MOLT-4). Rectum (normal; colorectal adenocarcinoma SW480). Lung (normal; lung carcinoma A549). FIG. 6D . Northern blot containing 20 μg of total RNA isolated from 3 different human tumors (T) and normal tissue (N) excised at the same operational site. HCaRG expression is decreased in brain, kidney and liver tumors.
[0035] FIG. 7 . In situ hybridization of HCaRG mRNA in the kidney and adrenal. In situ hybridization of HCaRG mRNA in the rat adrenal shows specific detection in the zona fasciculata and medulla. Specific hybridization in the kidney is restricted to proximal tubules, contrasting with virtual absence in the glomeruli (G). (Upper panels: antisense probe, lower panels: sense probe).
[0036] FIG. 8 . Analysis of kidney mRNA of HCaRG and c-myc obtained after ischemia and various periods of reperfusion. FIG. 8A . Dot blot of total RNA taken from the medulla of kidneys which underwent 60-min ischemia and reperfusion for various time periods (full lines) or from contralateral control kidneys (dotted lines). HCaRG mRNA declined rapidly to its lowest levels at 3 h and 6 h of reperfusion. It then increased steadily to exceed baseline at 48 h of reperfusion. In contrast, c-myc mRNA levels rose dramatically by 12 h and returned below HCaRG mRNA levels at 48 h of reperfusion. FIG. 8B . Representative northern blots of HCaRG and c-myc mRNA from the cortex of kidneys which underwent 60-min ischemia and 3 h, 6 h, 12 h, 24 h or 48 h (HCaRG) or 12 h or 24 h (c-myc) of reperfusion (I/R) or from contralateral control kidneys (C).
[0037] FIG. 9 . Characterization of stable cell lines. FIG. 9A . HEK93 cells transfected with pcDNA1/Neo or pcDNA1/Neo rat HCaRG were examined for expression of rat HCaRG by northern blot using rat HCaRG as a probe. Rat HCaRG was undetectable in cells transfected with the empty vector while different levels of expression were observed in cells transfected with the vector expressing HCaRG. FIG. 9B . The levels of ectopic expression were determined by densitometric measurement and normalized to GAPDH.
[0038] FIG. 10 . HCaRG expression inhibits cell proliferation. Stable clones Neo1, Neo6, Neo Poly, HCaRG8, HCaRG9, and HCaRG Poly were plated at low density. For each time point, triplicate plates were counted, and average cell number was recorded ( FIG. 10A ). The level of DNA synthesis was monitored by measuring [ 3 H] thymidine incorporation (X) ( FIG. 10B ). Representative experiment performed in triplicate.
[0039] FIG. 11 . Localization of HCaRG on rat chromosome 7. HCaRG Bgl 11 polymorphism was used as marker on genomic DNA from SHR and BN.1x rat inbred strains with multiple well characterized SDPS. HCaRG cosegregated with D7CebrpI87s3/D7Cebr77sl of rat chromosome 7 in 31 out of 33 strains. Two recombinations mapped the HCaRG between Cyp 11β 2 and Myc genes. cM represents distance in centimorgans on rat chromosome 7. On the right side, a possible linkage position of human homologous gone is depicted as based on conserved linkages on rat chromosome 7 and human chromosome B.
DETAILED DESCRIPTION OF THE INVENTION
[0040] The cloning of a novel extracellular calcium-responsive gene (HCaRG) in the rat parathyroid gland from SHR is described here. HCaRG mRNA and protein levels were higher in cultured PTC and in several organs of SHR, compared to their normotensive counterparts. They were negatively regulated by extracellular calcium, i.e. lowering extracellular calcium led to increases in HCaRG mRNA. The identification of an extracellular calcium-sensing receptor from the parathyroid gland has provided novel insights into the mechanisms of direct action of extracellular calcium on several cell types. The calcium sensor has also been localized in the cerebral cortex and cerebellum, in the tubular region of the kidney cortex, the thyroid, adrenal medulla, lung, and blood vessels (1, 32, 33). As shown here, HCaRG mRNA levels are also detected in several of these tissues. The calcium receptor is a member of the superfamily of G protein-coupled receptors activating phospholipase C (34, 35). In the parathyroid gland, it is a key mediator of inhibition of PTH expression by high calcium (36). The calcium sensor has been shown, in the kidney, to be directly related to inhibition of tubular reabsorption of calcium and magnesium in the thick ascending loop (for review, see 34). In PTC cultures prepared from human or bovine parathyroids, low extracellular calcium (0.3 mM) has been demonstrated to increase PTH secretion and mRNA levels whereas augmentation of calcium in the incubation medium reduces PTH mRNA. Similar regulation was observed for PHF in rat parathyroid cells (9). The present inventors show here that HCaRG expression is regulated in a manner similar to PTH and PHF in PTC isolated from the rat.
[0041] To date, very few extracellular calcium-negative responsive genes have been cloned. Parathormone was the first gene described to possess a negative calcium-responsive element (nCARE) in its 5′ flanking region (37). Several types of nCARE have been reported. Type 2 is a regulatory element consisting of a palindromic core sequence and several upstream T nucleotides originally described in the PTH gene. Its transcriptional inhibitory activity is orientation-specific. The nCARE core is present in an Alu-repeal in 111 copies in the human genome, suggesting the possibility that other genes may possess functional nCARE (38). With the properties described in the present study, HCaRG may be one of them.
[0042] HCaRG is not only expressed in the parathyroid gland but also in most organs tested, although at highly variable levels. Elevated HCaRG levels have been noted consistently in the tissues of genetically hypertensive animals, suggesting abnormalities of HCaRG regulation in several organs of SHR that could be due to either: 1) decreased extracellular calcium levels; 2) an abnormal response to extracellular calcium; 3) abnormal transcription/stability of HCaRG mRNA in hypertensive rats, or 4) a combination of these. A state of negative calcium balance has been described in SHR that could support the first possibility. On the other hand, 2-fold higher HCaRG mRNA levels were observed in PTC from SHR than from WKY at normal calcium concentration ( FIG. 2C ). Thus, the modest reduction of calcemia in hypertension will not be the sole explanation of increased levels, suggesting increased expression or decreased degradation of this gene product in hypertension.
[0043] No homologous protein sequence to the HCaRG open reading frame was found in the SWISSPROTEIN database. The HCaRG coding sequence contains 1 consensus motif known as the EF-hand or HLH Ca motif ( FIG. 3 , dashed box). This motif generally consists of a 12-residue, Ca-binding loop flanked by 2 a-helices. Eight of the 10 most conserved amino acids are present in HCaRG protein. Usually, the basic structural/functional unit consists of a pair of calcium binding sites rather than a single HLH motif. The HCaRG coding sequence contains only 1 EF like motif but it is possible that its high a-helix content favors coiled-coil interactions and dimerization of the protein. Pairing of the 2 EF-hand motifs may enhance its calcium function. Hodges and collaborators (39, 40) have demonstrated that domain III of troponin C (a synthetic 34-residue calcium-binding domain) can form a symmetric 2-site homodimer in a head-to-tail arrangement in the presence of calcium (41). Similarly, a 39-residue proteolytic fragment containing calcium-binding site IV of troponin C was shown to form a dimer (42). These studies and others (43-45) have demonstrated that dimerization of single HLH structures controls calcium affinity and that even homodimers can bind 2 calcium molecules with positive cooperativity (40). Hydrophobic interactions at the interface between calcium-binding sites appear to stabilize the calcium domains. The present inventors' in vitro translation studies showed the appearance of a protein band of about 43 kDa under non-reducing conditions. HCaRG protein might form reductant-sensitive, non-covalent homodimers compatible with its putative high a-helix content, but the existence of a functional calcium domain in HCaRG protein remains to be established. Several characteristics of HCaRG are similar to those of S100A2 protein, a calcium binding protein of the EF-hand type that is preferentially expressed in the nucleus of normal cells but down-regulated in tumors (44). As with HCaRG, S100A expression is down-regulated by calcium (46, 47).
[0044] The present inventors also cloned the human homolog of HCaRG from a VSMC cDNA library, using a 437-bp fragment of rat HCaRG as a probe. The coding sequence was found to be 80% homologous to the rat sequence and to contain the putative EF-hand domain. A restriction fragment length polymorphism permitted the present inventors to localize the HCaRG locus on chromosome 7 of rats ( FIG. 11 ). The gene was assigned within a 4.4-cM region on the long arm of chromosome 7 between Mit 3 and Mit 4 genes. By analogy, the present inventors suggested the assignment of HCaRG on human chromosome 8q21-24. In a recent search of HCaRG homologous sequences in GenBank, homologies were found with 3 chromosome 8 clones containing ZFP7. It was, therefore, possible to localize HCaRG on chromosome 8q24.3, confirming the present inventors' initial assignment ( FIG. 11 ). This region contains loci involved in several bone diseases, including osteopetrosis and multiple exostosis and several human neoplasms (48, 49).
[0045] Many DNA-binding proteins utilize zinc-containing motifs to bind DNA. Other classes of DNA binding proteins have a DNA-recognition domain at their N terminus that dimerizes to form a 2-chain coiled-coil of a-helices, also known as a “leucine zipper.” The present inventors identified 4 overlapping “leucine zipper” regions conserved in the rat and human sequence, and the high a-helix content of HCaRG makes it a possible DNA-binding protein. The present inventors are currently investigating this possibility. It has been shown that nuclear receptors require the ligand-dependent recruitment of co-activator proteins to effectively stimulate gene transcription (50). The nuclear receptor interaction domain of these factors is highly conserved and contains the consensus sequence LXXLL (where X is any amino acid). This motif is sufficient for ligand-dependent Interaction with nuclear receptors (51). The present inventors have identified 1 of these motifs in HCaRG. Nuclear localization of HCaRG protein makes this gene a potential transcription regulator.
[0046] Recently, a new transcription factor from the rat kidney (Kid-1) was identified (52-55). It was reported that Kid-1 mRNA levels declined after renal injury secondary to ischemia (55). Similarly, decreased HCaRG mRNA levels are seen when epithelial cells are de-differentiated and proliferate (following ischemia and reperfusion). In the model of unilateral ischemic injury, it was shown that contralateral uninephrectomy attenuates apoptotic cell death and stimulates tubular cell regeneration (28-31). The present inventors demonstrate here that HCaRG mRNA levels decreased 3 and 6 h after ischemia in contrast to c-myc expression which is correlated with hyperplastic responses (31). The present inventors also observed that its levels are lower in all fetal organs tested when compared to adult organs, and lower in tumors and the cancerous cell lines tested. It is possible that the gene product may exert a negative effect on growth. This was confirmed by the stable expression of HCaRG in HEK293 cells. The present inventors found that HCaRG overexpression had a profound inhibiting effect an HEK293 cell proliferation. This was shown not only by lower cell number but also by lower DNA synthesis, suggesting that the effect seen was not due to a death promoting effect of HCaRG.
[0047] Included within this invention are nucleic acid sequences having 60% or greater homology to all or part of the sequence of the gene for HCaRG of the rat as shown in FIG. 1 . Furthermore, this invention includes nucleic acid sequences having 60% or greater homology to all or part of the translated portion of the gene for HCaRG of the rat. This would include nucleic acid sequences whose codon usage has been modified to suit a particular host. Sense, antisense and mRNA sequences are encompassed by the term “nucleic acid sequences.”
[0048] Also included within this invention are nucleic acid sequences having 60% or greater homology to all or part of the sequence of the gene coding for HCaRG of the human as shown in FIG. 4 . Furthermore, this invention includes nucleic acid sequences having 60% or greater homology to all or part of the translated portion of the gene for HCaRG of the human. This would include nucleic acid sequences whose codon usage has been modified to suit a particular host. Again, sense, antisense and mRNA sequences are encompassed by the term “nucleic acid sequences.”
[0049] Furthermore, proteins encoded by all or part of the nucleic acid sequences of the gene for HCaRG of the rat and of the human are within this invention. One protein would include the amino acid sequence for the HCaRG protein of the rat as shown in FIG. 4 (top lines; SEQ ID NO:2). Another protein would include the amino acid sequence for the HCaRG protein of the human as shown in FIG. 4 (bottom lines; SEQ ID NO:5). Again, proteins having 60% or greater homology to all or part of these proteins are within this invention. It will be appreciated that a protein encoded by the genes of this invention may be modified by substituting amino acids for like amino acids. For example, a basic amino acid may be substituted with a different basic or non-basic amino acid. The substitutions would be chosen so as not alter the properties of the protein encoded by the genes of this invention.
