Calcification-resistant materials and methods of making same through use of multivalent cations

• US 5,368,608 A
• Filed: 04/23/1991
• Issued: 11/29/1994
• Est. Priority Date: 04/01/1988
• Status: Expired due to Term

• Current Assignee: Board of Regents of the University of Michigan (University of Michigan)
• Original Assignee: Board of Regents of the University of Michigan (University of Michigan)
• Inventors: Levy, Robert J., Sintov, Amnon
• Primary Examiner(s): McFarlane, Anthony
• Assistant Examiner(s): PHAN, NHAT
• Application Number:
  US07/689,652
• Time in Patent Office: 1,316 Days
• Field of Search: 8/94.11, 8/94.19, 8/94.28, 8/94.29, 623/1-3, 623/11, 623/12, 623/66, 128/DIG. 8
• US Class Current: 8/94.11
• CPC Class Codes: A61L 2300/102 Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
• CPC Class Codes: A61L 2300/21 Acids
• CPC Class Codes: A61L 2300/216 with other specific functional groups, e.g. aldehydes, ketones, phenols, quaternary phosphonium groups
• CPC Class Codes: A61L 2300/40 characterised by a specific therapeutic activity or mode of action
• CPC Class Codes: A61L 2300/45 Mixtures of two or more drugs, e.g. synergistic mixtures
• CPC Class Codes: A61L 2400/02 Treatment of implants to prevent calcification or mineralisation in vivo
• CPC Class Codes: A61L 2430/40 Preparation and treatment of biological tissue for implantation, e.g. decellularisation, cross-linking
• CPC Class Codes: A61L 27/3604 characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
• CPC Class Codes: A61L 27/3687 characterised by the use of chemical agents in the treatment, e.g. specific enzymes, detergents, capping agents, crosslinkers, anticalcification agents
• CPC Class Codes: A61L 27/50 Materials characterised by their function or physical properties , e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: Y10S 128/08 Collagen
• CPC Class Codes: Y10S 623/921 Blood vessel

Abstract

Bioprosthetic materials, either natural or synthetic, are treated with trivalent aluminum or iron cations, or salts, to prevent in vivo calcification. Such bioprosthetic materials include porcine aortic valve leaflets, bovine pericardium, aortic homografts, biocompatible elastomers, and the like which are intended for invasive, or in-dwelling use in a human or animal body. Simple incubation of the natural bioprosthetic materials in an ion-containing solution, such as aqueous AlCl₃ or FeCl₃, prior to implantation has been found to inhibit calcification of the biomaterial over a prolonged period, and to do so without adverse side effects. Incorporation of an aluminum-containing compound into the formulation for polymers, such as polyurethane, has also been found to inhibit calcification with no adverse side effects.

Claims

1. An implant formed of a biocompatible biomaterial which is insoluble in the interior of the body of a host, living being, said biomaterial having incorporated therein an effective amount of trivalent aluminum cations to render said biomaterial resistant to in vivo pathologic calcification.

2. The implant of claim 1 wherein said biocompatible biomaterial is a tissue which occurs naturally in a donor living being.

3. The implant of claim 2 wherein said biomaterial is selected from the group consisting of bovine pericardium, porcine heart valve leaflets, saphenous bypass grafts, and aortic homografts.

4. The implant of claim 1 wherein said biocompatible biomaterial is a biocompatible synthetic polymer.

5. The implant of claim 4 wherein said biocompatible synthetic polymer is an organic synthetic material selected from the group consisting of polydimethylsiloxane, polyurethane, ethylene vinyl acetate, polymethyl methacrylate, polyamide, polycarbonate, polyester, polyethylene, polypropylene, polystyrene, polyvinyl chloride, polytetrafluoroethylene, polysulfone, and cellulose acetate.

6. A material suitable for implantation in the interior of the body of a living being, the material being a biocompatible biomaterial having incorporated therein an effective amount of trivalent aluminum cations to render the biomaterial resistant to pathologic calcification in an in vivo environment.

7. The material of claim 6 wherein said biomaterial is a tissue which occurs naturally in a donor living being.

8. The material of claim 7 wherein said biomaterial is selected from the group consisting of bovine pericardium, porcine heart valve leaflets, saphenous bypass grafts, and aortic homografts.

9. The material of claim 6 wherein the biomaterial is a biocompatible synthetic polymer.

10. The material of claim 9 wherein the biocompatible synthetic polymer is selected from the group consisting of polydimethylsiloxane, polyurethane, ethylene vinyl acetate, polymethyl methacrylate, polyamide, polycarbonate, polyester, polyethylene, polypropylene, polystyrene, polyvinyl chloride, polytetrafluoroethylene, polysulfone, and cellulose acetate.

