US5436291A
Expired / Lapsed
US
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Calcification-resistant synthetic biomaterials
Assignee: University of Michigan (System)
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Filing: 1994-01-21
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Granted: 1995-07-25
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Expires: 2014-01-21
Abstract
Abstract Synthetic biomaterials are provided with irreversibly bound amino diphosphonate, polyphosphonate, or other anticalcification agent to prevent in vivo calcification. Such biomaterials include biocompatible elastomers such as polyurethane and/or polydimethylsiloxane, and the like which are intended for invasive, or in-dwelling use in a human or animal body. Illustratively, reaction conditions utilizing hi-or polyfunctional epoxides result in epoxide bridge incorporation of the anticalcification agent to the biomaterial elastomer.
Inventors
- 👤 Robert J. Levy
- 👤 Ravi Joshi
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-22 22:50
CPC Classifications
C; C08; C08K; C08K5/00; C08K5/49; C08K5/51; C08K5/53; C08K5/5317; C08K5/5333; C08K5/5353; A; A61; A61L; A61L27/00; A61L27/14; A61L27/18; A61L27/50; A61L27/54; A61L33/00; A61L33/0005; A61L33/0011; C08G; C08G59/00; C08G59/14; C08G59/1433; C08G59/1488; C08L; C08L101/00; C08L101/02; A61L2400/00; A61L2400/02
Claims Analysis
Total Claims: 44
Claim 1
Independent Claim
62 words
A material for implantation in the interior of the body of a living being, the material comprising a biocompatible synthetic polymer which is substantially insoluble in the interior of the body of a host living being and which has irreversibly bound thereto an effective amount of an polyphosphonate anticalcification agent for rendering said biocompatible synthetic polymer resistant to in vivo pathologic calcification.
Claim 2
Dependent Claim
62 words
A material for implantation in the interior of the body of a living being, the material comprising a biocompatible synthetic polymer which is substantially insoluble in the interior of the body of a host living being and which has irreversibly bound thereto an effective amount of an polyphosphonate anticalcification agent for rendering said biocompatible synthetic polymer resistant to in vivo pathologic calcification.
Claim 3
Dependent Claim
40 words
The material of claim 1 wherein the biocompatible synthetic polymer is selected from the group consisting of polyurethane, polydimethylsiloxane, ethylene vinyl acetate, polymethyl methacrylate, polyamide, polycarbonate, polyester, polyethylene, polypropylene, polystyrene, polyvinyl chloride, polytetrafluoroethylene, polysulfone, or cellulose acetate and copolymers thereof.
Claim 4
Dependent Claim
24 words
The material of claim 1 wherein the polyphosphonate anticalcification agent is selected from the group consisting of aminopropanehydroxydiphosphonate, ethanehydroxydiphosphonate, aminotri(methylenephosphonic acid), and diethylentriaminepenta(methylenephosphonic acid).
Claim 5
Dependent Claim
33 words
The material of claim 1 further comprising an effective amount of the anticoagulant heparin irreversibly bound to said biocompatible synthetic polymer for rendering said biocompatible synthetic polymer resistant to in vivo thrombus formation.
Claim 6
Dependent Claim
79 words
A material for implantation in the interior of the body of a living being, the material being characterized by a biocompatible synthetic polymer which is substantially insoluble in the interior of the body of a host living being and which has irreversibly bound thereto via epoxide linkages an effective amount of an anticalcification agent, the anticalcification agent having at least one functional group having an active hydrogen, for rendering said biocompatible synthetic polymer resistant to in vivo pathologic calcification.
Claim 7
Dependent Claim
79 words
A material for implantation in the interior of the body of a living being, the material being characterized by a biocompatible synthetic polymer which is substantially insoluble in the interior of the body of a host living being and which has irreversibly bound thereto via epoxide linkages an effective amount of an anticalcification agent, the anticalcification agent having at least one functional group having an active hydrogen, for rendering said biocompatible synthetic polymer resistant to in vivo pathologic calcification.
Claim 8
Dependent Claim
18 words
The material of claim 5 wherein the anticalcification agent has an amine, amide, alcohol, or carboxylic acid functionality.
Claim 9
Dependent Claim
27 words
The material of claim 6 wherein the anticalcification agent is selected from the group consisting of polyphosphonates, sulfaminotricarballyate, alpha amino oleic acid, pyrophosphate, statherin, polylysine, and polyarginine.
Claim 10
Dependent Claim
30 words
The material of claim 5 further comprising heparin irreversibly bound thereto via epoxide linkages in an amount effective for rendering said biocompatible synthetic polymer resistant to in vivo thrombus formation.