[0050] Mimetics of the protein may also be used in the methods and compositions of the invention. The term “mimetic” refers to compounds which have a related three dimensional structure, i.e., compounds which have the characteristic structure of the protein encoded by the DNA sequences of this invention. Mimetics may be based on the biologically active portion of the proteins of this invention and may try to mimic the three dimensional structure of that active portion.
[0051] There is abnormal calcium transport, concentration and binding in patients with hypertension including calcium leak in cortical tubules. This invention provides additional solutions for patients having hypertension and other diseases caused by abnormal calcium levels.
[0052] In addition to hypertension, abnormal modulation of calcium levels can lead to a number of other diseases, disorders or abnormal physical states including hyperthyroidism, osteoporosis, osteopetrosis, heart failure, insulin dependent and independent diabetes, disorders of the central nervous system including stroke, cancer (including breast, thyroid, colon, kidney and leukemia), arteriosclerosis, gastrointestinal diseases, inflammatory bowel disease and asthma. The nucleic acid sequence of this invention could be used (1) for the treatment of diseases related to the modulation in calcium levels, (2) to develop pharmaceutical compositions for the treatment of diseases related to the modulation in calcium levels, or (3) to diagnose diseases related to the modulation in calcium levels. As certain types of cancer are characterized by an increase in intracellular free calcium, the nucleic acid sequence could be used to generate immunological assays (or markers) for these types of cancers and to develop pharmaceutical compositions to treat these types of cancers.
[0053] Similarly, all or part of the proteins encoded by the nucleic acid sequences of this invention or antibodies to the proteins could be used to generate immunological assays (or markers) to test for diseases, disorders or abnormal physical states associated with abnormal modulation of calcium levels. The assays could be screening assays to determine whether a product enhances or inhibits calcium levels or whether a product has had its intended effect in enhancing or inhibiting calcium levels.
[0054] In the assays of this invention, the complexes may be isolated by conventional methods known to those skilled in the art, such as isolation techniques, for example, chromatography, electrophoresis, gel filtration, fractionation, absorption, polyacrylamide gel electrophoresis, or combinations thereof. The complexes or free protein or mimetics may be assayed using known methods. To facilitate the assay, antibody against the protein or mimetic may be labeled or a labeled compound may be used. Detectable markers or labels which would serve to identify the complexes could include fluorescein, HRP and biotin.
[0055] The invention also relates to pharmaceutical compositions to treat patients having abnormal modulation of calcium levels. The compositions could include (1) nucleic acid sequence for use in gene therapy in which the sense sequence of the HCaRG gene is used in liposomes or a recombinant vehicle, for example, to enhance the gene, (2) nucleic acid sequence for use in gene therapy in which the antisense sequence of the HCaRG gene is used in liposomes or a recombinant vehicle, for example, to suppress the gene, (3) a protein or mimetic which competes with the protein encoded by the nucleic acid sequences of this invention thus suppressing the native protein's effect, (4) a protein encoded by the nucleic acid sequence of this invention to enhance the native protein's effect. The composition could include an acceptable carrier, auxiliary or excipient.
[0056] The pharmaceutical compositions may be used as an agonist or antagonist of the interaction of a protein encoded by HCaRG and a receptor. The compositions can be for oral, topical, rectal, parenteral, local, inhalant or intracerebral use. There may be in solid or semisolid form, for example pills, tablets, creams, gelatin capsules, capsules, suppositories, soft gelatin capsules, gels, membranes, tubelets. The compositions of the invention may also be conjugated to transport molecules to facilitate transport of the molecules.
[0057] The pharmaceutical composition can be administered to humans or animals. Dosages to be administered depend on patient needs, on the desired effect and on the chosen route of administration.
[0058] The pharmaceutical compositions can be prepared by known methods for the preparation of pharmaceutically acceptable compositions which can be administered to patients, and such that an effective quantity of the active substance is combined in a mixture with a pharmaceutically acceptable vehicle. Suitable vehicles are described, for example in Remington's Pharmaceutical Sciences (Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., USA 1985).
[0059] On this basis, the pharmaceutical compositions include the active compound or substance in association with one or more pharmaceutically acceptable vehicles or diluents, and contained in buffered solutions with a suitable pH and iso-osmotic with the physiological fluids. The methods of binding the compound to the vehicles or combining them with diluents is well known to those skilled in the art. The composition could include a targeting agent for the transport of the active compound to specified sites within cells, tissues or organs. Compounds could be targeted to cells such as vascular smooth muscle, renal or cardiac cells, for example.
[0060] The invention also relates to a composition for use in gene therapy. Liposomes or a recombinant molecule, for example could contain a sense or antisense sequence of the nucleic acid molecule of this invention. In the case of a recombinant molecule, the molecule would contain suitable transcriptional or translational regulatory elements.
[0061] Suitable regulatory elements may be derived from a variety of sources, and they may be readily selected by one or ordinary skill in the art. If one were to upregulate the expression of the gene, one would insert the sense sequence and the appropriate promoter into the vehicle. If one were to down regulate the expression of the gene, one would insert the antisense sequence and the appropriate promoter into the vehicle. These techniques are known to those skilled in the art
[0062] Examples of regulatory elements include: a transcriptional promoter and enhancer or RNA polymerase binding sequence a ribosomal binding sequence, including a translation initiation signal. Additionally, depending on the vector employed, other genetic elements, such as selectable markers, may be incorporated into the recombinant molecule. The recombinant molecule may be introduced into cells of a patient using in vitro delivery vehicles such as retroviral vectors, adenoviral vectors, DNA virus vectors and liposomes. They may also be introduced into such cells in vivo using physical techniques such as microinjection and electroporation or chemical methods such as coprecipitation and incorporation of DNA into liposomes. The compositions may also be delivered in the form of an aerosol or by lavage.
[0063] The present invention also provides for methods in which a patent suffering from a condition requiring modulation of calcium levels is treated with an effective amount of a composition.
LIST OF ABBREVIATIONS
[0000]
ANP atrial natriuretic peptide
BN./x Brown-Norway rats
DMEM Dulbecco's modify Eagle's medium
FBS Fetal bovine serum
FCS Fetal calf serum
GFP Green fluorescent protein
GST Glutathione S-transferase
HCaRG Hypertension-Related, Calcium-Regulated Gene
IP3 Inositol 1,4,5 trisphosphate
MTE Multiple tissue expression
nCARE Negative calcium-responsive element
PAGE Polyacrylamide gel electrophoresis
PBS Phosphate-buffered saline
PCR Polymerase chain reaction
PHF Parathyroid hypertensive factor
PTC Parathyroid cells
PTH Parathyroid hormone
RACE Rapid amplification of cDNA ends
RT Reverse transcription
SDS Sodium dodecyl sulfate
SHR Spontaneously hypertensive rat
SSC Standard sodium citrate
VSMC Vascular smooth muscle cells
WKY Wistar-Kyoto rats
ZFP7 Zinc finger protein 7.5
EXAMPLE 1
Isolation of a Novel cDNA whose Expression is Negatively Regulated by Extracellular Calcium in the SHR Parathyroid Gland
[0089] Using sense candidate primers (from a putative amino acid sequence of PHF (24)) and a hybrid oligo dT primer, 3′-RACE experiments, performed on total RNA extracted from SHR PTC cultured in low-calcium medium, generated 1 major 700-bp fragment that was digested and cloned in the BamH I site of pSP72. As a BamH I site was present in the 700-bp fragment, a recombinant plasmid containing a 300-bp insert was isolated and sequenced. This fragment was used to screen the PTC library and to generate new oligonucleotide primers to extend the cDNA towards the 5′- and 3′-ends by RACE. From 7 overlapping DNA fragments isolated in the above experiments and from SHR PTC cDNA library screening, a 1100-bp cDNA was reconstituted ( FIG. 1A ). The rat 1100-bp reconstituted cDNA sequence contained an open reading frame of 224 codons preceded by 2 in-frame stop codons and followed by the most frequent variant of the poly A tail ( FIG. 1B ). A 342-bp intron was localized at position-52 from the translation initiation site.
[0090] Poly A RNA was Isolated as described and analyzed by Northern hybridization with the 32 P labeled 300-bp fragment ( FIG. 2A ). Two bands were detected with this probe, at approximate lengths of 1.2 and 1.4 kb These results suggest either the existence of 2 genes or differential splicing. Furthermore, they indicate that the reconstituted 1100-bp cDNA is almost full length cDNA, estimated at 1.2 Kb by the major band in the northern hybridization experiments.
[0091] Regulation of the expression of this novel gene was investigated by competitive RT-PCR assay in PTC from WKY and SHR. Cells between 5 and 12 passages were tested in these studies. In WKY PTC, lowering of ambient calcium from 2.0 mM to 0.3 mM induced a rapid 2-fold increase in the mRNA levels of this novel gene at 2 h, which lasted up to 48 h ( FIG. 2B ). This calcium regulation was detected in WKY PTC up to about 12 passages but disappeared in long term cultures. Lowering of calcium concentrations in the cell medium also increased the mRNA levels of this novel gene in SHR PTC but to a lesser extent than in WKY cells (data not shown). The present inventors then compared its mRNA levels between 2 normotensive rat strains (Brown Norway, BN./x. or WKY) and hypertensive animals (SHR). The present inventors observed that the mRNA levels of this novel gene were significantly higher in PTC derived from SHR ( FIG. 2C left panel) compared to normotensive WKY rats at normal calcium. Similarly, when the present inventors extracted RNA ( FIG. 2C right panel) or proteins ( FIG. 2D ) directly from the kidneys, the present inventors found significantly higher levels of this novel gene in hypertensive rats. These results clearly show that this novel gene is negatively regulated by extracellular calcium concentrations and that its levels are significantly higher in genetically hypertensive rats compared to 2 normotensive strains. The present inventors, therefore, named this gene Hypertension-related, Calcium-Regulated Gene (HCaRG).
EXAMPLE 2
Sequence and Structure of HCaRG cDNA
[0092] The deduced protein contained 224 amino acids with a calculated molecular weight of 22456 Da. The estimated pi of the protein was 6.0. It comprised no known membrane-spanning motif but had an estimated 67% a-helix content. The absence of a putative signal peptide sequence suggested an intracellular protein. There were 2 cysteines In the sequence, indicating possible intra- or inter-molecular disulfide bridges (Cys 64-cys-218). The protein had several putative phosphorylation sites for C- and A-kinases and 1 potential Asn-glycosylation site (Asn 76). To confirm that HCaRG mRNA encodes a peptide of expected size, the HCaRG cDNA inserted into pSP72 was incubated in vitro in a coupled transcription/translation labeling system. It was transcribed by T7 RNA polymerase, and translated in rabbit reticulocyte lysate. As shown in FIG. 3 (lane 4), HCaRG mRNA directed the synthesis of a peptide with a molecular mass of 27 kDa which closely corresponded to the molecular weight calculated from the amino acid sequence. PAGE analysis of the reaction product in the absence of the reducing agent 03-mercaptoethanol showed bands of 27 and 43 kDa ( FIG. 3 , lane 5). These results suggest possible intramolecular or intermolecular disulfide bridges and the formation of homodimers or heterodimers with other protein(s) present In the lysate.
EXAMPLE 3
Cloning of Human HCaRG
[0093] The present inventors then used a 439-bp cDNA fragment of rat HCaRG (+1 to +440 in FIG. 1 ) to screen a human VSMC cDNA library. The present inventors identified several positive clones that were purified, subcloned in pBluescript vector and sequenced. The present Inventors obtained a 1355-bp sequence containing full length human cDNA, while all other clones contained only partial sequences. A recent sequence search in GenBank revealed a region with complete DNA sequence homology within 3 cosmids containing the zinc finger protein 7 (ZFP7) gene (accession numbers AF124523, AF146367 and AF118808). Although the nucleotide sequence of human HCaRG could be found in these cosmids, the present inventors are the first to assign an expressed gene sequence to this DNA region.
[0094] Sequence comparison between human HCaRG and rat HCaRG showed 80% identity at the nucleotide level (data not presented) and, similarly, 80% homology at the amino acid level ( FIG. 4 ). Analysis of protein structure with the PROSEARCH database revealed 4 overlapping putative “leucine zipper” consensus motifs ( FIG. 4 underlined). Further analysis revealed homology to the EF-hand calcium-binding motif (8 out of the 10 most conserved amino acids) ( FIG. 4 dashed box). We also identified a nuclear receptor-binding motif ( FIG. 4 bold and italics). All these motifs were conserved in the rat and human amino acid sequence.
