Capping bioprosthetic tissue to reduce calcification

• US 9,029,418 B2
• Filed: 12/23/2013
• Issued: 05/12/2015
• Est. Priority Date: 12/21/2007
• Status: Active Grant

• Current Assignee: Edwards Lifesciences Corporation
• Original Assignee: Edwards Lifesciences Corporation
• Inventors: Dove, Jeffrey S., Dobler, Darin P., Davidson, James A., Wright, Gregory A.
• Primary Examiner(s): Desai, Anand
• Assistant Examiner(s): MERCIER, MELISSA S
• Application Number:
  US14/139,367
• Publication Number:
  US 20140200659A1
• Time in Patent Office: 505 Days
• Field of Search: None
• US Class Current: 514/557
• CPC Class Codes: A61F 2/0095 Packages or dispensers for prostheses or other implants for intraocular lenses A61F2/1691; for dental surgery A61C19/02
• CPC Class Codes: A61F 2/2412 with soft flexible valve members, e.g. tissue valves shaped like natural valves check valves with flexible valve members in general F16K15/14
• CPC Class Codes: A61F 2/2415 Manufacturing methods
• CPC Class Codes: A61F 2/2418 Scaffolds therefor, e.g. support stents
• 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 27/3604 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 27/3629 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
• CPC Class Codes: A61L 27/3691 characterised by physical conditions of the treatment, e.g. applying a compressive force to the composition, pressure cycles, ultrasonic/sonication or microwave treatment, lyophilisation
• CPC Class Codes: A61L 27/507 for artificial blood vessels apparatus for applying cells on a blood vessel prosthesis A61F2/062

Abstract

A treatment for bioprosthetic tissue used in implants or for assembled bioprosthetic heart valves to reduce in vivo calcification. The method includes applying a calcification mitigant such as a capping agent or an antioxidant to the tissue to specifically inhibit oxidation in tissue. Also, the method can be used to inhibit oxidation in dehydrated tissue. The capping agent suppresses the formation of binding sites in the tissue that are exposed or generated by the oxidation and otherwise would, upon implant, attract calcium, phosphate, immunogenic factors, or other precursors to calcification. In one method, tissue leaflets in assembled bioprosthetic heart valves are pretreated with an aldehyde capping agent prior to dehydration and sterilization.

Claims

1. A method for mitigating calcification in a bioprosthetic tissue, the method comprising:

at least partially cross-linking the bioprosthetic tissue;

treating the bioprosthetic tissue with a capping agent, wherein the capping agent reacts with functional groups associated with the bioprosthetic tissue; and

treating the bioprosthetic tissue with a reducing agent, wherein the reducing agent reduces any Schiff bases created by the reaction of the capping agent and the functional groups associated with the bioprosthetic tissue.

2. The method of claim 1, wherein the bioprosthetic tissue is selected from the group consisting of bovine pericardium, porcine tissue, blood vessel, skin, dura mater, pericardium, small intestinal submucosa, tissue heart valve, ligaments, and tendon.

3. The method of claim 1, wherein the at least partially cross-linking the bioprosthetic tissue is performed with glutaraldehyde or other aldehyde-containing agents.

4. The method of claim 1, wherein the treating steps are performed after the at least partially cross-linking step and wherein the functional groups are associated with the at least partially cross-linked bioprosthetic tissue.

5. The method of claim 1, wherein the functional groups are associated with in vivo toxicity, calcification, and immunogenicity of the bioprosthetic tissue.

6. The method of claim 5, wherein the functional groups are one or both of an aldehyde group and a carboxylic acid group.

7. The method of claim 1, wherein the capping agent is one or more selected from the group consisting of:

an amine, an alkyl amine, an amino alcohol, an ethanolamine, an amino acid, a lysine, a hydroxylysine, an amino sulfonate, a taurine, an amino sulfate, a dextran sulfate, a chondroitin sulfate, a hydrophilic multifunctional polymer, a polyvinyl alcohol, a polyethyleneimine, a hydrophobic multifunctional polymer, an α

-dicarbonyl, a methylglyoxal, a 3-deoxyglucose, a glyoxal, a hydrazide, an adipic hydrazide, a heparin, a mono-epoxy alkane, a di-epoxy alkane, and a polyepoxyalkane.

8. The method of claim 1, wherein the reducing agent is selected from the group consisting of:

a sodium borohydride and a sodium cyanoborohydride.

9. The method of claim 1, further comprising one of dehydrating the at least partially-crosslinked tissue or treating the at least partially cross-linked bioprosthetic tissue with a glycerol solution.

10. The method of claim 9, further comprising packaging the at least partially cross-linked bioprosthetic tissue after dehydrating or treating with the glycerol solution.

11. The method of claim 10, further comprising sterilizing the packaged, at least partially cross-linked bioprosthetic tissue.

