Stabilization of implantable bioprosthetic devices

• US 6,861,211 B2
• Filed: 08/22/2001
• Issued: 03/01/2005
• Est. Priority Date: 04/27/1999
• Status: Expired due to Term

• Current Assignee: Children's Hospital of Philadelphia (Children's Hospital of Philadelphia Foundation)
• Original Assignee: Children's Hospital of Philadelphia (Children's Hospital of Philadelphia Foundation)
• Inventors: Vyavahare, Narendra, Levy, Robert J.
• Primary Examiner(s): SAUCIER, SANDRA E
• Application Number:
  US09/933,680
• Publication Number:
  US 20020081564A1
• Time in Patent Office: 1,287 Days
• Field of Search: 435/1.1, 600/36, 623/2.13, 623/1.1, 623/13.11, 623/15.12, 8 9/411
• US Class Current: 435/1.1
• CPC Class Codes: A61F 2/30756 Cartilage endoprostheses A61F2/3603 takes precedence
• CPC Class Codes: A61L 2430/40 Preparation and treatment of biological tissue for implantation, e.g. decellularisation, cross-linking
• CPC Class Codes: A61L 27/20 Polysaccharides
• CPC Class Codes: A61L 27/24 Collagen
• 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 27/38 containing added animal cells organs or tissue containing native cells A61L27/36
• CPC Class Codes: A61L 27/507 for artificial blood vessels apparatus for applying cells on a blood vessel prosthesis A61F2/062
• CPC Class Codes: C08L 5/08 Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof

Abstract

The invention relates to methods of stabilizing glycosaminoglycans in a biological tissue (e.g. a bioprosthetic implant) in conjunction with cross-linking of protein in the tissue. The methods of the invention improve the mechanical integrity of the device and improves its stability in vivo. The invention also includes biological tissues having stabilized glycosaminoglycans and cross-linked proteins and kits for preparing such tissues.

Claims

1. A method of treating on implantable biological tissue, said method comprising stabilizing glycosaminoglycans on the tissue and cross-linking proteins on the tissue, wherein the glycosaminoglycans stabilizing comprises contacting the tissue with (a) a water-soluble carbodiimide composition having a pH of 6.9 to 7.9 or (b) a carbohydrate oxidizing agent and a bi-functional carbohydrate-protein linking agent, and the proteins cross-linking comprises contacting the tissue with a cross-linking reagent, wherein the cross linking reagent is a member selected from the group consisting of glutaraldehyde, formaldehyde, a dialdehyde, carbodiimide, and a polyepoxy ether.

2. The method of claim 1, wherein said glycosaminoglycans are endogenous to the tissue.

3. The method of claim 2, wherein the tissue is a part of an implantable bioprosthetic device.

4. The method of claim 3, wherein said device is selected from the group consisting of a heart valve prosthesis, a vascular graft, a skin graft, a dura mater graft, a cartilage graft, a cartilage implant, a pericardium graft, a urinary bladder prosthesis, a ligament prosthesis, and a tendon prosthesis.

5. The method of claim 4, wherein said device is a heart valve prosthesis.

6. The method of claim 5, wherein said heart valve prosthesis is selected from the group consisting of a porcine heart valve and a bovine pericardium-derived heart valve prosthesis.

7. The method of claim 1, wherein the stabilization of glycosaminoglycans on the tissue is achieved prior to cross-linking proteins on the tissue.

8. The method of claim 7, wherein

a) the difference between i) the thermal shrinkage temperature of the tissue after contacting the tissue with said carbodiimide and ii) the thermal shrinkage temperature of the tissue prior to contacting the tissue with said carbodiimide is less than half of

b) the difference between i) the thermal shrinkage temperature of the tissue after cross-linking proteins on the tissue and ii) the thermal shrinkage temperature of the tissue prior to cross-linking proteins on the tissue.

9. The method of claim 1, wherein said carbodiimide is 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide.

10. A biological tissue treated by the method of claim 1.

11. The method of claim 1, wherein the stabilizing of glycosaminoglycans on the tissue is achieved by contacting the tissue with the carbohydrate oxidizing agent to generate aldehyde groups on said glycosaminoglycans and contacting the tissue with a bi-functional carbohydrate-protein linking agent.

12. The method of claim 11, wherein said carbohydrate oxidizing agent is selected from the group consisting of bromine, periodate, nitric acid, and lead tetraacetate.

13. The method of claim 11, wherein the bi-functional carbohydrate-protein linking agent is a member selected from the group consisting of glutaraldehyde, a diamine, and an azido hydrazide.

14. The method of claim 1, wherein the cross-linking comprises contacting the tissue with glutaraldehyde.

15. The method of claim 1, wherein the cross-linking comprises contacting the tissue with glutaraldehyde, provided that the cross-linking is performed after the stabilizing of glycosaminoglycans.

16. The method of claim 1, wherein the stabilizing comprises contacting the tissue with a water-soluble carbodiimide composition having a pH of 6.9 to 7.9, and the cross-linking comprises contacting the tissue with a cross-linking reagent, wherein the cross-linking reagent is a member selected from the group consisting of glutaraldehyde, formaldehyde, a dialdehyde, carbodiimide, and a polyepoxy ether.

17. A method of treating an implantable biological tissue, said method comprising stabilizing glycosaminoglycans on the tissue and cross-linking proteins on the tissue, wherein the glycosaminoglycans stabilizing comprises contacting the tissue with a water-soluble carbodiimide composition having a pH of 6.9 to 7.9, and wherein the cross-linking comprises contacting the tissue with glutaraldehyde.

18. A biological tissue treated by the method of claim 17.

19. A method of treating an implantable biological tissue, said method comprising stabilizing glycosaminoglycans on the tissue and cross-linking proteins on the tissue, wherein the glycosaminoglycans stabilizing comprises (i) contacting the tissue with periodate and (ii) contacting the tissue with a bi-functional carbohydrate-protein linking agent and wherein the cross-linking comprises contacting the tissue with glutaraldehyde.

20. A biological tissue treated by the method of claim 19.