EXAMPLE 4
Subcellular Localization of HCaRG
[0095] The present inventors expressed GFP-HCaRG in COS-7 cells. Fluorescence study showed that GFP-HCaRG localized in the nucleus while cytoplasmic fluorescence was very faint ( FIG. 5B ). GFP, on the other hand, had a very diffuse localization ( FIG. 5A ). This result was confirmed by immunofluorescence using antibodies specific to HCaRG ( FIG. 5C ) and by electron microscopy ( FIG. 5D ). Electron microscopy was also performed on different tissues. In all tissues studied, HCaRG was found in the nucleus with some labeling in protein synthesis sites.
EXAMPLE 5
HCaRG Expression in Various Human Tissues
[0096] A human MTE TM array was hybridized with human 32 P-labeled HCaRG cDNA as a probe. The array contained 76 polyA RNAs from various adult tissues, cell lines, fetal tissues and cancerous call lines. These arrays were normalized to 8 different housekeeping genes. Analysis of the array showed that HCaRG was expressed preponderantly in the heart, stomach, jejunum, kidney, liver and adrenal glands. Comparison of HCaRG expression in fetal to adult organs revealed that HCaRG mRNA was less expressed in all fetal tissues compared ( FIG. 6A ), particularly in the heart, kidney and liver. Northern blots confirmed the lower abundance of HCaRG in the fetal heart compared to all regions of the adult heart ( FIG. 6B ). The present inventors also compared HCaRG mRNA levels in various cancerous cell lines to normal tissues ( FIG. 6C ). HCaRG mRNA levels were decreased in all cancerous cell lines studied. They were also much lower in a glioblastoma, a partly differentiated renal cell carcinoma and a moderately differentiated hepatocellular tumor compared to the same amount of normal RNA of adjacent tissues excised from the same operational site ( FIG. 6D ).
EXAMPLE 6
In Situ Hybridization of HCaRG mRNA in the Kidney and Adrenal
[0097] HCaRG expression was determined in SHR Tissues by in situ hybridization. The labeled antisense riboprobe hybridized to the medulla and zona fasciculata of the adrenal cortex ( FIG. 7 ). In the kidney, labeling was almost exclusively located in the cortex and concentrated In the tubular component, contrasting with virtual absence of the signal in glomeruli ( FIG. 7 ). In these organs, the signal was clearly greater in hypertensive rats compared to their normotensive controls (Lewanczuk et al.; unpublished data). The sense probe was used as a negative control and appropriately revealed a low signal under the present inventors' hybridization conditions, demonstrating specificity of the reaction ( FIG. 7 lower panels).
EXAMPLE 7
HCaRG mRNA Levels After Ischemia-Reperfusion
[0098] The process of kidney injury and repair recapitulates many aspect of development. It involves de-differentiation and regeneration of epithelial cells, followed by differentiation (25-27). Since the present inventors observed that HCaRG mRNA levels are lower in fetal than in adult organs, the present inventors evaluated HCaRG expression after unilateral renal ischemia in uninephrectomized rats (19) as contralateral nephrectomy has been shown to stimulate cell regeneration (28-31). The present inventors noted that HCaRG mRNA declined rapidly to its lowest levels at 3 h and 6 h of reperfusion ( FIG. 8A ). These values then increased steadily to higher than baseline at 48 h of reperfusion. This was observed in both the kidney medulla ( FIG. 8A ) and cortex ( FIG. 6B ). In contrast to the decline in HCaRG mRNA levels, the proto-oncogene c-myc expression, which is correlated with hyperplastic response in mammalian cells, was rapidly increased following renal ischemia and reperfusion (31). c-myc mRNA levels were low in control kidneys and increased dramatically in the post-ischemic kidney at 3 h of reperfusion, at a time when HCaRG mRNA levels were already reduced ( FIGS. 8A and 8C )
EXAMPLE 8
Overexpression of HCaRG Inhibits Cell Proliferation
[0099] HEK293 cells were stably transfected with either plasmid alone or with plasmid containing rat HCaRG. After transfection, several clones were examined for the determination of rat HCaRG mRNA levels. Four clones HCaRG clones 1, 5, 8 and 9) expressed variable amounts of rat HCaRG mRNA, as detected by northern blots, while no HCaRG mRNA levels were found in clones transfected with the plasmid alone ( FIG. 9 ). Clones expressing the highest levels of HCaRG (clones 8 and 9) were selected for cell proliferation studies. For these studies, cells that were transfected with the vector alone or polyclonal HCaRG-transfected cells served as controls. The proliferation rates of the HCaRG-transfected cell lines and vector control calls were examined under normal growth conditions (10% FCS and G-418) by counting cell numbers every day for a period of 8 days after plating. Cell lines transfected with the vector alone (Neo clones 1 and 6) showed a similar growth rate as non-transfected cells (not presented) Clones 8 and 9 expressing high levels of rat HCaRG revealed a much lower proliferation rate than vector control cells while polyclonal cells expressing intermediate values of HCaRG fell in between ( FIG. 10A ) Consistent with a lower proliferation rate, stable HCaRG transfection clones 8 and 9 showed much lower 3 H-thymidine incorporation than clones transfected with the empty vector ( FIG. 10B ).
EXAMPLE 9
Enhanced Sensibility to Cell Death by Apoptosis and Necrosis
[0100] In order to investigate the cellular function of HCaRG, we have studied the effects of ectopic overexpression of HCaRG protein in HEK 293 cells. Stably transfected cell lines which expressed either plasmid alone (pcDNA1/Neo) or plasmid containing rat HCaRG (pcDNA1/Neo-HCaRG) were used in these studies. The level of [3H]-Thymidine incorporation was significantly lower in HCaRG transfected clones compared to the vector control cell lines. Cell cycle analysis revealed a G.sub.2M phase accumulation of HCaRG cells suggesting a cell cycle-dependent mechanism of growth suppression, which was associated with upregulation of the cyclin dependent kinase (cdk)-inhibitor p21Cip1/WAF-1, both at the mRNA and protein level. The reduced cell proliferation was associated with some enhanced sensitivity to cell death by apoptosis and necrosis which was apparently secondary to cell cycle-dependent G 2 M phase accumulation. HCaRG transfected cells had a larger size and a greater total protein content per cell, consistent with cellular hypertrophy. Previous studies, including those using immunohistochemical techniques, have demonstrated Atrial natriuretic peptide (ANP) is present in the tubules of kidneys of several species including rat and human in vivo (68-70). Furthermore, the developmental pattern of ANP immunoreactivity in the rat was studied and found to coincide with the differentiation and maturation of the tubular epithelium (68). Additional studies have provided evidence that an ANP-like peptide is produced and secreted by primary cultures of neonatal and adult rat kidney cells (71, 72). The human embryonic kidney cell line (HEK 293) Is derived from renal cortical cells and exhibits several phenotypic characteristics of renal distal tubular cells, including a basal synthesis and release of an ANP-like immunoreactivity (or Urodilatin) (73). We assessed the direct functional effects of the novel gene HCaRG, on cellular proliferation, cell cycle regulation and cell phenotype in vitro. Since the HEK 293 cell line is considered to be most representative of natriuretic peptide (NP)-secreting human distal cortical tubular cells, we have stably transfected these cells with HCARG in order to assess the direct effect of ectopic HCARG expression on several aspects of renal epithelial cell function in vitro. Overexpression of the HCaRG gene caused a 6-8 fold increase in the rate of ANP release from HEK 293 cells. Light and electron microscopy revealed a lower incidence of mitotic figures as well as the development of more differentiated junctions in HCaRG transfected cells only. In conclusion, HCaRG gene transfer to HEK 293 cells in vitro caused a change in cell phenotype which was manifest as: a reduction in cell growth: increased cell doubling time; cell cycle G 2 M phase accumulation; increased cell size and total protein content per cell and increased synthesis and secretion of an ANP-like immunoreactivity. Taken together, all of these findings are consistent with the hypothesis that HCaRG can suppress cell proliferation in a cell cycle-dependent manner, and induce features characteristic of differentiation in vitro, apparently by affecting cell cycle progression which is associated with up-regulation of p21 Cp1/WAF-1 .
EXAMPLE 10
HCaRG Expression in Mammalian Cells
[0101] Because bacteria are unable to post-translationally modify proteins as mammalian cells, a bacterial protein may be inactive. We express the HCaRG protein in mammalian cells to circumvent this problem. Gene transfer techniques to COS7 cells are used routinely In the lab. The expression vector is pcDNAneol (Invitrogen) available in the lab. The cloned HCaRG is inserted as a Hind III-BgI II fragment in Hind III-BamHI sites in the vector to place the gene under the CMV promoter. A plasmidic neo gene enables the selection of stable transformants.
[0102] High expression is selected by Northern blots and protein is purified when antibodies are available. Various biological activities however, are tested Immediately on cells expressing HCaRG. The initial candidate activities are calcium channel function calmodulin-phosphodiesterase activator activity, cell proliferation, cell death and apoptosis.
EXAMPLE 111
Gene Therapy: The Intracellular Function of a Protein can be also Studied by Inhibition of its Expression by Antisense Molecules
[0103] Recently, antisense oligonucleotides have been used extensively to inhibit expression of specific genes (65). Although, the exact mechanism of this inhibition is not known, evidence suggest that RNAse H-like activity degrades RNA oligonucleotide duplexes (61). While modified oligonucleotides such as methylphosphonates diffuse freely across the cell membrane, unmodified and modified oligonucleotides have been shown to be actively transported into living cells by binding to membrane receptors (63, 66). It is therefore possible to inhibit the expression of specific genes and their gene products by adding specific antisense molecules to the culture medium. We explore the capacity of the oligonucleotide antisense spanning the translation initiation site of HCaRG to inhibit PHF as well as CPA synthesis. Parathyroid cells or other cells expressing HCaRG, PHF or CPA are treated with antisense oligonucleotides. Cells are incubated in medium containing up to 100 μM antisense oligonucleotide. Lipofection helps to increase the percentage of uptake of oligonucleotides in certain cells. Fresh antisense molecules are added every 24 hrs. After 24 to 48 hrs cell culture medium is tested for the presence of PHF activity and intracellular CPA activity is assessed. Non-sense and sense oligonucleotides are used as control for determination of specificity of the effect. Other parameters such as cyclic nucleotides and intracellular calcium levels are also measured since they may constitute an additional step to define the mechanism of action of HCaRG.
EXAMPLE 12
TPA, a Protein Kinase C Agonist, Increases mRNA Levels
[0104] We have initiated studies on the regulation of HCaRG. Hormonal signal transduction pathways are stimulated by different agonists, in cultural parathyroid cells incubated in low or normal calcium medium. Our initial studies showed that TPA, a protein kinase C agonist, (Protein kinase C is the main target on intracellular calcium and is involved in the phosphorylation regulation of many target proteins including, ionic channel, contractile proteins and hormonal receptors) increases the mRNA levels of HCaRG when cells are incubated in normal calcium medium. These data suggest that Protein kinase C could mediate, inside of the cell, these effects of extracellular calcium. Interestingly, the calcium sensor Is linked to the protein kinase C pathway. Other hormonal systems are tested for their effects on HCaRG expression. These include glucocorticoid, catecholamine's, Vitamin D, prohormone, growth factors, cytokines. These tests define the mechanisms controlling HCaRG synthesis and delineate their anomalies in disease states.
EXAMPLE 13
Chromosomal Localization
[0105] With the obtention of the cDNA coding for the HCaRG from human and rat and the putative full length open reading frame, our research includes genomic structure, search of genetic control elements. Our research relates to the pathophysiological regulation of its expression and to in vitro expression of a functional protein.
[0106] Southern blot analysis was performed on 10 μg genomic DNA of SHR and BN.1x rats with the following restriction enzymes BamH1, BgIII, EcoRI, HindIII, KpnI and PstI. The probe consisted of the 32P-labeled fragment of 860 bp of HCaRG shown in FIG. 1 . A clear RFLP genotyping for the B BN.1x allele (12 kb) or S(SHR) allele (2.2 kb) was then detected with the BgI II restriction enzyme ( FIG. 11 ) in the 33 recombinant inbred strains. The strain distribution pattern of this RFLP was then analyzed by Pearson's correlation for segregation with 500 markers localized in the rat genetic map using the Map Manager program of Manly (version 2.6.5). The address of RATMAP is “http://www.ratmap.gen.gu.se.”
