Stabilization of implantable bioprosthetic tissue

• US 20020172706A1
• Filed: 05/15/2002
• Published: 11/21/2002
• Est. Priority Date: 02/09/2000
• Status: Active Grant

• 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: Levy, Robert J., Alferiev, Ivan, Vyavahare, Narendra
• Granted Patent: US 6,824,970 B2
• Time in Patent Office: Days
• US Class Current: 424/423
• CPC Class Codes: A61L 27/3641 characterised by the site of application in the body materials for artificial blood vessels A61L27/507; materials for use in artificial skin A61L27/60
• 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 27/507 for artificial blood vessels apparatus for applying cells on a blood vessel prosthesis A61F2/062

Abstract

The invention relates to implantable bioprostheses (e.g. implantable biological tissues) and to compositions and methods for stabilizing them. Implantable bioprostheses stabilized as described herein exhibit improved mechanical properties and reduced post-implantation calcification. The implantable bioprosthesis is made by contacting a bioprosthesis (e.g. a tissue obtained from an animal or an article comprising a tissue and a synthetic material) with a polyepoxy amine compound.

Claims

1. An implantable bioprosthesis comprising proteins cross-linked with a poly-(2-hydroxyorgano)amino moiety.

2. The implantable bioprosthesis of claim 1, wherein a methylthio group of the bioprosthesis is linked with the poly-(2-hydroxyorgano)amino moiety.

3. The implantable bioprosthesis of claim 1, wherein an amine group of the bioprosthesis is linked with the poly-(2-hydroxyorgano)amino moiety.

4. The implantable bioprosthesis of claim 1, wherein a phenolic hydroxyl group of the bioprosthesis is linked with the poly-(2-hydroxyorgano)amino moiety.

5. The implantable bioprosthesis of claim 1, wherein a phosphate group of the bioprosthesis is linked with the poly-(2-hydroxyorgano)amino moiety.

6. The implantable bioprosthesis of claim 1, wherein a carboxyl group of the bioprosthesis is linked with the poly-(2-hydroxyorgano)amino moiety.

7. The implantable bioprosthesis of claim 1, wherein substantially all epoxy-reactive groups of the bioprosthesis are linked with the poly-(2-hydroxyorgano)amino moiety.

8. The implantable bioprosthesis of claim 1, wherein the implantable bioprosthesis is selected from the group consisting of an artificial heart, a heart valve prosthesis, an annuloplasty ring, a dermal graft, a vascular graft, a vascular stent, a structural stent, a vascular shunt, a cardiovascular shunt, a dura mater graft, a cartilage graft, a cartilage implant, a pericardium graft, a ligament prosthesis, a tendon prosthesis, a urinary bladder prosthesis, a pledget, a suture, a permanently in-dwelling percutaneous device, a surgical patch, a vascular stent, a cardiovascular stent, a structural stent, a coated stent, a vascular shunt, a cardiovascular shunt, and a coated catheter.

9. The implantable bioprosthesis of claim 8, wherein the implantable bioprosthesis is a heart valve prosthesis.

10. The implantable bioprosthesis of claim 1, wherein the implantable bioprosthesis comprises a biological tissue.

11. The implantable bioprosthesis of claim 10, wherein the tissue is selected from the group consisting of a heart, a heart valve, an aortic root, an aortic wall, an aortic leaflet, a pericardial tissue, a connective tissue, dura mater, a bypass graft, a tendon, a ligament, a dermal tissue, a blood vessel, an umbilical tissue, a bone tissue, a fascia, and a submucosal tissue.

12. The implantable bioprosthesis of claim 10, wherein the tissue is harvested from an animal.

13. The implantable bioprosthesis of claim 12, wherein the animal is selected from the group consisting of a human, a cow, a pig, a dog, a seal, and a kangaroo.

14. The implantable bioprosthesis of claim 1, wherein the implantable bioprosthesis comprises a synthetic analog of a bioprosthetic tissue.

15. The implantable bioprosthesis of claim 1, wherein the poly-(2-hydroxyorgano)amino moiety is a poly-(2-hydroxypropyl)amino moiety.

17. The implantable bioprosthesis of claim 16, wherein the bioprosthesis is contacted with the polyepoxy amine compound in an aqueous liquid having a pH of about 6 to 10.

18. The implantable bioprosthesis of claim 16, wherein the proteins are cross-linked by contacting the bioprosthesis with the polyepoxy amine compound in an aqueous liquid having a pH of about 7 to 10.

19. The implantable bioprosthesis of claim 16, wherein the proteins are cross-linked by contacting the bioprosthesis with the polyepoxy amine compound in an aqueous liquid having a pH of about 7.0 to 7.4.

20. The implantable bioprosthesis of claim 16, wherein the polyepoxy amine compound is triglycidyl amine.

21. The implantable bioprosthesis of claim 16, wherein the proteins are cross-linked by contacting the polyepoxy amine compound with moieties of the proteins which are independently selected from the group consisting of a methylthio moiety, a primary amine moiety, a phenolic hydroxyl moiety, a phosphate moiety, and a carboxyl moiety.

22. The implantable bioprosthesis of claim 16, wherein the implantable bioprosthesis is treated with a second stabilization reagent.

23. The implantable bioprosthesis of claim 22, wherein the second stabilization reagent is a cross-linking reagent.

24. The implantable bioprosthesis of claim 22, wherein the second stabilization reagent is a calcification inhibitor.

25. The implantable bioprosthesis of claim 24, wherein the calcification inhibitor is aluminum chloride.

26. The implantable bioprosthesis of claim 22, wherein the second stabilization reagent is a glycosaminoglycan-stabilizing reagent.

27. The implantable bioprosthesis of claim 26, wherein the glycosaminoglycan-stabilizing reagent is a carbodiimide.

16. An implantable bioprosthesis comprising proteins cross-linked by contacting the bioprosthesis with a polyepoxy amine compound

28. A method of stabilizing an implantable bioprosthesis, the method comprising contacting the bioprosthesis and a polyepoxy amine compound, whereby the bioprosthesis is stabilized.

29. A composition for stabilizing an implantable bioprosthesis, the composition comprising a polyepoxy amine compound and at least one of a calcification inhibitor, a glycosaminoglycan-stabilizing reagent, and a second cross-linking reagent.