Blocked functional reagants for cross-linking biological tissues

• US 6,177,514 B1
• Filed: 04/09/1999
• Issued: 01/23/2001
• Est. Priority Date: 04/09/1999
• Status: Active Grant

• Current Assignee: Sulzer Carbomedics Inc. (Zimmer Biomet Holdings, Inc.)
• Original Assignee: Sulzer Carbomedics Inc. (Zimmer Biomet Holdings, Inc.)
• Inventors: Philips, Richard E. Jr., Pathak, Chandrashekhar P., Moore, Mark A.
• Primary Examiner(s): Nutter, Nathan M.
• Application Number:
  US09/289,426
• Time in Patent Office: 655 Days
• Field of Search: 525/54.1, 623/1, 623/2, 623/11, 623/13, 514/12, 600/36
• US Class Current: 525/54.1
• 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: Y10S 623/915 Method or apparatus for preparing biological material

Abstract

A method for cross-linking biological tissue is provided which uses as a cross-linking agent a low molecular weight, substantially monomeric polyfunctional aldehyde formed in situ or just prior to cross-linking. The polyfunctional aldehyde is essentially free of the undesirable heterogeneous polymeric species that result from polyfunctional aldehyde self-reactivity. Also provided is biological tissue that is cross-linked with a substantially monomeric glutaraldehyde.

Claims

1. A method for cross-linking biological tissue comprising:

(a) contacting a biological tissue with a solution comprising a polyfunctional aldehyde, wherein the aldehyde groups of said polyflnctional aldehyde have been blocked with a blocking group selected from the group consisting of dioxolanes, oximes, imines, oxazolidines, and inorganic salts;

(b) removing the blocking groups from said polyfunctional aldehyde to regenerate substantially monomeric polyfunctional aldehyde; and

(c) incubating the biological tissue for between 1 min and 2 days.

2. The method of claim 1, wherein the polyfunctional aldehyde contains a linear or branched aliphatic component having 2-36 carbon atoms.

3. The method of claim 1, wherein the polyfunctional aldehyde contains a linear or branched aliphatic chain having 2-10 carbon atoms.

4. The method of claim 1, wherein the aldehyde groups of said polyfunctional aldehyde are blocked with a blocking group comprising sodium bisulfite.

5. The method of claim 1, wherein the aldehyde groups of said polyfunctional aldehyde are blocked with a blocking group comprising a 1,3-dioxolane.

6. The method of claim 1, wherein the polyfunctional aldehyde is glutaraldehyde.

7. The method of claim 1, wherein removing the blocking group is achieved by effecting a change in the pH of the solution.

8. The method of claim 1, wherein biological tissue is a prosthetic heart valve, vascular graft, tendon, ligament, or patch.

9. Cross-linked biological tissue produced according to the method of claim 1.

33. The method of claim 1, wherein said incubating step occurs for between 1 hr and 6 hr.

10. A method for cross-linking biological tissue comprising:

(a) providing a solution comprising a polyfunctional aldehyde, wherein the aldehyde groups of said polyfunctional aldehyde have been blocked with a blocking group selected from the group consisting of dioxolanes, oximes, imines, oxazolidines, and inorganic salts;

(b) removing the blocking groups so as to regenerate substantially monomeric polyfunctional aldehyde;

(c) contacting the solution with a biological tissue for between 1 min and 2 days.

11. The method of claim 10, wherein the polyfunctional aldehyde contains a linear or branched aliphatic component having 2-36 carbon atoms.

12. The method of claim 10, wherein the polyflnctional aldehyde contains a linear or branched aliphatic component having 2-10 carbon atoms.

13. The method of claim 10, wherein the aldehyde groups of said polyfunctional aldehyde are blocked with a blocking group comprising sodium bisulfite.

14. The method of claim 10, wherein the aldehyde groups of said polyfunctional aldehyde are blocked with a blocking group comprising a 1,3-dioxolane.

15. The method of claim 10, wherein the polyfunctional aldehyde is glutaraldehyde.

16. The method of claim 10, wherein removing the blocking group is achieved by effecting a change in the pH of the solution.

17. The method of claim 10, wherein biological tissue is a prosthetic heart valve, vascular graft, tendon, ligament, or patch.

18. The method of claim 10, wherein step (c) is performed within 24 hours of step (b).

19. The method of claim 10, wherein step (c) is performed within 6 hours of step (b).

20. The method of claim 10, wherein step (c) is performed within 1 hours of step (b).

21. Cross-linked biological tissue produced according to claim 10.

34. The method of claim 10, wherein said contacting step occurs for between 1 hr and 6 hr.

22. A biological tissue comprising collagen that is cross-linked with a substantially monomeric polyfunctional aldehyde.

23. The biological tissue of claim 22, wherein less than 10% of the polyfunctional aldehyde present in the tissue is in a polymeric form.

24. The biological tissue of claim 22, wherein less than 5% of the polyfunctional aldehyde present in the tissue is in a polymeric form.

25. A method for cross-linking biological tissue comprising:

(a) providing a solution comprising a polyfunctional aldehyde, wherein the aldehyde groups of said polyfunctional aldehyde have been blocked with a blocking group selected from the group consisting of dioxolane and sodium bisulfite;

(b) removing the blocking groups so as to regenerate substantially monomeric polyfunctional aldehyde;

(c) contacting the solution with a biological tissue for between 1 min and 2 days.

26. The method of claim 25, wherein the polyfunctional aldehyde contains a linear or branched aliphatic component having 2-36 carbon atoms.

27. The method of claim 25, wherein the polyfunctional aldehyde contains a linear or branched aliphatic chain having 2-10 carbon atoms.

28. The method of claim 25, wherein the aldehyde groups of said polyfunctional aldehyde are blocked with a blocking group comprising a 1,3-dioxolane.

29. The method of claim 25, wherein the polyfunctional aldehyde is glutaraldehyde.

30. The method of claim 25, wherein removing the blocking group is achieved by effecting a change in the pH of the solution.

31. The method of claim 25, wherein biological tissue is a prosthetic heart valve, vascular graft, tendon, ligament, or patch.

32. Cross-linked biological tissue produced according to the method of claim 25.

35. The method of claim 25, wherein said contacting step occurs for between 1 hr and 6 hr.