EXAMPLE 14
Pathophysiological Regulation of Expression of HCaRG
[0107] Northern blot and in situ hybridization experiments have shown that rat tissues which demonstrate a significant expression of HCaRG are the parathyroid gland, the medulla and inner cortical section of the adrenal gland, the cortical tubular segments of the kidney and the brain cortex and medulla. In most organs, the expression was higher in SHR than in normotensive rat. The effect of dietary sodium and calcium is tested on HCaRG expression in these organs in salt sensitive and salt-resistant hypertensive rat strains with a protocol previously described in Chang et al, (60) and Tremblay et al. (67). These earlier reports have shown an increased in CPA activity by high sodium intake and normalization by high dietary calcium suggesting that this factor could be a biological marker of salt sensitivity in the population. We have recently detected the expression of HCaRG in human lymphocytes. This is a readily available source of human RNA and we have developed a semi-quantitative RT-PCR assay to quantify the mRNA levels of HCaRG in humans. Human samples are obtained from controls and patients with abnormal calcium metabolism such as patients with cardiovascular diseases, osteoporosis, atherosclerosis and cancer. In addition, biopsies of cancer tissues are obtained. We have already detected the mRNA of HCaRG in colon cancer as well as in breast cancer. These studies use HCaRG as a biological marker of abnormal calcium metabolism in humans.
EXAMPLE 15
HCaRG Expression in Bacteria and Antibody Preparation
[0108] Rat and human HCaRG are inserted into bacterial expression vectors in order to produce large amounts of HCaRG protein. For HCaRG, we use the pMAL-c2 (New England Biolabs) to generate a fusion protein of HCaRG following the maltose-binding protein. A blunt HCaRG cDNA obtained by PCR and starting at the initiator methionine is inserted in the Xmnl site of pMAL-c2. This strategy places the HCaRG product next to the Factor Xa cleavage site of the fusion protein.
[0109] Because protein expression in E. coli varies according to the vector used and the nature of the protein expressed, we prepare other fusion proteins. The pGEX-5X plasmid (Pharmacia) allows for the introduction of genes to produce glutathione S-transferase fusion proteins. The vector exists in three frames and has extensive restriction insertion sites for easy insertion of foreign gene. For example, the cloned rat HCaRG is inserted in the EcoRI-XhoI sites to produce the fusion protein with HCaRG product localized after a Factor Xa cleavage site. In both systems, the fusion proteins enable the rapid purification of the expressed protein through affinity chromatography. Crude bacterial extracts containing cytoplasmic proteins are analyzed. According to the amount of protein synthesized, purification steps are determined or crude extract is used directly. To generate antibodies by injection into rabbits, urea extracted aggregates, SDS-page purified bands or protein extracts are used (64).
[0110] Experimental Procedures
[0111] Cell Cultures. Parathyroid cells (PTC) were isolated from SHR and Wistar-Kyoto (WKY) rats. Primary cultures were passaged in Dulbecco's modified Eagle's medium (DMEM) with 10% fetal calf serum (FCS), as described previously (9). They were then maintained in Ham F12 medium containing a low (0.3 mM) or normal (2.0 mM) total calcium concentration for 2 or 48 h. COS-7 or HEK293 cells were cultured in DMEM containing 10% fetal calf serum. All cell types were maintained in 5% CO 2 at 37° C.
[0112] Ischemia-Reperfusion. SHR were anesthetized with light flurane, and the right kidney was removed through a mid abdominal incision. The left kidney was subjected to warm transient ischemia by occlusion of the left renal artery and vein with a micro-clip, as described previously (19). The skin Incision was temporarily closed. After 80 min of occlusion, the clip was removed, and the wound was closed with a 2-0 suture. The rats had access to water immediately after surgery.
[0113] SHR Parathyroid cDNA Library. Parathyroid glands were remove from 100 12-week-old SHR and frozen immediately in liquid nitrogen. The glands were added to a guanidinium thiocyanate solution and homogenized in this solution. Poly A RNA was obtained by phenol-chloroform extraction, ethanol precipitation and isolated on an oligo(dt) column. Poly A RNA was stored in ethanol at −80° C. until used. The cDNA library was constructed with Poly A RNA as template and the ZAP-cDNA synthesis kit (Stratagene, La Jolla, U.S.A.). A summary of the protocol is as follows: mRNA was reverse-transcribed from an XhoI-linker oligo(dT) primer using Moloney-Murine leukemia virus reverse transcriptase. Second strand synthesis was then produced with DNA polymerase I in the presence of RNaseH. The cDNA was then extracted using phenol/chloroform, precipitated with sodium acetate, washed with 80% ethanol and resuspended in sterile water. cDNA termini were blunted by incubation with the Klenow fragment of DNA polymerase I and dNTPs. cDNA was again precipitated and washed. EcoRI adaptors were added using T4 ligase, and the ends phosphorylated with T4 polynucleotide kinase. This mixture was then digested with XhoI to release adaptors and residual linker-primer from the 3′ end of the cDNA. The resulting mixture was separated on a Sephacryl S-400 column. Eluted cDNA was precipitated with 100% cold ethanol and resuspended in sterile water. cDNAs were ligated into the Uni-ZAP XR vector using T4 DNA ligase, thus forming the cDNA library, and packaged into Gigapack II Gold packaging extract. The packaged products were plated onto XL1-Blue MRF′ cells and recombinant numbers determined. The library was then amplified by mixing the packaging mixture with host bacteria (XL1-alue MRF′ cells). The library was stored at −80° C. until screened. To screen the cDNA library, phages were plated onto bacterial host plates (XL1-Blue MRF′) and incubated overnight. After chilling at 4° C. for 2 h, a nitrocellulose filter was overlaid for 2 min. The fitter was then denatured in 1.5M NaCl/0.5M NaOH, neutralized in 1.5M NaCl with 0.5 Tris-Cl (pH 8.0). The filter was then rinsed and the DNA crosslinked to it with UV light. Hybridization was performed with digoxigenin-dUTP labeled probes (Roche Molecular Biochemicals, Laval, Canada) derived from 3′- and 5′-RACE (rapid amplification of cDNA ends), products described below.
[0114] RNA and cDNA Preparation. Total RNAs were prepared from rat cells and organs according to the standard guanidinium thiocyanate-phenol-chloroform method (20) and kept at −70° C. until used. mRNA was extracted from total RNA with the PolyATtract system (Promega, Nepean, Canada). cDNAs, unless stated, were synthesized with random hexamers for first strand synthesis and reverse/transcribed. Radiolabeled DNA probes were prepared by the random priming technique or polymerase chain reaction (PCR) amplification with 32 P-dCTP.
[0115] r 5′ RACE. Four mixtures of degenerate oligonucleotide primers were initially designed according to the putative amino acid sequence of PHF with the following degenerate sequence: 5′ TA(T/C) TCI GTI TCI CA(T/C) TT(T/C) (A/C) G 3′. From initial RACE experiments (described below), 1 unique sequence primer TAC TCC GTG TCC CAC TTC CG was selected for its ability to generate reverse transcription (RT)-PCR DNA fragments from PTC total RNA and used subsequently as candidate primer for 3′-RACE. In brief, for 3′-RACE, total RNA from PTC was reverse-transcribed with a hybrid primer consisting of oligo(dT) (17-mer) extended by a unique 17-base oligonucleotide (adaptor). PCR amplification was subsequently performed with the adapter, which bound to cDNA at Its 3′-ends, and the candidate primer mentioned above (21) For 5′-RACE, RT was undertaken with an internal primer derived from the sequence of the cDNA fragment generated by 3′-RACE. A dA homopolymer tail was then appended to the first strand reaction products using terminal deoxynucleotidyl transferase. Finally, PCR amplification was accomplished with the hybrid primer described previously and a second internal primer upstream to the first one (21).
[0116] Subcloning. The DNA fragments generated from the RACE experiments were separated by electrophoresis, isolated from agarose gel and extracted by the phenol-chloroform method (20). pSP72 plasmid (Promega) was digested at the SmaI site and ligated to blunt DNA fragments with T4 DNA ligase. Transformed DH5a E. coli bacteria were grown and recombinant bacteria were selected by PCR. Similarly, HCaRG was subcloned in pcDNA1/Neo (Invitrogen, Carlsbad, U.S.A.).
[0117] To determine the subcellular localization of HCaRG protein in mammalian cells, the coding region of HCaRG was fused to green fluorescent protein (GFP) cDNA and was transfected in the cells. Briefly, the entire coding region of HCaRG was amplified by PCR with the primers ATG TCT GCT TTO GGG GOT GCA GCT CCA TAC TTG CAC CAT CCC and TAA TAC GAC TCA CTA TAG GGA GAC, gel purified, and fused in-frame to GFP in pFGFP-C1 (Clontech, Palo Alto, U.S.A.) through a blunt Hind III site. pEGFP-HCaRG was then sequenced Similarly, the coding sequence of HCaRG was fused in frame to glutathione S-transferase (GST) in pGEX-3X (Amersham Pharmacia Biotech, Baie d'Urfe, Canada) through a SmaI site and a blunt EcoRI site.
[0118] Sequencing. Double-stranded sequencing of cloned cDNA inserts was performed with Sequenase Version 2.0 (United States Biochemical, Cleveland, U.S.A.). 5 μg of recombinant plasmid template were denatured, annealed with T7 or SP6 primers, and labeled with 35 S-dATP by extension, using the chain termination method of Sanger according to the manufacturers protocol
[0119] Cloning of Human HCaRG. A 439-bp cDNA fragment of rat HCaRG was 32 P-labeled and served as a probe for screening a human VSMC cDNA library. cDNA from positive phages was purified and the fragments were cloned in pBluescript. All fragments were sequenced. We obtained a 1355-bp fragment containing the coding region of HCaRG.
[0120] Northern Blot Hybridization, Dot Blot Hybridization and Competitive RT-PCR. 2 μg of poly A RNA from PTC or 10 μg of total RNA from kidneys were denatured at 68.degree. C. and separated on denaturing formamide 1% agarose gel. The gel was transferred onto nitrocellulose by vacuum transfer with 20+SSC. The membrane was exposed to UV light to fix RNA, and pre-hybridized in a solution containing SSPE, SDS. Denhardt's and dextran sulfate for at least 4 hours. Hybridization was performed overnight in the same buffer containing .sup.32P labeled probes generated from cDNA clone(s) by PCR or random labeling method. 1 μg of total RNA was used in dot blot experiments. A human multiple tissue expression (MTE TM) array (Clontech) and human fetal and tumor panel Northern Territory TM RNA Plots (Invitrogen, Carlsbad Calif., U.S.A) were hybridized with 32 P-labeled human HCaRG cDNA according to the manufacturers specifications. For quantitative determinations of HCaRG mRNA, total RNA was extracted from PTC and reverse-transcribed. A HCaRG competitor was constructed using the PCR Mimic Construction Kit (Clontech) with the following composite primers: GCA CGA GCC ACA GCC AGC TAC CCC AGC CAC CCA TTT GTA CC (SEQ ID NO: ______; sense) and TGT GAC TGT CAG CGG GAT GGA GTC CGA GAT GTA GAG GGC (SEQ ID NO: ______; antisense). The 344-bp DNA obtained was cloned into pSP72 and transcribed with SP6 RNA polymerase. The resulting RNA was quantified by photometry and subsequently used in competitive RT-PCR. The competitive reaction contained 1 or 2 μg total RNA with increasing amounts of competitor cRNA along with 32 P-labeled nucleotide. Two primers TGT GAC TGT CAG CGG GAT GG (SEQ ID NO: ______) and GCA CGA GCC ACA GCC AGC TACC (SEQ ID NO: ______) flanking the HCaRG intron were employed to amplify a 186-bp cDNA fragment. PCR was performed: 15 sec at 95.degree. C., 20 sec at 68.degree. C., 30 sec at 72.degree. C., for 30 cycles, followed by a 5 min elongation step at 72° C. 10 μl of the PCR were loaded on 1.8% agarose gel, then dried and exposed in a Phosphorimager cassette for quantification.
