Double cross-linkage process to enhance post-implantation bioprosthetic tissue durability

• US 9,351,829 B2
• Filed: 11/15/2011
• Issued: 05/31/2016
• Est. Priority Date: 11/17/2010
• Status: Active Grant

• Current Assignee: Edwards Lifesciences Corporation
• Original Assignee: Edwards Lifesciences Corporation
• Inventors: Carpentier, Sophie M., Carpentier, Alain F.
• Primary Examiner(s): Kim, Taeyoon
• Assistant Examiner(s): Patury, Srikanth
• Application Number:
  US13/297,192
• Publication Number:
  US 20120123557A1
• Time in Patent Office: 1,659 Days
• Field of Search: 514/693, 8 9/4, 530/345, 530/350
• US Class Current: 1/1
• CPC Class Codes: A61F 2/02 Prostheses implantable into the body closure means for urethra or rectum or for artificial body openings therefor A61F2/0004
• CPC Class Codes: A61F 2/2415 Manufacturing methods
• CPC Class Codes: A61F 2240/001 Designing or manufacturing processes
• CPC Class Codes: A61J 1/00 Containers specially adapted for medical or pharmaceutical purposes capsules or the like for oral use A61J3/07; specially adapted for surgical or diagnostic appliances or instruments A61B50/30; containers for radioactive substances G21F5/00
• CPC Class Codes: A61K 35/34 Muscles; Smooth muscle cells; Heart; Cardiac stem cells; Myoblasts; Myocytes; Cardiomyocytes vascular smooth muscle A61K35/44
• CPC Class Codes: A61L 2400/02 Treatment of implants to prevent calcification or mineralisation in vivo
• CPC Class Codes: A61L 2430/20 for reconstruction of the heart, e.g. heart valves
• CPC Class Codes: A61L 27/24 Collagen
• CPC Class Codes: A61L 27/3612 Cartilage, synovial fluid
• CPC Class Codes: A61L 27/362 Skin, e.g. dermal papillae
• CPC Class Codes: A61L 27/3625 Vascular tissue, e.g. heart valves
• CPC Class Codes: A61L 27/3629 Intestinal tissue, e.g. small intestinal submucosa
• 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

Abstract

Bioprosthetic tissues and methods for making same, comprising fixing bioprosthetic implant tissue by treatment with 0.1 to 10 wt. % glutaraldehyde at elevated temperature, capping said fixed tissue by treatment with a diamine crosslinking agent, and treating said capped tissue with about 0.6 wt. % glutaraldehyde.

Claims

1. A method for preparing bioprosthetic implant tissue, comprising:

fixing a biological tissue with glutaraldehyde,

exposing said fixed tissue to a polyetheramine cross-linking agent under reducing conditions,

treating said exposed tissue with glutaraldehyde, and

storing said treated tissue in a terminal sterilization solution or further subjecting said treated tissue to a glycerol treatment solution.

2. The method of claim 1, wherein the fixing is conducted with 0.1 to 10 wt % concentration of glutaraldehyde at about 50°

C. and pH 5.8 for 2 to 25 days.

3. The method of claim 1, wherein the exposing step is conducted in the presence of a reducing agent.

4. The method of claim 3, wherein the reducing agent is sodium borohydride.

5. The method of claim 1, wherein the polyetheramine cross-linking agent is delivered in water or a buffer solution.

6. The method of claim 1, wherein the polyetheramine cross-linking agent is at a concentration of 0.01M to 1M and the exposing is performed for a period of 1 hour to 7 days, at temperatures between 4°

C. and 50°

C., and at pH between 8 and 13.

7. The method of claim 6, wherein the polyetheramine cross-linking agent is at a concentration of 0.1M, and the exposing is performed for 48 hrs, at a temperature of 37°

C., and at a pH 11.7.

8. The method of claim 4, wherein sodium borohydride is used as an adjunct to the polyetheramine cross-linking agent at a concentration between 0.05% and 1%, and the exposing is performed for a period of 1 hr to 3 days at a temperature between 4°

C. and 40°

C.

9. The method of claim 8, wherein the sodium borohydride is at a concentration of 0.25% and the exposing is performed for a period of 24 h at a temperature of 37°

C.

10. The method of claim 1, wherein during the fixing step, the glutaraldehyde concentration is 0.6 to 10 wt. %, and the fixing is performed for 1 to 90 days, at a temperature from 37°

C. to 75°

C., at a pH of 5.4 to 6.8.

11. The method of claim 10, wherein during the fixing step, the glutaraldehyde concentration is 5%, and the fixing is performed for a time of 18 days, at a temperature of 52±

2.5°

C., at a pH of 5.8.

12. The method of claim 1, further comprising treating the fixed tissue in a surfactant solution thereby substantially eliminating phospholipids.

13. The method of claim 12, wherein the surfactant solution contains formaldehyde, ethanol and polyoxyethylene 20 sorbitan monooleate.

14. The method of claim 1, wherein said biological tissue is selected from the group consisting of bovine pericardium, porcine tissue, blood vessels, skin, dura mater, pericardium, small intestinal submucosa, tissue heart valves, ligaments, and tendons.

15. The method of claim 1, wherein said biological tissue is a native valve treated and mounted as a whole valve.

16. The method of claim 1, wherein the treated biological tissue is stored in the terminal sterilization solution and wherein the terminal sterilization solution is a glutaraldehyde solution of 0.1% to 0.6 wt. % concentration.

17. The method of claim 1, wherein the treated biological tissue is further subjected to the glycerol treatment solution and stored dry.

18. The method of claim 17, wherein the biological tissue is dehydrated after being further subjected to the glycerol treatment solution.

19. The method of claim 18, wherein the dehydrated tissue is sterilized in ethylene oxide.

25. The method of claim 1, wherein the fixing is performed before the exposing.

20. A method of preparing bioprosthetic implant tissue comprising:

fixing a biological tissue with at least 0.2 wt. % glutaraldehyde at pH 5-6.8 between 45°

-75°

C. for 1 to 90 days;

exposing said fixed tissue to a polyetheramine cross-linking agent followed by reduction of Schiff base with NaBH₄,

treating said exposed tissue with about 0.6 wt. % glutaraldehyde and then treating with a surfactant;

wherein the foregoing steps are performed while stirring.

21. The method of claim 20, wherein the fixing is done at a temperature of 50°

C. for 18 days.

22. The method of claim 20, wherein the treating said tissue with about 0.6 wt. % glutaraldehyde is performed for at least 1 month.

23. The method of claim 20, further comprising storing the tissue in 0.6% glutaraldehyde at 4°

C. for at least 2 months after treating the tissue with the surfactant.

24. The method of claim 20, further comprising treating the tissue with a glycerol solution after treating the tissue with the surfactant.