Claim 11
Dependent Claim
34 words
The material of claim 7 wherein the anticalcification agent is a polyphosphonate, the polyphosphonate having reactive hydroxy groups on the phosphonate moieties and less reactive hydroxy groups on the alkyl, aryl, or aralkyl moiety.
Claim 12
Dependent Claim
19 words
The material of claim 9 wherein the epoxide linkage is through the reactive hydroxy groups on the phosphonate moieties.
Claim 13
Dependent Claim
17 words
The material of claim 9 wherein the epoxide linkage is through the hydroxy group on the alkane.
Claim 14
Independent Claim
47 words
A method of making a calcification-resistant biocompatible polymeric material comprising the steps of: forming a monoadduct of a polyphosphonate anticalcification agent and a reactive polyfunctional epoxide; adding the monoadduct to a prepolymer base of a biocompatible copolymer; adding the second component of the biocompatible copolymer; and polymerizing.
Claim 15
Independent Claim
47 words
A method of making a calcification-resistant biocompatible polymeric material comprising the steps of: forming a monoadduct of a polyphosphonate anticalcification agent and a reactive polyfunctional epoxide; adding the monoadduct to a prepolymer base of a biocompatible copolymer; adding the second component of the biocompatible copolymer; and polymerizing.
Claim 16
Dependent Claim
12 words
The method of claim 12 wherein the biocompatible copolymer is a polyurethane.
Claim 17
Dependent Claim
18 words
The method of claim 13 wherein the prepolymer base is a polyol and the second component is diisocyanate.
Claim 18
Dependent Claim
22 words
The method of claim 12 wherein the polyphosphonate is selected from the group consisting of aminopropanehydroxydiphosphonate, ethanehydroxydiphosphonate, aminotri(methylenephosphonic acid), and diethylentriaminepenta(methylenephosphonic acid).
Claim 19
Dependent Claim
29 words
The method of claim 12 wherein the polyfunctional epoxide is selected from the group consisting of diglycidyl butanediol ether, ethanediol diglycidyl ether, butanediol diglycidyl ether, and polyglycerol polyglycidyl ethers.
Claim 20
Independent Claim
48 words
A method of making a calcification-resistant polymeric material comprising the steps of: forming a solution of a polyphosphonate anticalcification agent and a reactive polyfunctional epoxide in a solvent; adding to the solution a second solution of a prepolymerized biocompatible polymer to form a mixture; and polymerizing the mixture.
Claim 21
Independent Claim
48 words
A method of making a calcification-resistant polymeric material comprising the steps of: forming a solution of a polyphosphonate anticalcification agent and a reactive polyfunctional epoxide in a solvent; adding to the solution a second solution of a prepolymerized biocompatible polymer to form a mixture; and polymerizing the mixture.
Claim 22
Dependent Claim
22 words
The method of claim 17 wherein the polyphosphonate is selected from the group consisting of aminopropanehydroxydiphosphonate, ethanehydroxydiphosphonate, aminotri(methylenephosphonic acid), and diethylentriaminepenta(methylenephosphonic acid).
Claim 23
Dependent Claim
29 words
The method of claim 17 wherein the polyfunctional epoxide is selected from the group consisting of diglycidyl butanediol ether, ethanediol diglycidyl ether, butanediol diglycidyl ether, and polyglycerol polyglycidyl ethers.
Claim 24
Independent Claim
41 words
A method of making a calcification-resistant polymeric material comprising the steps of: forming a diisocyanate-terminated prepolymer by reacting a soft segment component of a polyurethane and a hard segment component of the polyurethane; adding a chain extender to the diisocyanate-terminated prepolymer.
Claim 25
Independent Claim
41 words
A method of making a calcification-resistant polymeric material comprising the steps of: forming a diisocyanate-terminated prepolymer by reacting a soft segment component of a polyurethane and a hard segment component of the polyurethane; adding a chain extender to the diisocyanate-terminated prepolymer.
Claim 26
Dependent Claim
21 words
The method of claim 20 wherein the chain extender is a short chain diol and the product is an hydroxy-terminated polyurethane.
Claim 27
Dependent Claim
24 words
The method of claim 21 comprising the further step of reacting the hydroxy-terminated polyurethane with a polyphosphonate anticalcification agent to produce a phosphonate-terminated polyurethane.
Claim 28
Dependent Claim
50 words
The method of claim 22 wherein said step of reacting comprises the steps of: forming a solution of the polyphosphonate anticalcification agent and a reactive polyfunctional epoxide in a solvent; adding to the solution a second solution of the hydroxy-terminated anticalcification agent to form a mixture; and polymerizing the mixture.
Claim 29
Dependent Claim
21 words
The method of claim 20 wherein the chain extender is a polyphosphonate anticalcification agent and the product is a phosphonate-terminated polyurethane.