12. The method of claim 11, wherein the sterilizing is performed by ethylene oxide, gamma irradiation, or electron beam irradiation.

13. A bioprosthetic heart valve comprising the bioprosthetic implant tissue treated in accordance with claim 1.

31. The method of claim 1, wherein the reducing agent is selected from the group consisting of:

a sodium bisulfite in acetylacetone and formic acid in formaldehyde.

33. The method of claim 1, wherein the capping agent is one or more selected from the group consisting of;

a hydroxylysine, a taurine, a dextran sulfate, a chondroitin sulfate, a polyvinyl alcohol, an a-dicarbonyl, the methylglyoxal, a 3-deoxyglucosonc, a glyoxal, a hydrazide, an adipic hydrazide, a heparin, a mono-epoxy alkanel, a di-epoxy alkane, and a polyepoxy alkane.

14. A method for mitigating calcification in a biological tissue, the method comprising:

at least partially cross-linking the bioprosthetic tissue with glutaraldehyde or other aldehyde-containing agents; and

exposing the cross-linked bioprosthetic tissue to a capping agent, the capping agent being one or a combination selected from the group consisting of;

an amino alcohol, an ethanolamine, an amino acid, a lysine, a hydroxylysine, an amino sulfonate, a taurine, an amino sulfate, a dextran sulfate, a chondroitin sulfate, a polyvinyl alcohol, an α

-dicarbonyl, a methylglyoxal, a 3-deoxyglucosone, a glyoxal, a hydrazide, an adipic hydrazide, a heparin, a mono-epoxy alkane, a di-epoxy alkane, and a polyepoxy alkane.

15. The method of claim 14, wherein the bioprosthetic tissue is selected from the group consisting of bovine pericardium, porcine tissue, blood vessel, skin, dura mater, pericardium, small intestinal submucosa, tissue heart valve, ligaments, and tendon.

16. The method of claim 14, wherein the exposing steps are performed after the at least partially cross-linking step and wherein the functional groups are associated with the at least partially cross-linked bioprosthetic tissue.

17. The method of claim 14, wherein the capping agent is ethanolamine.

18. The method of claim 14, wherein the capping agent is taurine.

19. The method of claim 14, wherein the capping agent is provided in one or a combination of an aqueous solution, an organic solvent and an organic buffered solution.

20. The method of claim 19, wherein the aqueous solution is selected from the group consisting of:

a buffered solution, water, short chain alcohols, glycerol, and a plasticizer.

21. The method of claim 14, further comprising exposing the bioprosthetic tissue to a reducing agent simultaneously with or after the step of exposing the bioprosthetic tissue to the capping agent.

22. The method of claim 21, wherein the reducing agent is selected from the group consisting of:

a sodium borohydride and a sodium cyanoborohydride.

23. The method of claim 14, further comprising one of dehydrating the at least partially cross-linked bioprosthetic tissue or treating the at least partially cross-linked bioprosthetic tissue with a glycerol solution.

24. The method of claim 23, further comprising packaging the at least partially cross-linked bioprosthetic tissue after the dehydrating or treating with the glycerol solution.

25. The method of claim 24, further comprising sterilizing the packaged, at least partially cross-linked bioprosthetic tissue.

26. The method of claim 25, wherein the sterilizing is performed by ethylene oxide, gamma irradiation, or electron beam irradiation.

27. A bioprosthetic heart valve comprising the bioprosthetic implant tissue treated in accordance with claim 14.

32. The method of claim 14, wherein the reducing agent is selected from the group consisting of:

a sodium bisulfite in acetylacetone and formic acid in formaldehyde.

34. The method of claim 14, wherein the capping agent is one or more selected from the group consisting of;

the hydroxy lysine, the taurine, the dextran sulfate, the chondroitin sulfate, the polyvinyl alcohol, the a-dicarbonyl, the methylglyoxal, the 3-deoxyglucosone, the glyoxal, the hydroxide, the adipic hydrazide, the heparin, the mono-epoxy Alkane, the di-cpoxy alkane, and the polyepoxy alkane.

28. A method for mitigating calcification in a bioprosthetic tissue, the method comprising:

at least partially cross-linking the bioprosthetic tissue; and

treating the bioprosthetic tissue with a capping agent solution to react with carboxylic acid functional groups associated with the bioprosthetic tissue, the capping agent solution comprising an amine in combination with one or more of N,N-disuccinimidyl carbonate, carbodiimides, 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide, N-cyclohexyl-N′

-(2-morpholinoethyl)carbodiimide, 1,3-dicyclohexyl carbodiimide, 2-chloro-1-methylpyridium iodide, and N-hydroxysulfosuccinimide.

29. The method of claim 28, wherein the capping agent solution comprises ethanolamine, 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide hydrochloride and N-hydroxysulfo succinimide.

30. A bioprosthetic heart valve comprising the bioprosthetic implant tissue treated in accordance with claim 28.