11. A material for implanting in the interior of a human or animal living body, the material being prepared by the process of:

(a) dissolving a biocompatible synthetic polymeric material in an organic solvent;

(b) adding a soluble salt of trivalent aluminum cations to the dissolved biocompatible synthetic polymeric material to form a mixture; and

(c) forming said mixture into a desired configuration.

12. The material for implanting in the interior of a human or animal living body prepared by the process of claim 11 wherein said step of forming said mixture into said desired configuration comprises the step of casting said mixture into a film.

13. The material for implanting in the interior of a human or animal living body prepared by the process of claim 12 further comprising the step of drying the cast film in a vacuum oven at 50°

to 55°

C.

14. The material for implanting in the interior of a human or animal living body prepared by the process of claim 11 wherein said step of forming said mixture into said desired configuration comprises the step of molding said mixture.

15. The material for implanting in the interior of a human or animal living body prepared by the process of claim 11 wherein the salt of a metallic trivalent cation is selected from the group consisting of aluminum silicate, aluminum oxide, aluminum phosphate, aluminum palmitate, aluminum oleate, aluminum oxalate, aluminum magnesium silicate, aluminum stearate, aluminum diacetate, aluminum hydroxide, aluminum isopropoxide, and aluminum hypophosphite.

16. The material for implanting in the interior of a human or animal living body prepared by the process of claim 11 wherein said biocompatible synthetic polymeric material is selected from the group consisting of polydimethylsiloxane, polyurethane, ethylene vinyl acetate, polymethyl methacrylate, polyamide, polycarbonate, polyester, polyethylene, polypropylene, polystyrene, polyvinyl chloride polytetrafluoroethylene, polysulfone, and cellulose acetate.

17. The material for implanting in the interior of a human or animal living body prepared by the process of claim 16 wherein said biocompatible synthetic polymeric material is selected from the group consisting of polyurethanes and polydimethylsiloxanes and copolymers thereof, and said organic solvent is selected from the group consisting of dimethyl sulfoxide, dimethylacetamide, and tetrahydrofuran.

18. A method of making a calcification-resistant synthetic polymeric material suitable for implanting in the interior of a human or animal living body, the method comprising the steps of:

(a) combining biocompatible synthetic polymeric precursor materials with a salt of trivalent aluminum cations to form a mixture; and

(b) polymerizing said mixture so that the trivalent aluminum cations become part of the matrix of the resulting synthetic polymeric material.

19. A method of making a calcification-resistant biomaterial comprising the step of subjecting bioprosthetic tissue to a solution containing a soluble salt of trivalent aluminum ranging from 0.1 M to 0.001 M for a period of time sufficient to complex aluminum cations in the solution with the bioprosthetic tissue.

20. The method of claim 19 wherein the solution containing a soluble salt of trivalent aluminum further contains a soluble anticalcification agent selected from the group of citrates and diphosphonates.

21. The method of claim 20 wherein the soluble anticalcification agent is a citrate selected from the group consisting of citric acid and sodium citrate.

22. The method of claim 20 wherein the soluble anticalcification agent is a diphosphonate selected from the group consisting of ethanehydroxydiphosphonate and aminopropanehydroxydiphosponate.

23. The method of claim 20 wherein the soluble salt of trivalent aluminum and soluble anticalcification agent are both in the concentration range from 0.1 to 0.00001 M.

24. The method of claim 19 wherein the soluble salt of trivalent aluminum is selected from the group consisting of aluminum chlorate, aluminum lactate, aluminum potassium sulfate, aluminum sodium sulfate, aluminum sulfate, aluminum nitrate, and aluminum chloride.

25. A method of making a calcification-resistant synthetic polymeric biomaterial suitable for implanting in the interior of a human or animal living body, the method comprising the steps of:

(a) dissolving a biocompatible synthetic polymeric material in an organic solvent;

(b) adding a soluble salt of trivalent aluminum cations to the dissolved biocompatible synthetic polymeric material to form a mixture; and

(c) forming said mixture into a desired configuration.

26. The method of claim 25 wherein said step of forming said mixture into said desired configuration comprises the step of casting said mixture into a film.

27. The method of claim 25 wherein said step of forming said mixture into said desired configuration comprises the step of molding said mixture.

28. The method of claim 25 wherein said biocompatible synthetic polymeric material is selected from the group consisting of polydimethylsiloxane, polyurethane, ethylene vinyl acetate, polymethyl methacrylate, polyamide, polycarbonate, polyester, polyethylene, polypropylene, polystyrene, polyvinyl chloride, polytetrafluoroethylene, polysulfone, and cellulose acetate.

29. The method of claim 25 wherein the salt of trivalent aluminum cation is selected from the group consisting of aluminum silicate, aluminum oxide, aluminum phosphate, aluminum palmitate, aluminum oleate, aluminum oxalate, aluminum magnesium silicate, aluminum stearate, aluminum diacetate, aluminum hydroxide, aluminum isopropoxide, and aluminum hypophosphite.