Method of making calcification-resistant bioprosthetic tissue

• US 5,746,775 A
• Filed: 10/21/1993
• Issued: 05/05/1998
• 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: University of Michigan
• Inventors: Hirsch, Danielle, Levy, Robert J.
• Primary Examiner(s): GRIFFIN, WALTER DEAN
• Application Number:
  US08/140,722
• Time in Patent Office: 1,657 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
• 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 27/3625 Vascular tissue, e.g. heart valves
• 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 623/922 Heart

Abstract

A method of treating a collagenous biomaterial, such as porcine aortic valve leaflets or bovine pericardium, by exposing the biomaterial to an alcohol to inhibit in vivo calcification. The biomaterial, preferably glutaraldehyde-pretreated, is subjected to an aqueous solution of 60% to 80% lower aliphatic alcohol, such as ethanol for a period of at least 20 minutes, and preferably, 24 to 72 hours. The biomaterial is rinsed, and then stored in either a glutaraldehyde-free environment or an ethanolic solution of glutaraldehyde. In some embodiments, the treatment solutions include an additional anticalcification agent which may be a soluble salt of a metallic cation, such as Al⁺³ or Fe⁺³.

Claims

1. A method of treating a biomaterial, the method comprising the steps of:

(1) forming a liquid treatment solution consisting essentially of greater than 50% by volume of a water-soluble C1-C3 aliphatic alcohol in an aqueous buffer of a pH between 6.0 and 8.0;

(2) exposing the biomaterial, wherein the biomaterial is a collagenous material derived from a mammalian species selected from the group consisting of bovine pericardium, porcine aortic heart valves, saphenous bypass grafts, aortic homografts, and dura mater, to the liquid treatment solution for a period of time sufficient to render the biomaterial resistant to calcification; and

(3) rinsing the exposed biomaterial with a rinsing solution.

2. The method of claim 1 wherein the biomaterial rendered resistant to calcification is rendered resistant to in vivo pathologic calcification.

3. The method of claim 1 wherein said step of exposing comprises immersing the biomaterial in the liquid treatment solution.

4. The method of claim 3 wherein the alcohol is present in an amount of approximately between 60% and 80% by volume of the liquid treatment solution.

5. The method of claim 3 wherein the treatment solution further contains an anticalcification agent.

6. The method of claim 5 wherein the anticalcification agent is a multivalent metallic cation selected from the group consisting of a salt of Al⁺³ and Fe⁺³ which is soluble in the treatment solution.

7. The method of claim 6 wherein the anticalcification agent is AlCl₃ in a concentration range of from about 0.1M to 0.001M.

8. The method of claim 1 wherein the water-soluble aliphatic alcohol is selected from the group consisting of methanol, ethanol, propanol, and isopropanol.

9. The method of claim 8 wherein the water-soluble aliphatic alcohol is ethanol.

10. The method of claim 1 wherein the biomaterial has been cross-linked.

11. The method of claim 10 wherein the biomaterial has been crosslinked with glutaraldehyde.

12. The method of claim 1 wherein the time sufficient to render the biomaterial resistant to calcification is at least about 20 minutes.

13. The method of claim 12 wherein the time sufficient to render the biomaterial resistant to calcification is between about 24 to 96 hours.

14. The method of claim 1 wherein there is provided the further step of storing the treated biomaterial in a sterile, glutaraldehyde-free environment.

15. The method of claim 1 wherein there is provided the further step of storing the treated biomaterial in a storage solution of a lower aliphatic alcohol and glutaraldehyde.

16. The method of claim 15 wherein the storage solution is an aqueous solution containing approximately between 60% to 80% by volume of ethanol and approximately between 0.2% to 0.5% glutaraldehyde.

17. The method of claim 3 wherein the biomaterial is an aortic valve cusp and the alcohol is ethanol.

18. The method of claim 5 wherein the biomaterial is an aortic valve wall, and the anticalcification agent is an aluminum salt in ethanol.

19. The method of claim 1 wherein there is provided the further step of sterilizing the bioprosthetic tissue.

20. The method of claim 3 wherein the treatment solution is buffered to a pH in the range of between 7.0 and 7.6.

21. The method of claim 20 wherein the liquid treatment solution is buffered to a pH of 7.4.

22. The method of claim 4 wherein the alcohol is present in an amount of approximately 80% by volume of the liquid treatment solution.

32. A biomaterial produced by the process of claims 1 or 23 or 30.

23. A method of making calcification-resistant biomaterial for use in the interior of a human or animal, the method comprising the steps of:

a) subjecting glutaraldehyde pre-treated bioprosthetic tissue, wherein the bioprosthetic tissue is a collagenous material derived from a mammalian species selected from the group consisting of bovine pericardium, porcine aortic heart valves, saphenous bypass grafts, aortic homografts, and dura mater, to an aqueous, treatment solution of at least about 50% by volume of a water-soluble C1-C3 aliphatic alcohol for a period of time between about 20 minutes and 96 hours; and

b) rinsing the bioprosthetic tissue.

24. The method of claim 23 wherein there is provided the further step of:

c) storing the bioprosthetic tissue in a sterile, buffered solution of approximately between 0.2% to 0.5% glutaraldehyde and at least 60% ethanol.

25. The method of claim 23 wherein the alcohol is ethanol.

26. The method of claim 23 wherein the solution further contains an anticalcification agent which is a multivalent metallic cation selected from the group consisting of a salt of A1⁺³ and Fe⁺³.

27. The method of claim 26 wherein the anticalcification agent is an aluminum salt in ethanol.

28. The method of claim 23 wherein the alcohol is present in an amount of approximately between 60% and 80% by volume of the treatment solution.

29. The method of claim 28 wherein the alcohol is present in an amount of approximately 80% by volume of the liquid treatment solution.

30. A method of treating a biomaterial, the method comprising the steps of:

(1) forming a liquid treatment solution consisting essentially of a water-soluble C1-C3 aliphatic alcohol in an amount of greater than about 40% by volume and a further organic solvent, wherein the combined amount of the alcohol and organic solvent is greater than about 50% by volume, in an aqueous buffer at pH between about 6.0 and 8.0;

(2) exposing the biomaterial, wherein the biomaterial is a collagenous material derived from a mammalian species selected from the group consisting of bovine pericardium, porcine aortic heart valves, saphenous bypass grafts, aortic homografts, and dura mater, to the liquid treatment solution for a period of time sufficient to render the biomaterial resistant to calcification; and

(3) rinsing the exposed biomaterial in a rinsing solution.

31. The method of claim 30 wherein the treatment solution includes about 40% alcohol and 40% organic solvent.