[0121] In Situ mRNA Hybridization. Tissues from SHR and WKY rats were rinsed in phosphate buffer, fixed in 4% paraformaldehyde and embedded in paraffin. 3- to 5-.mu.m sections were cut and mounted on microscope slides pretreated with aminopropylthiethoxysilane. The slides were first dried at 37° C., then at 60° C. for 10 min prior to use. The probe applied was a unique 3′-RACE 300-bp fragment (3r 290 in FIG. 2A ) which had been subcloned into the BamH I site of a pSP72 vector. Briefly the DNA was purified and linearized with HindIII and EcoR1 digestion followed by phenol-chloroform extraction. After gel confirmation, the DNA was transcribed using T7 or SP6 polymerases to create sense and antisense riboprobes which were labeled with digoxigenin-UTP using a tailing reaction. They were validated by dot blot hybridization with template DNA. Prehybridization of slides was undertaken after de-waxing in xylene, followed by progressive ethanol-water hydration (95% to 50%). The slides were rinsed in phosphate-buffered saline (PBS) and incubated with proteinase K (20 μg/ml) for 20 min at room temperature. After this digestion, they were rinsed successively in glycine buffer, PBS and then dehydrated in ethanol. Actual prehybridization was done with 50% formamide, 0.2% sodium docdecyl sulfate (SDS), 0.1% Sarcosyl, 5.times. standard sodium citrate (SSC; NaCl (0.15M), sodium citrate (0.015M, pH 7.0)) and 2% blocking reagent (Roche Molecular Biochemicals) for 1 h at 60° C. Hybridization was performed by adding the probe (200 ng/ml) to 50 g. of 4.times.SSC and 50% formamide per section. The slides were incubated overnight at 60.degree. C. in a chamber humidified with 4.times.SSC and 50% formamide. During hybridization, a coverslip was placed over the tissue section After hybridization, it was removed and the sections rinsed with 4×SSC, then washed with 4×SSC for 15 min and in 2×SSC for 15 min, at room temperature. Finally, the sections were washed with 0.1% SSC for 30 min at 60.degree. C. Hybridization was detected by color reaction. For coloration, the sections were washed with Buffers 1 and 2 of the DIG Luminescent Detection Kit (Roche Molecular Biochemicals). They were then incubated with anti-DIG alkaline phosphatase antibody (1:500) in Buffer 2 for 40 min, washed twice in Buffer 1 for 15 min and in Buffer 3 for 2 min. Incubation in the color solution (NBT/x-phos) was carried out for 45 min, after which the slides were washed in distilled water and dry-mounted with Geltol.
[0122] In Vitro Translation. The full length of the HCaRG coding sequence was synthesized by RT-PCR with specific primers and inserted downstream of the T7 promoter into the pSP72 vector. In vitro transcription and translation were performed using a TNT-17-coupled reticulocyte lysate system (Promega) in the presence of 35 S-methionine A plasmid containing the luciferase gene supplied by the manufacturer was used as a control. The synthesized proteins were analyzed by 15% SDS polyacrylamide gel electrophoresis (PAGE). In the absence or presence of β-mercaptoethanol. Radioactive protein bands were detected by scanning with a Phosphorimager.
[0123] Antibody Production. E. coli cells transformed with pGEX-3 were grown in LB medium containing 50 μg/ml ampicillin at 37° C. until A595 nm=0.5. Isopropyl-b-D-thiogalactopyranoside was added to a final concentration of 0.1 mM, and the cells were cultured for 2 h Purification of GST-HCaRG was performed according to the manufacturer's protocol. Polyclonal antisera with antibodies recognizing HCaRG were produced by immunization of rabbits with GST-HCaRG protein.
[0124] Immunocytological Reaction at the Electron Microscopic Level. Rat tissues (liver, anterior pituitary, spleen, heart and adrenal gland) were quickly removed and fixed in 4% paraformaldehyde with 0.05% glutaraldehyde in phosphate buffer solution for DO min. A part of the specimens was cryoprotected in 0.4M sucrose phosphate buffer solution for 30 min at 4° C., then frozen in a cold gradient of fuming nitrogen (Biogel, CFPO, Saint Priest, France) to −4° C., and immersed in liquid nitrogen, as described previously (22). Ultrathin frozen sections of 80 nm thickness were obtained using a dry sectioning method at −120° C. with an Ultrarut S microtome (Lelca, Lyon, France). The other part of the specimens was dehydrated before embedding in Lowicryl K4M with the AFS system (Leica) (23). Sections were mounted on 400 mesh collodion-carbon-coated nickel grids. For ultrastructural localization of HCaRG protein, the grids were first placed in buffer containing 0.1 M phosphate buffer, 0.15 M NaCl, and 1% albumin, pH 7.4, for 10 min. They were then incubated for 1 h with polyclonal IgG raised against HCaRG protein at concentrations of 1:1000 and 1:50 for ultrathin frozen sections and Lowicryl sections respectively. After 10-min washing in the same buffer, antigen/antibody complexes were revealed with anti-rabbit IgG conjugated with 10 nm gold particles in buffer containing 0.05 M Tris, 0.15 M NaCl, 1% albumin, pH 7.6, for 1 h. The grids were washed in the same buffer and fixed with 2.5% glutaraldehyde. The specificity of the immunocytological reaction was tested on sections with omission of primary antibody and incubation of the primary antibody with particle-adsorbed antigen. No signal was observed on these tissue sections. Before observation in a Philips CM 120 electron microscope at 80 kV, the cryosections were contrasted in 2% uranyl acetate, embedded in 8% methylcellulose, and the Lowicryl sections were contrasted for 20 min in 5% uranyl acetate.
[0125] Transfection and Subcellular Localization. COS-7 cells were plated at .about.30-50% confluency 1 day prior to transfection which was performed with 5 μg/well of pEGP-HCaRG or pcDNA1/Neo-HCaRG, according to the calcium phosphate method. After 24 h, the cells were fixed with 4% paraformaldehyde in PBS for 30 min at room temperature. Following 3 washes with PBS, cells transfected with pEGFP-HCaRG or pcDNA1/Neo-HCaRG were mounted on coverslips. The cells were permeabilized with 0.3% Triton X-100 for 12 min, blocked with 1% BSA-1% gelatin for 15 min, incubated with HCaRG antibodies at 37° C. for 1 h, washed in 0.5% BSA, incubated with anti-rabbit FITC-labeled antibodies and washed again. Fluorescence and immunofluorescence were detected with a Zeiss fluorescence microscope.
[0126] Stable Transfection. HEK293 cells were plated in a 100-mm plate at a density of 0.5×10 6 cells/plate. They were transfected with the control plasmid pcDNA1/Neo (Invitrogen, Faraday, U.S.A.) or with the plasmid containing rat HCaRG using a standard calcium phosphate coprecipitation method. 48 h after transfection, the cells were plated in 150-mm plates in the presence of 400 μg/ml G418 (Life Technologies, Burlington, Canada). After 2 weeks, the clones were picked and the level of ectopic HCaRG expression was determined by northern hybridization.
[0127] Cell Counting and 3 H-Thymidine Incorporation. The rate of stable clone cell proliferation was measured by counting the number of cells after plating, Cells were seeded at a density of 0.1×10 6 cells/6-well plate, with triplicate plates for each cell line. Every 24 h, the calls were trypsinized and counted in a hemocytometer HEK293 cells which stably expressed either Neo control plasmid or HCaRG were used for the estimation of DNA synthesis by 3 H-thymidine incorporation. The clones were trypsinized at 90% confluency, counted in a standard hemocytometer and inoculated at an identical initial cell density of 40,000 cells/ml in DMEM containing 10% FBS and G418 at 400 μg/ml. All cells were inoculated in Poly-D-lysine-pretreated 24-well plates in a volume of 1 ml/well (40,000 cells/well). They were allowed to attach and grow for a period of 24-48 h. The growth media were then replaced by DMEM containing 0.2% FBS and G418 (400 μg/ml) for a period of 48 h to synchronism the cells. After the synchronization period, the cells were supplied with fresh medium containing 10% FBS and allowed to grow for 48 h. [.sup.3H]-thymidine, 1 μCi/ml (ICN) was added to the cells for the last 4 h of the 48 h-growth period. At the end of incubation, the medium was removed and the monolayers washed twice with PBS. The cells were then fixed with ethanol:acetic acid (3:1, V:V), and DNA was digested/extracted with 0.5N PCA at 80-90° C. for 20 min.
[0128] The above results show that modulation of the expression of HCaRG has at least an effect on cell proliferation. Overexpression of HCaRG gene leads to inhibition of cell proliferation. This effect of overexpressing the gene (which could be replaced by administering the protein itself) indicates that the gene or the protein, peptide or mimetics are useful at least against proliferative diseases such as cancer. As well, since vascular cells express HCaRG, having these cells to overexpress the gene (or alternatively putting the cells in contact with the HCaRG protein, peptide or mimetic) would reduce cell proliferation provoked by different stimuli (such as occurring during restenosis or atherosclerosis, for example). Of course, any condition where cell proliferation would need to be increased would be treated the opposite way e.g. by silencing the HCaRG gene or by inhibiting the activity of the gene product.
[0129] Another immediate use for the probes or primers capable of hybridizing with HCaRG gene or for the antibodies capable of binding the HCaRG protein is the detection of a Ca-dependent condition. High levels are associated to low calcemia while low levels are associated with high calcemia and high calcium-dependent disorders. As shown above, certain types of hypertension as well as hypocalcemia correlates with high levels of HCaRG, while a “high calcium” disease like cancer correlate with low levels of the same.
[0130] Although the present Invention has been described hereinabove by way of preferred embodiments thereof and annexed figures, it can be modified, without departing from the spirit and nature of the subject invention. Any such modification is under the scope of this invention as defined in the appended claims.
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REFERENCE TO RELATED APPLICATIONS
[0001] This application is a national stage application under 35 USC 371 of International Application No. PCT/GB2007/003500, filed Sep. 14, 2007, which claims the priority of United Kingdom Application No. 0619181.1, filed Sep. 29, 2006, the contents of both of which prior applications are incorporated herein by reference.
FIELD OF INVENTION
[0002] This invention relates to a surface treating appliance, such as a vacuum cleaner.
BACKGROUND OF THE INVENTION
[0003] Surface treating appliances such as vacuum cleaners and floor polishers are well known. The majority of vacuum cleaners are either of the ‘upright’ type or of the ‘cylinder’ type, called canister or barrel cleaners in some countries. A typical upright vacuum cleaner comprises a main body which houses the main components of the vacuum cleaner, such as a motor and fan for drawing dirty air into the machine and some form of separating apparatus for separating dirt, dust and other debris from a dirty airflow drawn in by the fan. The main body also houses filters for trapping fine particles in the cleaned airflow. A cleaner head is rotatably mounted to the lower end of the main body. A supporting wheel is mounted on each side of the lower part of the main body, in a fixed relationship to the main body. In use, a user reclines the main body of the vacuum cleaner and then pushes and pulls a handle which is fixed to the main body of the cleaner. The vacuum cleaner rolls along the floor surface on the supporting wheels.
[0004] A dirty-air inlet is located on the underside of the cleaner head. Dirty air is drawn into the dust separating apparatus via the dirty-air inlet by means of the motor-driven fan. When the dirt and dust entrained within the air has been separated from the airflow in the separating apparatus, air is conducted to the clean air outlet by a second air flow duct, and via one or more filters, and expelled into the atmosphere.
[0005] Conventional upright vacuum cleaners have a disadvantage in that they can be difficult to manoeuvre about an area in which they are used. They can be pushed and pulled easily enough, but pointing the cleaner in a new direction is more difficult. It has been proposed to make an upright vacuum cleaner more manoeuvrable by substituting a wide rolling support for the supporting wheels, such as is described in our patent application GB2422094. A support assembly is provided to give further support to the main body when in the vertical position. The support assembly is moveable between a supporting position, in which it supports the main body of the appliance, and a stored position, in which it lies substantially against the main body. The support assembly is released from its supporting position by a user-operable foot pedal.
[0006] A problem which may be encountered with this type of support assembly is that there is a risk of inadvertent release of the support assembly from its supporting position. For example, if the user accidentally depresses the pedal, or if an object falls on it, the support assembly is brought out of its supporting position. Without the support of the support assembly, the main body has a tendency to tilt backwards and thus the appliance might topple over.
SUMMARY OF THE INVENTION
[0007] The invention provides a surface-treating appliance having a main body, a surface-treating head and a support assembly arranged to be moveable out of a supporting position in which it supports the main body by a user performing both of the following steps: actuating a mechanism on the support assembly and subsequently tilting the main body.
[0008] The provision of a support assembly that is releasable from its supporting position by a plurality of steps reduces the likelihood of accidental release of the support assembly from its supporting position. If the user depresses the pedal alone, the support assembly remains in its supporting position.
[0009] Advantageously, the support assembly is arranged to be moveable into a retracted position, where it lies substantially against the main body. The provision of a support assembly that lies substantially against the main body of the appliance when not needed improves the manoeuvrability and range of motion achievable by the appliance in use.
[0010] Advantageously, the appliance has a rolling support assembly comprising a plurality of rollers arranged relative to one another to define a region into which components of the appliance are mountable, such as the change over valve, and/or at least some of the components of the support assembly when in the retracted position.