Claim 30
Independent Claim
56 words
A method of making a calcification-resistant polymeric material comprising the steps of: forming a tetraester derivative of a polyphosphonate anticalcification agent; reacting the tetraester derivative of a polyphosphonate anticalcification agent and a reactive polyfunctional epoxide to form a phosphonated epoxide monoadduct; reacting the phosphonated epoxide monoadduct with an hydroxy-terminated polymer to form a tetraester-terminated biocompatible polymer.
Claim 31
Independent Claim
56 words
A method of making a calcification-resistant polymeric material comprising the steps of: forming a tetraester derivative of a polyphosphonate anticalcification agent; reacting the tetraester derivative of a polyphosphonate anticalcification agent and a reactive polyfunctional epoxide to form a phosphonated epoxide monoadduct; reacting the phosphonated epoxide monoadduct with an hydroxy-terminated polymer to form a tetraester-terminated biocompatible polymer.
Claim 32
Dependent Claim
20 words
The method of claim 25 comprising the further step of hydrolyzing the tetraester-terminated biocompatible polymer to a phosphonate-terminated biocompatible polymer.
Claim 33
Dependent Claim
19 words
The method of claim 26 wherein the step of hydrolyzing comprises reacting the tetraester-terminated biocompatible polymer with bromotrimethyl silane.
Claim 34
Dependent Claim
18 words
The method of claim 26 wherein the step of hydrolyzing comprises subjecting the tetraester-terminated biocompatible polymer to water.
Claim 35
Independent Claim
46 words
A method of making a thromboresistant polymeric material comprising the steps of: forming a solution of heparin and a reactive polyfunctional epoxide to form a heparin-epoxide monoadduct; adding a solution of a prepolymerized biocompatible polymer to the monoadduct to form a mixture; and polymerizing the mixture.
Claim 36
Independent Claim
46 words
A method of making a thromboresistant polymeric material comprising the steps of: forming a solution of heparin and a reactive polyfunctional epoxide to form a heparin-epoxide monoadduct; adding a solution of a prepolymerized biocompatible polymer to the monoadduct to form a mixture; and polymerizing the mixture.
Claim 37
Independent Claim
63 words
A method of making a calcification-resistant polyurethane comprising the following steps: (a) preparing an isocyanate-terminated prepolymer; (b) reacting the isocyanate-terminated prepolymer with a chain extender to form a polyurethane base polymer having a hard segment and a soft segment; (c) epoxidizing the polyurethane base polymer at unsaturated double bonds of the soft segment; and (d) covalently binding EHDP to the epoxidized base polymer.
Claim 38
Independent Claim
63 words
A method of making a calcification-resistant polyurethane comprising the following steps: (a) preparing an isocyanate-terminated prepolymer; (b) reacting the isocyanate-terminated prepolymer with a chain extender to form a polyurethane base polymer having a hard segment and a soft segment; (c) epoxidizing the polyurethane base polymer at unsaturated double bonds of the soft segment; and (d) covalently binding EHDP to the epoxidized base polymer.
Claim 39
Dependent Claim
39 words
A calcification-resistant polyurethane having hard segments and soft segments characterized in that the soft segment is epoxidized at the site of unsaturated carbons and that at least some of the epoxidized sites have covalently bound thereto an anticalcification agent.
Claim 40
Dependent Claim
39 words
A calcification-resistant polyurethane having hard segments and soft segments characterized in that the soft segment is epoxidized at the site of unsaturated carbons and that at least some of the epoxidized sites have covalently bound thereto an anticalcification agent.
Claim 41
Independent Claim
34 words
A method of making a calcification-resistant polyurethane comprising the following steps: (a) coupling a hard segment modifier to polyurethane; and (b) coupling a diphosphonate to the polyurethane by reaction with free isocyante functional groups.
Claim 42
Independent Claim
34 words
A method of making a calcification-resistant polyurethane comprising the following steps: (a) coupling a hard segment modifier to polyurethane; and (b) coupling a diphosphonate to the polyurethane by reaction with free isocyante functional groups.
Claim 43
Dependent Claim
14 words
The method of claim 32 wherein said hard segment modifier is a polyfunctional isocyanate.
Claim 44
Dependent Claim
10 words
The method of claim 32 wherein said diphosphonate is EHDP.
References Cited (Backward Citations)
US4259472A
Cited
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1998-07-24 | 1999-01-23 | 1999-07-25 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 2002-07-24 | 2003-01-23 | 2003-07-25 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2006-07-24 | 2007-01-23 | 2007-07-25 | $7700.00 | Window Closed / Lapsed |