Bioprosthetic heart valves having high calcification resistance

• US 5,697,972 A
• Filed: 06/07/1995
• Issued: 12/16/1997
• Est. Priority Date: 07/13/1994
• Status: Expired due to Fees

• Current Assignee: Korea Advanced Institute of Science and Technology
• Original Assignee: Korea Advanced Institute of Science and Technology
• Inventors: Kim, Hack Joo, Han, Dong Keun, Kim, Young Ha, Park, Ki Dong
• Primary Examiner(s): Prebilic, Paul B.
• Application Number:
  US08/480,318
• Time in Patent Office: 923 Days
• Field of Search: 623/2, 623/11, 623/901, 427/2.24, 427/2.25
• US Class Current: 128/898
• CPC Class Codes: A61F 2/24 Heart valves ; Vascular valves, e.g. venous valves; Heart implants, e.g. passive devices for improving the function of the native valve or the heart muscle; Transmyocardial revascularisation [TMR] devices; Valves implantable in the body
• CPC Class Codes: A61L 2400/02 Treatment of implants to prevent calcification or mineralisation in vivo
• CPC Class Codes: A61L 27/34 Macromolecular materials
• CPC Class Codes: A61L 27/36 containing ingredients of undetermined constitution or reaction products thereof , e.g. transplant tissue, natural bone, extracellular matrix isolated natural compounds, e.g. collagen A61L27/24
• 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 27/3645 Connective tissue
• 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 27/507 for artificial blood vessels apparatus for applying cells on a blood vessel prosthesis A61F2/062
• CPC Class Codes: C08L 71/02 Polyalkylene oxides
• CPC Class Codes: Y10S 623/901 Method of manufacturing prosthetic device
• CPC Class Codes: Y10S 623/918 Heart

Abstract

The specification describes an invention of calcification resistant bioprosthetic heart valves which can be used for a long term, and have good blood compatibility and in vivo stability, and have high calcification resistance. The bioprosthetic heart valves of the invention can be prepared by binding sulfonated polyethylene oxide (PEO) derivatives covalently to the tissue. The valves have an anionic effect equal to that of chondroitin sulfate, space filling effect, and blocking effect of the carboxyl group of collagen which has been known as one factor of the calcium deposition,. In particular, the present method has better advantages in view of calcification resistance than any other conventional methods, because it suppresses thrombosis and embolism and decreases incidence of infection.

Claims

1. A calcification resistant bioprosthetic heart valve prepared by binding an anionic hydrophilic polymer derivative of sulfonated polyethylene oxide covalently to tissue selected from the group consisting of porcine aortic valve and bovine pericardium.

2. The heart valve of claim 1, wherein the sulfonated polyethylene oxide is X--PEO--SO₃, wherein X is an amine or aldehyde group and PEO is polyethylene oxide, and said sulfonated polyethylene oxide is selected from the group consisting of H₂ --N--PEO--SO₃ and OHC--PEO--SO₃.

3. The heart valve of claim 1, wherein the PEO has a molecular weight of 100 to 20,000.

4. The heart valve of claim 1, wherein the PEO has a molecular weight of 200 to 10,000.

5. The heart valve of claim 2, wherein the H₂ N--PEO--SO₃ is prepared by sulfonating a terminal group of an amine terminated PEO with an alkyl sultone.

6. The heart valve of claim 5, wherein the alkyl sultone is propane sulfone.

7. The heart valve of claim 2, wherein the OHC--PEO--SO₃ is prepared by reacting an amine group of an amine-terminated sulfonated PEO with a dialdehyde.

8. The heart valve of claim 7, wherein the dialdehyde is glutaraldehyde.

9. The heart valve of claim 1, wherein the sulfonated PEO is added and bound to the tissue during oxidation with sodium metaperiodate, neutralization with ethylene glycol, or aldehyde activation with glutaraldehyde, thereof.

10. The heart valve of claim 1, wherein the sulfonated PEO is bound to the tissue by pre- or post-treatment of glutaraldehyde.

11. The heart valve of claim 1, wherein the sulfonated PEO is bound to the tissue using a carbodiimide.

12. The heart valve of claim 11, wherein the carbodiimide is 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide.

13. The heart valve of claim 12, wherein the carbodiimide is in aqueous solution having a pH of 3.0 to 5.0.

14. The heart valve of claim 1, wherein said heart valve is in glutaraldehyde for fixation, storage and aldehyde-activation of the tissue.

15. The heart valve of claim 1, wherein said heart valve is in a phosphate buffered saline solution as a buffer for stabilizing the tissue.

16. The heart valve of claim 11, wherein amine groups on the tissue are blocked with a blocking agent before using said carbodiimide.

17. The heart valve of claim 2, wherein said tissue is a porcine aortic valve.

18. The heart valve of claim 2, wherein said tissue is a bovine pericardium.

19. A method for preparing calcification resistant bioprosthetic heart valves which comprises binding an anionic hydrophilic polymer derivative of sulfonated polyethylene oxide covalently to tissue selected from the group consisting of porcine aortic valve and bovine pericardium.

20. A method according to claim 19, wherein the sulfonated polyethylene oxide is X--PEO--SO₃ in which X is an amine or aldehyde group and PEO is polyethylene oxide, said sulfonated polyethylene oxide being selected from the group consisting of H₂ N--PEO--SO₃ and OHC--PEO--SO₃.

21. A method according to claim 19, wherein the PEO has a molecular weight of 100 to 20,000.

22. A method according to claim 19, wherein the PEO has a molecular weight of 200 to 10,000.

23. A method according to claim 19, wherein said sulfonated polyethylene oxide is an amine-terminated sulfonated PEO of the formula H₂ N--PEO--SO₃ prepared by sulfonating one of two terminals of amine terminated PEO with an alkyl sulfone.

24. A method according to claim 19, wherein said sulfonated polyethylene oxide is an aldehyde-terminated sulfonated PEO of the general formula OHC--PEO--SO₃ prepared by reacting the amine group of the amine-terminated sulfonated PEO with a dialdehyde.

25. A method according to claim 19, wherein the sulfonated PEO is added and bound to the tissue during oxidation with sodium metaperiodate, neutralization with ethylene glycol, or aldehyde activation with glutaraldehyde.

26. The method according to claim 19, wherein the sulfonated PEO is bound to the tissue by glutaraldehyde treatment.

27. The method according to claim 19, wherein the sulfonated PEO is bound to the tissue using a carbodiimide.

28. The method according to claim 27, wherein said carbodiimide is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and said carbodiimide is in aqueous solution at a pH of 3.0 to 5.0.

29. The method according to claim 19, wherein said tissue is fixed and activated, and glutaraldehyde is used for the fixation and aldehyde-activation of the tissue.

30. The method according to claim 19, wherein a phosphate buffered saline solution is used as a buffer for stabilizing the tissue.

31. The method according to claim 26, wherein a blocking agent is used to block amine groups of the tissue prior to reacting the tissue with sulfonated PEO.