[0011] The invention is particularly suitable for inclusion in upright vacuum cleaners having a wide, ball-like rolling support assembly, but may be applied to more conventional upright cleaners and other domestic appliances.
[0012] The term “surface treating appliance” is intended to have a broad meaning, and includes a wide range of machines having a head for travelling over a surface to clean or treat the surface in some manner. It includes, inter alia, machines which apply suction to the surface so as to draw material from it, such as vacuum cleaners (dry, wet and wet/dry), as well as machines which apply material to the surface, such as polishing/waxing machines, pressure washing machines, ground marking machines and shampooing machines. It also includes lawn mowers and other cutting machines.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] The invention will now be described, by way of example, with reference to the accompanying drawings, in which:
[0014] FIG. 1 is a side view of a surface-treating appliance constructed according to the invention;
[0015] FIG. 2 is a rear view of the appliance of FIG. 1 ;
[0016] FIG. 3 is a side view of the appliance of FIGS. 1 and 2 being put into a mode of cleaning by a user;
[0017] FIG. 4 is an exploded view of components of the support assembly of the appliance of FIGS. 1 to 3 ;
[0018] FIG. 5 a is a plan view of some of the components of FIG. 4 in a first position;
[0019] FIG. 5 b is a sectional view along the line A-A of FIG. 5 a;
[0020] FIG. 6 a is a plan view of the components of FIG. 5 a in a second position;
[0021] FIG. 6 b is a sectional view along the line B-B of FIG. 6 a;
[0022] FIG. 7 is an exploded view of components of the change over valve of the appliance of FIGS. 1 to 3 ;
[0023] FIG. 8 a is a perspective view of the change over valve of FIG. 7 in a first position;
[0024] FIG. 8 b is a perspective view of the change over valve of FIG. 7 in a second position;
[0025] FIG. 9 a is a side view of part of the support assembly of FIG. 4 and the change over valve of FIG. 7 in the first position;
[0026] FIG. 9 b is a side view of the components of FIG. 9 a in an intermediary position;
[0027] FIG. 9 c is a side view of the components of FIG. 9 a in the second position;
[0028] FIG. 10 is a perspective view of the appliance in a mode of use;
[0029] FIG. 11 is a perspective view of part of the appliance including a component of the support assembly; and
[0030] FIG. 12 is a side view of the appliance being returned to the position of FIG. 1 .
[0031] Like reference numerals refer to like parts throughout the specification.
DETAILED DESCRIPTION OF THE INVENTION
[0032] With reference to FIGS. 1 and 2 , the surface treating appliance is shown in the form of a vacuum cleaner and is indicated generally by the reference numeral 1 . The vacuum cleaner 1 comprises a main body 2 , a user-operable handle 3 and a roller assembly 4 for rolling the cleaner along a floor surface. The handle 3 extends upwardly from the rear part of the main body 2 . The main body 2 houses a motor and fan for generating a suction airflow (not visible in these drawings) as well as separating apparatus 5 for separating dirt, dust and other debris from a dirty airflow drawn into the machine by the fan and motor.
[0033] In this embodiment, the separating apparatus 5 is cyclonic, in which the dirt and dust is spun from the airflow. The cyclonic separating apparatus 5 comprises two stages of cyclone separation arranged in series with one another. The first stage is a cylindrically-walled chamber 6 and the second stage comprises a set 7 of tapering, substantially frusto-conically shaped chambers arranged in parallel with one another. Airflow is directed tangentially into the upper part of a first cyclonic chamber 6 by a duct 8 . Larger debris and particles are removed and collected in the first cyclonic chamber 6 . The airflow then passes through a shroud 9 to the set 7 of smaller frusto-conically shaped cyclonic chambers. Finer dust is separated by these chambers and the separated dust is collected in a common collecting region.
[0034] The main body 2 also houses filters (not visible in these drawings) for trapping fine particles in the cleaned airflow. These filters remove any fine particles of dust which have not already been removed from the airflow by the separating apparatus. A first filter, called a pre-motor filter, is provided before the motor and fan. A second filter, called a post-motor filter, is provided after the motor and fan. Where the motor for driving the suction fan has carbon brushes, the post-motor filter also serves to trap any carbon particles emitted by the brushes. Clean air is then expelled to the atmosphere.
[0035] A cleaner head 10 is pivotably mounted to the lower end of the main body 2 , and serves, in use, to treat the floor surface. In this embodiment, it comprises a housing with a chamber for supporting an agitator in the form of a brush bar 11 . The lower, floor-facing side of the chamber has an air inlet slot 12 and the brush bar 11 is rotatably mounted in the chamber such that bristles on the brush bar can protrude through the inlet slot and can agitate the floor surface over which the cleaner head passes. The brush bar 11 is rotatably driven by a dedicated motor 13 positioned on the cleaner head 10 .
[0036] The roller assembly 4 permits the cleaner to be manoeuvred easily along a floor surface. However, the roller assembly 4 may not provide sufficient support for the cleaner when the main body 2 is in the vertical, or substantially vertical position. To this end, a support assembly 14 is provided.
[0037] FIG. 4 is an exploded view of the main components of the support assembly 14 . Minor features such as fasteners and washers have been omitted for clarity. The support assembly 14 comprises a stand 15 shaped so as to form two legs 16 a, 16 b, with a strut 17 therebetween to provide structural strength to the stand 15 . Each of the legs 16 a, 16 b, has a wheel 18 a, 18 b attached to an end portion. The wheels 18 a, 18 b aid a user in guiding the cleaner 1 between rooms. In this embodiment, each of the wheels 18 a, 18 b is wide and the face furthest from the leg 16 a, 16 b is rounded. This gives smooth running on a variety of floor surfaces. Each wheel 18 a, 18 b is attached to a respective leg 16 a, 16 b by axles 19 a, 19 b such that the wheels are outside the legs of the stand 15 . This provides a wide wheel-base for extra stability.
[0038] The end portion of the stand 15 remote from the wheels 18 a, 18 b has outwardly facing pins 20 a, 20 b, only one of which ( 20 a ) is visible in this drawing. The pins 20 a, 20 b are arranged to engage in apertures on a yoke 21 associated with the main body 2 of the cleaner 1 so that the stand 15 is attached to the yoke, and can move pivotably with respect to the main body.
[0039] The support assembly 14 also comprises a pedal 22 , which is intended to be depressible by the user's foot. The pedal 22 extends between the legs 16 a, 16 b of the stand 15 , above the strut 17 . The pedal 22 has outwardly-facing pins 23 a, 23 b, which engage with recesses 24 a, 24 b on the inwardly-facing surface of the stand 15 , so that the pedal 22 is pivotable with respect to the stand.
[0040] Another component of the support assembly 14 is an actuator 25 , which is approximately T-shaped. The end of the actuator 25 that corresponds with the foot of the T has outwardly-facing pins 26 a, 26 b that are arranged to engage in apertures (not shown) on the main body 2 . Thus, the actuator 25 is pivotable with respect to the main body 2 . Resilient means in the form of a helical spring 27 is also provided between the actuator 25 and the main body 2 , and is biased so that the actuator tends to pivot upwardly, with the arms 28 a, 28 b of the T uppermost. Ordinarily, when the support assembly 14 is supporting the main body 2 of the cleaner 1 , the actuator 25 is arranged to bear against a lower surface of the foot pedal 22 , thereby urging it upwardly, so that it stands proud of the stand 15 . Thus, the pedal 22 is conspicuous to the user.
[0041] The support assembly 14 also comprises a locking member 29 , which is provided to give further support for the cleaner 1 . The locking member 29 comprises two legs 30 a, 30 b, with a reinforcing strut 31 therebetween. One end portion of each leg 30 a, 30 b has an outwardly-facing projection 32 a, 32 b that engages in respective apertures (not shown) on the main body 2 , close to the bottom of the hose 33 on the rear of the cleaner 1 . Thus, the locking member 29 is pivotable with respect to the main body 2 . The other end portion of each leg 30 a, 30 b has outwardly facing locking-pins 34 a, 34 b. Ordinarily, when the support assembly 14 is supporting the main body 2 of the cleaner 1 , the locking pins 34 a, 34 b engage with co-operating notches 35 a, 35 b on the foot pedal 22 . Thus, the foot pedal 22 , being urged into a predetermined position by the sprung actuator 25 , engages the locking member 29 in a position where it provides support for the main body 2 of the cleaner 1 .
[0042] Other features of the support assembly 14 include a locking pin lever 36 , which is arranged to fit in a recess 37 on an inwardly-facing surface of the stand 15 . The locking pin lever 36 is pivotably attached to the stand 15 , and is resiliently biased with respect to it by means of helical spring 38 . The recess 37 for the locking pin lever 36 communicates with a locking pin groove 39 . A corresponding locking pin groove (not visible in these drawings), is provided on the other side of the stand 15 . The stand 15 also comprises actuator ramps 40 a, 40 b, only one of which is visible in this drawing. There is also provided on the stand 15 a change over valve pin 41 . These features will be discussed in more detail further in the specification.
[0043] When the cleaner 1 is in the position shown in FIGS. 1 and 2 , it can be used in a cylinder mode, in which case the handle 3 may be released and used as a hose and wand assembly in conjunction with the hose 33 . Air is drawn into the cleaner 1 through the end of the wand which can be released from the cleaner for appropriate manipulation. The inlet 12 in the cleaner head 10 is automatically shut off.
[0044] When the cleaner 1 is to be used in conventional upright mode, the user reclines the main body 2 . In order to do so, the support assembly 14 must be released from the supporting position shown in FIGS. 1 and 2 . The first step is for the user to depress the pedal 22 with his foot. This is illustrated in FIGS. 5 a and 5 b.
[0045] The action of depressing the pedal 22 moves it out of engagement with the locking pins 34 a, 34 b. Thus, the weight of the main body 2 bears against the locking member 29 , and the pins 34 a, 34 b of the locking member bear against the stand 15 . The locking pin lever 36 resists movement of the pin 34 b, and hence the locking member 29 out of this supporting position. The support assembly 14 maintains its supporting position and continues to support the main body 2 , even though the pedal 22 has been depressed. This is an important safety feature, as it prevents the main body 2 from toppling backwards if the user accidentally depresses the pedal 22 .
[0046] In order to bring the support assembly 14 out of its supporting position, the user must subsequently apply a turning moment to the main body 2 by pivoting the handle 3 towards him, as illustrated in FIG. 3 , to bring the main body out of its substantially vertical position. This action causes the main body 2 to bear against the locking member 29 with a force having a greater horizontal component than that experienced by the locking member when the main body 2 is vertical. Consequently, the pin 34 b of the locking member 29 is urged against the locking pin lever 36 . The force is sufficient to cause the locking pin lever 36 to pivot downwardly in its recess 37 against the force of its spring 38 . This permits the pin 34 b, and hence the pin 34 a, to move out of their supporting position and into the locking pin grooves 39 on the stand 15 . Thus, the support assembly 14 is brought out of its supporting position only when the user is supporting the cleaner 1 himself by means of the handle 3 .
[0047] As the user continues to recline the main body 2 , the locking pins 34 a, 34 b slide along the grooves 39 in the stand 15 . The wheels 18 a, 18 b on the stand remain on the floor surface and so, as the main body 2 reclines, the stand 15 is brought closer to the rear of the main body. The action of depressing the pedal 22 and sliding the stand 15 causes the arms 28 a, 28 b of the actuator 25 to be pushed under the actuator ramps 40 a, 40 b provided on the stand. Over the range of positions up to this point, the actuator 25 applied a spring force to the pedal 22 , as shown in FIG. 5 b. When the actuator arms 28 a, 28 b, engage with, and move along the actuator ramps 40 a, 40 b on the stand 15 , the actuator 25 ceases to act on the pedal 22 but instead applies a spring force to the stand. Over the range of positions beyond this point, the actuator acts on the stand 15 . The actuator 25 is biased so as to push upwardly against the ramps 40 a, 40 b, and hence urge the stand 15 upwards, as shown in FIGS. 6 a and 6 b. As the stand 15 pivots upwards, it lifts the wheels 18 a, 18 b and hence brings the support assembly 14 out of engagement with the floor surface. In the fully retracted position, as shown in FIG. 3 , the support assembly 14 lies substantially against the main body 2 of the cleaner 1 .
[0048] In reclining the main body 2 of the cleaner 1 , the user changes the mode of cleaning from the cylinder mode, in which air is drawn through the hose and wand assembly 3 , 33 , to the upright mode, in which air is drawn through the head 10 of the cleaner. A change over valve 42 is required in order to connect automatically the dust separating apparatus 5 to either the wand and hose 3 , 33 or the cleaner head 10 , in dependence on the mode of operation. As the user reclines the main body 2 of the cleaner 1 , the change over valve 42 automatically shuts off the air inlet at the distal end of the wand and connects the dust separating apparatus 5 to the cleaner head 10 . The support assembly 14 is arranged to act on the change over valve 42 such that it occupies the correct position for the mode of cleaning.
[0049] The main components of the change over valve 42 are shown in the exploded view of FIG. 7 . Minor components, such as seals, springs and fasteners have been omitted for clarity. The change over valve 42 comprises a casing 43 which houses a cylindrical drum 44 . The drum 44 is rotatably mounted in the casing 43 such that it rotates about its longitudinal axis. The drum 44 has an inlet 45 on its circumference and an outlet 46 at one end. The drum 44 defines a fluid flow path. The position of the drum 44 determines the mode of cleaning. FIGS. 8 a and 8 b illustrate the position of the change over valve 42 in the two modes of cleaning. The hose 47 , connected at one end portion of the casing 43 is internal to the cleaner head 10 and so defines the fluid outlet from the air inlet 12 on the cleaner head. The opening 48 at the other end of the casing 43 is arranged to connect with the main hose 33 and so defines the fluid outlet from the hose and wand assembly 3 , 33 . A wheel 49 is connected to the rotational axis of the drum 44 . Rotation of the wheel 49 causes the drum 44 to move between the positions defining the cleaning modes. A slot 50 in the circumference of the wheel 49 corresponds approximately to the position of the fluid inlet 45 on the circumference of the drum 44 .
[0050] In the position shown in FIG. 8 a, the cleaner is in cylinder mode, with the inlet 45 of the drum 44 facing the opening 48 . The cleaner head hose 47 is closed off. Air is drawn through the hose and wand assembly 3 , 33 , into the change over valve 42 and exits the outlet 46 of the drum 44 into a fluid conduit 51 . The fluid conduit 51 leads to the duct 8 connected to the dirt and dust separating apparatus 5 .
[0051] In the position shown in FIG. 8 b, the cleaner is in upright mode, with the inlet 45 of the drum facing the cleaner head hose 47 . The opening 48 that communicates with the hose and wand assembly 3 , 33 is closed off. Air is drawn through the cleaner head 10 via the inlet 12 , into the change over valve 42 and exits the outlet 46 of the drum 44 into the fluid conduit 51 .
[0052] Whilst the user is reclining the main body 2 of the cleaner 1 , the stand 15 moves pivotably relative to the main body. The change over valve pin 41 on the stand 15 engages with the slot 50 on the wheel 49 of the change over valve 42 . FIG. 9 a illustrates the point at which the change over valve pin 41 enters the opening of the slot 50 . The change over valve pin 41 bears against a wall 50 a of the slot and induces the wheel 49 to rotate, as shown in FIG. 9 b. Thus, the pivoting motion of the stand 15 is translated into rotational motion of the drum 44 of the change over valve 42 , in the manner of a Geneva drive. As the user moves the main body 2 into the reclined position, so that the stand 15 is urged upwards, the change over valve 42 is caused to rotate from the cylinder mode to the upright mode. The stand then continues to move into its fully retracted position, as shown in FIG. 9 c.
[0053] Another function of the support assembly 14 is to control the locking and release of the cleaner head 10 . When the main body 2 is in the vertical position, with the support assembly 14 in the supporting position, the cleaner head 10 is latched with respect to the main body 2 . This enables the user to tilt the cleaner 1 as a whole onto the wheels 18 a, 18 b of the support assembly 14 so that the cleaner can be wheeled from location to location without the cleaner head 10 drooping and obstructing manoeuvrability. The support assembly 14 is arranged to release the cleaner head 10 from this position as it moves into the retracted position so that, as the main body 2 of the cleaner 1 is reclined, the head remains in contact with the surface to be treated.
[0054] The cleaner head 10 is connected to the main body 2 of the vacuum cleaner 1 in such a manner that the cleaner head 10 remains in contact with a floor surface as the main body is manoeuvred through a wide range of operating positions, e.g. when moved from side-to-side or when the main body is twisted about its longitudinal axis. The yoke 21 connects the main body 2 to the cleaner head 10 . The yoke 21 is mounted to each end of a rotational axis of the roller assembly 4 . The yoke 21 can pivot independently of the main body 2 . At the forward, central part of the yoke 21 there is a joint 52 , which connects to the cleaner head 10 .
[0055] The main body 2 is rotatably connected to the roller assembly 4 , which lies at the base of the main body. The roller assembly 4 allows the apparatus to be easily pushed or pulled along a surface. The shape of the roller assembly 4 and the connections between the main body 2 and the roller assembly, and the roller assembly and the cleaner head 10 , allow the apparatus to be more easily manoeuvred than traditional vacuum cleaners.
[0056] The roller assembly 4 comprises a central roller 53 and a pair of outer rollers 54 a, 54 b, which are arranged relative to each other so as to provide a rolling support surface, but with rotational axes that are spaced from each other. The central roller 53 comprises an elongated and barrel-shaped shell, which shape provides both stability and manoeuvrability. A plurality of ridges 55 are provided around its circumference, to provide extra grip as the cleaner 1 is rolled along a surface to be treated. The outer rollers 54 a, 54 b are cap-shaped, having a larger diameter than the maximum diameter of the central roller 53 but a relatively narrow rolling support surface. This arrangement of rollers delimits a region into which components of the vacuum cleaner 10 may be mounted. In this embodiment, the region houses the change over valve mechanism 42 and also provides a space into which components of the support assembly 14 can fold into when the cleaner 1 is being used for upright cleaning. Thus, components of the support assembly 14 are hidden from the user when the support assembly is in the retracted position. This prevents the components from being damaged or tampered with, as well as being more aesthetically pleasing.
[0057] The arrangement of the pivotal mounting of the yoke 21 and joint 52 allows the main body 2 together with the roller assembly 4 to be rotated about the longitudinal axis 56 of the handle 3 , in the manner of a corkscrew, while the cleaner head 10 remains in contact with the floor surface. This arrangement also causes the cleaner head 10 to point in a new direction as the main body 2 is rotated about its longitudinal axis 56 .
[0058] FIG. 10 shows the vacuum cleaner in a turning position. The user rotates the main body 2 about its longitudinal axis 56 by means of the handle 3 . This causes the roller assembly 4 to tilt with respect to the floor. The joint 52 associated with the yoke 21 causes the cleaner head 10 to turn whilst remaining in contact with the floor. The extent to which the main body 2 is turned about its longitudinal axis 56 determines the extent to which the cleaner head 10 moves from its forward facing position towards the right or left. The support assembly 14 remains neatly tucked up against the rear of the main body 2 during this range of motions performed by the cleaner 1 . This permits the user easily to manoeuvre the cleaner 1 , even when cleaning under furniture and other low obstructions.
[0059] When the user wishes to return the cleaner 1 to the vertical position, he pivotally moves the main body 2 back towards the vertical, as indicated by the arrow in FIG. 12 . As the main body 2 rotates, an arm 57 fixed to the yoke 21 bears against a surface of the stand 15 , as shown in FIG. 11 . The arm 57 pushes the stand 15 out of its retracted position against the main body 2 . The stand 15 moves away from the main body 2 and, as it does so, pivots downwardly towards the floor surface.
[0060] The change over valve pin 41 on the stand 15 re-engages with the slot 50 on the wheel 49 of the change over valve 42 . The change over valve pin 41 bears against the other side wall 50 b of the slot and induces the wheel 49 to rotate in the opposite direction to that when the stand 15 was being retracted. As the user moves the main body 2 from its reclined position back into the vertical position, the change over valve 42 is caused to rotate from the upright mode to the cylinder mode. The motion of the stand 15 and valve 42 is the same as that shown in FIGS. 9 a to 9 c, but in reverse.
[0061] The pins 34 a, 34 b of the locking member 29 ride along the grooves 39 in the stand 15 as it moves out of the retracted position and cause the locking member to pivot outwardly from the main body 2 . When moving from the retracted position into the supporting position, the locking pins 34 a, 34 b are arranged to move along the upper surfaces of the grooves. Hence the locking pin 34 b moves over the locking pin lever 36 and into the top end of its groove 39 . As the main body 2 returns to its vertical position, the locking pin 34 b is prevented from sliding back along the groove 39 by the locking pin lever 36 .
[0062] The arms 28 a, 28 b of the actuator 25 slide along the actuator ramps 40 a, 40 b provided on the stand 15 , as the stand moves relative to the main body 2 . The actuator 25 continues to apply an upwardly-directed spring force to the stand 15 , but the force of the yoke arm 57 against the stand overcomes this spring force and prevents the stand from being urged back into the retracted position. When the actuator arms 28 a, 28 b reach the ends of the ramps 40 a, 40 b, the actuator 25 ceases to act on the stand 15 . Therefore, the spring force urging the stand 15 upwards is released. Hence, the stand 15 falls under the influence of gravity towards the floor surface and pivots so that its wheels 18 a, 18 b resume engagement with the floor. The actuator 25 , freed from the constraints of the ramps 40 a, 40 b, pivots upwards under the influence of the spring and re-engages the pedal 22 . The actuator 25 urges the pedal 22 upwards, so that the notches 35 a, 35 b on the pedal re-engage with the pins 34 a, 34 b of the locking member 29 . In this manner, the cleaner 1 is returned to its vertical position and the support assembly 14 supports the main body of the cleaner.
[0063] The components may be arranged to produce a click or other sound, to indicate to the user that the appliance has been fully returned to the vertical position. Thus, the user releases the handle 3 , leaving the main body 2 to be supported by the support assembly 14 .
[0064] Of course, variations may be made without departing from the scope of the invention. For example, the support assembly 14 may be coupled to the brush bar 11 , so that the brush bar, or other agitator, is driveable only as the user reclines the main body 2 for upright cleaning. This prevents the brush bar 11 from being energised when the cleaner is in the vertical position, when it may be stationary for an extended period of time. Thus, excessive wear and tear on the floor surface is prevented. The support assembly may further be arranged to cause the agitator to be driven automatically as the main body 2 is reclined, without the need for selective energisation by the user. Similarly, the support assembly 14 may be arranged automatically to interrupt driving of the agitator when the main body 2 is returned to the vertical position.
[0065] The provision of a depressible pedal 22 makes the cleaner user-friendly when converting from cylinder-type cleaning to upright cleaning. However, the foot pedal may be replaced by some other user-operable mechanism, such as a handle, lever or catch.
[0066] It is possible that some users may not acknowledge the presence of the pedal or other user-operable device and may be more familiar with cleaners in which the conversion between cylinder and upright modes is effected by pushing down on the cleaner head 10 itself as the body 2 is reclined. Therefore, the support assembly 14 may be arranged so as to release the cleaner head 10 from its latched position in the event that a downward force over a predetermined limit is applied to the cleaner head. This allows the head 10 to drop down onto the floor surface for upright-type cleaning. When the main body 2 is returned to the vertical position, the support assembly re-sets itself, so that the user can subsequently recline the main body 2 in the correct manner by means of the pedal 22 . This feature prevents the cleaner head 10 from being damaged if the user tries to deploy the cleaner head in the wrong manner.
[0067] It is also possible that a user may misuse the appliance, or else be unaware of the operation of the support assembly, and may try to move the components manually. The support assembly 14 is arranged to be completely self-resetting when the main body 2 is returned to the vertical position. This feature ensures that the sequence of operations activated by the support assembly does not get out of synchronisation if the cleaner 1 is used incorrectly.
[0068] While the illustrated embodiment shows a vacuum cleaner in which ducts carry airflow, it will be appreciated that the invention can be applied to cleaners which carry other fluids, such as water and detergents.
[0069] Separation of dust from the airflow could equally be carried out using other means such as a conventional bag-type filter, a porous box filter, an electrostatic separator or some other form of separating apparatus. For embodiments of the apparatus which are not vacuum cleaners, the main body can house equipment which is appropriate to the task performed by the machine. For example, for a floor polishing machine the main body can house a tank for storing liquid wax
[0070] The brush bar 11 can be driven in other ways, such as by a turbine which is driven by incoming or exhaust airflow, or by a coupling to the motor which is also used to drive the suction fan. The coupling between the motor and brush bar can alternatively be via a geared coupling. In alternative embodiments the brush bar can be removed entirely so that the machine relies entirely on suction or by some other form of agitation of the surface. For other types of surface treating machines, the cleaner head can include appropriate means for treating the floor surface, such as a polishing pad, a liquid or wax dispensing nozzle etc. The lower face of the cleaner head can include small rollers to ease movement across a surface. | 1a
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[0001] The present application claims the benefit of U.S. Provisional Patent Application No. 60/960,911, filed Oct. 19, 2007; and U.S. Provisional Patent Application No. 60/996,156, filed Nov. 5, 2007, whose disclosures are hereby incorporated by reference in their entirety in the present application.
BACKGROUND OF THE INVENTION
[0002] 1. Field of Invention
[0003] The present invention relates generally to the field of electronic music devices. More particularly, the invention relates to a device for inducing better sleep.
[0004] 2. Description of Related Art
[0005] Millions of people have difficulty falling asleep or staying asleep. Difficulty falling asleep may result stress, illness, or from disorders like insomnia. The effect of poor sleep can affect job performance and quality of life. The National Institutes of Health estimates that some 40 million people suffer from one or more chronic or long term sleep disorders in the United States alone, with another 20 million estimated to have frequent difficulty sleeping soundly at night and staying fully alert during the day.
[0006] Inducing sleep in children and infants is equally important and equally challenging. Similarly, elderly people, particularly those in the community living setting, often experience even greater difficulty sleeping than the general population. In addition, difficulty sleeping or falling asleep is often amplified when the sufferer is required to travel and/or attempt to sleep in an unfamiliar setting.
[0007] Several medicinal approaches have been developed for treating those who have difficulty sleeping and those who suffer from sleep disorders such as insomnia. Often times, however, doctors and sufferers of sleep difficulties are hesitant to pursue those approaches because of the addictive and residual effects that often accompany sleep medications. In addition, in the case of mild difficulty sleeping, prescription, and even non-prescription, steep medication often is not warranted.
[0008] A recent study on sleep quality was conducted by researchers at the Frances Payne Bolton School of Nursing of the Case Western Reserve University. The findings of that study provided evidence for the use of soothing music as an empirically-based intervention for sleep in older people. The study employed music having a tempo of 60 to 80 beats per minute.
[0009] While research has shown that soothing music can have a positive effect on sleep quality, there is a need for a mode of convenient and effective delivery of suitable music to a person suffering from difficulty sleeping for the purpose of inducing better sleep. The average person is not capable of identifying music having a tempo of only between about 60 and about 80 beats per minute. Further, a means for delivering music having only such a tempo is required. In addition, there is a need for a delivery mechanism for music having a tempo of only between 60 and 80 beats per minute that can be easily transported when a person is required to travel away from their usual place of sleep.
SUMMARY AND OBJECTS OF THE INVENTION
[0010] Accordingly, there exists a need for a device for playing music having a tempo within a range of about sixty to about eighty beats-per-minute. There also exists a need for a device for playing such music that can be integrated into portable devices that can be easily transported during travel. Such devices should be of compact construction so as to be easily combined with common travel items.
[0011] Briefly described, those and other objects and features of the present invention are accomplished, as embodied and fully described herein, by a device for inducing sleep comprising a memory for storing digital music; a digital signal processor for processing the digital music; and a power source; wherein the digital music has a tempo within a range of about 60 to about 80 beats per minute.
[0012] The objects and features of the device also include a timer for playing the digital music for a predetermined length of time.
[0013] The objects and features of the device further include an actuator for activating the digital music.
[0014] The objects and features of the device also include at least one speaker for playing music.
[0015] The objects and features of the device also include at least one input for receiving digital music for storing to the memory.
[0016] With those and other objects, advantages and features of the invention that may become hereinafter apparent, the nature of the invention may be more clearly understood by reference to the following detailed description of the invention, the appended claims and to the several drawings attached herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] FIG. 1 is a schematic drawing of the system architecture of the components of an embodiment of the present invention;
[0018] FIG. 2 is a drawing of an alarm clock embodiment of the present invention;
[0019] FIG. 3 is a drawing of a pillow embodiment of the present invention;
[0020] FIG. 4 is a drawing of a sleep mask embodiment of the present invention;
[0021] FIG. 5 is a drawing of a plush toy embodiment of the present invention;
[0022] FIG. 6 is a drawing of a mobile embodiment of the present invention;
[0023] FIG. 7 is a drawing of a crib embodiment of the present invention;
[0024] FIG. 8 is a drawing of an infant bouncy seat embodiment of the present invention;
[0025] FIG. 9 is a drawing of a baby monitor embodiment of the present invention;
[0026] FIG. 10 is a process flow diagram depicting an embodiment of the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0027] Several preferred embodiments of the invention are described for illustrative purposes, it being understood that the invention may be embodied in other forms not specifically shown in the drawings.
[0028] While the digitized music as described in the preferred embodiments is referred to as “Bedtime Beats” music, it is understood that the invention contemplates any music having a tempo of between about 60 and about 80 beats per minute.
[0029] Turning to FIG. 1 , the embodiments of the present invention comprise a chip 100 having a memory 102 for storing digitized music, a digital audio signal processor 104 for processing the digitized music, an output component such as a speaker 106 for outputting the digitized music and a power source 108 for supplying power to the system. Embodiments further comprise a housing 110 which can take on varying forms as would occur to a person of ordinary skill in the art, select examples of which are described in more detail below. The housing 110 may include an input 112 for receiving digital music to be stored to the memory 102 and an actuator 114 for beginning playback of the digital music.
[0030] Bedtime Beats Home Clock:
[0031] In one embodiment of the present invention as shown in FIG. 2 , a clock 200 is embedded with 120 minutes of Bedtime Beats music, or other predeterminable length of time as desired. The clock housing 202 may feature a “Secret to Sleep” button or other music actuator feature 204 that the user may use to start playback of the Bedtime Beats music. Upon activation, the Bedtime Beats music will play for the predetermined length of time. The clock may also feature an adjustable timer 206 and the user may be able to select the length of the music's playing time (for example, 120, 60, 30, 15 minutes, or other length of time as desired). The chip containing the Bedtime Beats music is housed inside the clock 200 . The clock has a speaker 208 for playing the music for the sleeper. In varying embodiments, the clock housing may contain the features of an alarm clock, a “fall asleep” clock, a personal music device docking station, or any combination of these features, or other features of a clock that would occur to a person of ordinary skill in the art.
[0032] This technology may be featured in similar types of device housings such as clock radios, portable audio devices, home audio devices, and docking devices for portable audio and/or video devices (e.g., iHome docking device for Apple iPod), as will be apparent to those of ordinary skill in the art.
[0033] Bedtime Beats Travel Clock:
[0034] In another embodiment of the present invention, the clock as previously described may be portable and may contain the same features as the Home Clock and may include 60 minutes of music, or other length of time as desired.
[0035] Bedtime Beats Standard Size Pillow:
[0036] In another embodiment of the present invention, a pillow 300 is embedded with 60 minutes of Bedtime Beats music, or other length of time as desired. The pillow housing 302 may be made of therapeutic foam or other soft material and may contain a protective compartment 304 to hold the chip, speaker and power source. The pillow 300 may contain an actuator for beginning playback of the music such as by squeezing the pillow 300 .
[0037] Bedtime Beats Travel Pillow:
[0038] In another embodiment of the present invention, a travel pillow may be similar to the standard size pillow 300 previously described but having a smaller size to facilitate easy transport during travel. The exterior may be covered in soft fleece or other soft material.
[0039] Bedtime Beats Sleep Mask:
[0040] Turning to FIG. 4 , shown therein is a sleep mask embodiment 400 with ear bud speakers 402 and an embedded chip containing 30 minutes of Bedtime Beats music, or other length of time as desired. The sleep mask 400 may have a piece of fabric, padding, or other material 404 for covering the eyes and an elastic band 406 or other mechanism for securing the mask over the eyes of the wearer. The mask may have ear bud speakers 402 attached to the fabric material 404 or, alternatively, to the elastic band 406 which allow the wearer to listen to the Bedtime Beats music while wearing the sleep mask 400 .
[0041] Bedtime Beats Toy:
[0042] In another embodiment of the present invention as shown in FIG. 5 , a very soft, washable plush toy (“Sleepie”) 500 is embedded with a speaker 502 and the chip containing 30 minutes of Bedtime Beats music, or other length of time as desired. The speaker 502 and chip may be placed in a protective compartment 504 and may be removable so that the Sleepie 500 can be washed. The Sleepie 500 may include an actuator 506 for beginning playback of the Bedtime Beats music by some action by the user such as squeezing the Sleepie 500 . The toy may be in the form of a stuffed animal, plush ball, a soft/fabric book, or other soft toy for infants. The toy may also be in the form of a stationary infant toy such as a song box or other toy that may be placed on a child's dresser or other location near the child's place of sleep.
[0043] Bedtime Beats Mobile:
[0044] Turning to FIG. 6 , in another embodiment of the present invention, a musical mobile 600 is embedded with a speaker 602 and a chip containing 30 minutes of Bedtime Beats music, or other length of time as desired. The mobile 600 may contain 6 small, rotating toys 604 , or such other number as desired. The toys 604 may be constructed of a plush material or other material and designed to take the form of animals, shapes, vehicles, or other forms. The mobile 600 may have a clip 606 for attaching it to a crib. In another embodiment, the mobile may include a stand so that it may rest on a dresser, desk, or other flat surface.
[0045] Bedtime Beats Crib:
[0046] In another embodiment of the present invention as shown in FIG. 7 , a crib 700 is embedded with speakers 702 and a chip containing 30 minutes of Bedtime Beats music, or other length of time as desired. The crib 700 may feature a “Secret to Sleep” button 704 or other music activation feature for starting playback of the Bedtime Beats music. The crib 700 may also feature an adjustable timer 706 and a user may be able to select the length of the music's playing time (for example, 120, 60, 30, 15 minutes, or other length of time as desired).
[0047] Bedtime Beats Baby Swing Bouncy Seat:
[0048] In another embodiment of the present invention as shown in FIG. 8 , shown therein is an infant bouncy seat or swing 800 inside of which a child rests. Typically positioned on the floor, the seat or swing is moveable. The baby swing 800 generally swings back and forth creating a rocking motion and can be battery operated or plugged in to a wall outlet. The swing 800 is embedded with speakers 802 and a chip containing 30 minutes of Bedtime Beats music, or other length of time as desired. The baby swing 800 may feature a “Secret to Sleep” button 804 or other music activation feature for starting playback of the Bedtime Beats music. The baby swing 800 may also feature an adjustable timer 806 and a user may be able to select the length of the music's playing time (for example, 120, 60, 30, 15 minutes, or other length of time as desired).
[0049] Similar to the baby swing 800 , the infant bouncy seat is a stand alone infant seat which contains a seat for the infant to sit inside of. The infant's legs are free to touch and push off the floor to create a bouncing motion. Bedtime Beats music is embedded in this device as in the infant bouncy seat 800 .
[0050] Bedtime Beats Baby Monitor:
[0051] Another embodiment of the present inventions is shown in FIG. 9 , wherein a baby monitor 900 is embedded with a chip containing 30 minutes of Bedtime Beats music, or other length of time as desired. Typically, a baby monitor consists of a pair of speaker/microphone combination devices, one in the parental bedroom and one in the child's bedroom that allows a parent to hear, speak to, and monitor the child remotely. The Bedtime Beats baby monitor housing 902 contains a speaker 904 which acts as both a speaker for the parents to monitor and hear the child and for administering of Bedtime Beats music which can play from the parental unit 908 on the child's speaker 904 . The child's unit 910 will also house the Bedtime Beats chip and can play music when an actuator 906 is switched over to “play” function. The units may be battery powered or plugged in to a standard wall outlet. The parental unit 908 and the child unit 910 may be of identical design to allow for interchangeability.
[0052] Turning to FIG. 10 , described therein is the process flow 1000 of the Bedtime Beats chip. In process step 1002 , a user activates the Bedtime Beats device. In process step 1004 , a preset timer begins to run. In process step 1006 , the Bedtime Beats music begins to play. In process step 1008 , if time remains on the timer, the music continues to play. If time has expired, the Bedtime Beats stops playing as shown in process step 1010 .
[0053] Although certain presently preferred embodiments of the disclosed invention have been specifically described herein, it will be apparent to those skilled in the art to which the invention pertains that variations and modifications of the various embodiments shown and described herein may be made without departing from the spirit and scope of the invention. Accordingly, it is intended that the invention be limited only to the extent required by the appended claims and the applicable rules of law. | 1a
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