Biodegradable crosslinking strategies using triglycidyl amine (TGA)

• US 20050244460A1
• Filed: 04/29/2005
• Published: 11/03/2005
• Est. Priority Date: 04/29/2004
• Status: Abandoned Application

• 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
• Application Number:
  US11/119,063
• Publication Number:
  US 20050244460A1
• Time in Patent Office: Days
• US Class Current: 424/426
• CPC Class Codes: A61L 27/34 Macromolecular materials
• CPC Class Codes: A61L 27/3683 subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
• 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 27/58 Materials at least partially resorbable by the body
• CPC Class Codes: A61L 31/10 Macromolecular materials
• CPC Class Codes: A61L 31/14 Materials characterised by their function or physical properties , e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• CPC Class Codes: A61L 31/148 Materials at least partially resorbable by the body
• CPC Class Codes: C08G 59/3227 Compounds containing acyclic nitrogen atoms

Abstract

The invention relates to implantable biodegradable bioprostheses and methods for making and using the bioprostheses. The implantable biodegradable bioprosthesis includes biomolecules having a reactive moiety and optionally a reactive group; and a biodegradable cross-linking moiety having (a) at least two linking moieties, wherein the at least two linking moieties are non-biodegradable and (b) a spacer, wherein the spacer is biodegradable and is in communication with the at least two linking moieties, provided that the biodegradable cross-linking moiety is artificial and is covalently bound to the reactive moiety. The implantable bioprosthesis is adapted to sufficiently degrade upon exposure to a cell or an enzyme to permit an expansion of the implantable bioprosthesis.

Claims

1. An implantable bioprosthesis comprising biodegradably and artificially cross-linked biomolecules.

2. An implantable bioprosthesis comprising:

biomolecules having a reactive moiety and optionally a reactive group; and

a biodegradable cross-linking moiety having (a) at least two linking moieties, wherein the at least two linking moieties are non-biodegradable and (b) a spacer, wherein the spacer is biodegradable and is in communication with the at least two linking moieties, provided that the biodegradable cross-linking moiety is artificial and is covalently bound to the reactive moiety, whereby the biomolecules are cross-linked.

3. The implantable bioprosthesis of claim 2, wherein the implantable bioprosthesis is adapted to sufficiently degrade upon exposure to a cell or an enzyme at a biodegradation rate to permit an expansion of the implantable bioprosthesis and wherein the biodegradation rate is affected by an amount of the spacer.

4. The implantable bioprosthesis of claim 2, wherein at least one of the at least two linking moieties comprises an amine moiety and a hydroxyl group formed by a ring-opening reaction of an epoxide.

5. The implantable bioprosthesis of claim 2, wherein at least one of the at least two linking moieties is a member selected from the group consisting of a derivative of polyepoxy amine and a derivative of aldehyde.

6. The implantable bioprosthesis of claim 5, wherein the derivative of polyepoxy amine is a member selected from the group consisting of

7. The implantable bioprosthesis of claim 5, wherein the derivative of polyepoxy amine is a derivative of triglycidyl amine.

8. The implantable bioprosthesis of claim 2, wherein the spacer comprises a disulfide group or a carbonyl group.

9. The implantable bioprosthesis of claim 8, wherein the spacer is represented by a formula:

wherein A¹ and A² each comprise at least one carbon atom, and Z¹ and Z² are nucleophilic groups capable of opening an epoxy ring.

10. The implantable bioprosthesis of claim 9, wherein at least one of the nucleophilic groups is a member selected from the group consisting of an amino group, an alkylthio group, a derivative of imidazole, a derivative of pyrazole, and a derivative of pyridine.

11. The implantable bioprosthesis of claim 9, wherein the spacer is represented by a formula:

—

NH—

(CH₂)₂—

S—

S—

(CH₂)₂—

NH—

 

 

(E)

12. The implantable bioprosthesis of claim 8, wherein the spacer is represented by a formula:

13. The implantable bioprosthesis of claim 2, wherein the biodegradable cross-linking moiety is represented by a formula:

14. The implantable bioprosthesis of claim 2, wherein the reactive group is a member selected from the group consisting of an amine group, a hydroxyl group, a phosphate group, and a carboxyl group.

15. The implantable bioprosthesis of claim 2, wherein the reactive moiety is a member selected from the group consisting of an amine moiety, a hydroxyl moiety, a derivative of a phosphate moiety, and a carboxyl moiety.

16. The implantable bioprosthesis of claim 2, further comprising a non-biodegradable cross-linking moiety comprising the at least one linking moiety, provided that the non-biodegradable cross-linking moiety is free of the spacer and is covalently bound to the reactive moiety.

17. The implantable bioprosthesis of claim 16, wherein the biodegradable cross-linking moiety and the non-biodegradable cross-linking moiety are at a ratio of about 1 to about 10.

18. The implantable bioprosthesis of claim 2, wherein the implantable bioprosthesis is a member 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.

19. The implantable bioprosthesis of claim 18, wherein the implantable bioprosthesis is the heart valve prosthesis.

20. The implantable bioprosthesis of claim 2, wherein the biomolecules are derived from a biological tissue and or a synthetic analog of a bioprosthetic tissue.

21. The implantable bioprosthesis of claim 20, 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.

22. The implantable bioprosthesis of claim 21, wherein the tissue is harvested from an animal.

23. The implantable bioprosthesis of claim 22, wherein the animal is selected from the group consisting of a human, a cow, a pig, a dog, a seal, and a kangaroo.

24. The implantable bioprosthesis of claim 2, wherein the biomolecules are members selected from the group consisting of proteins, glucosoaminoglucans, and an extracellular matrix.

25. The implantable bioprosthesis of claim 2, further comprising at least one of a calcification inhibiting moiety or a glucosoaminoglycan stabilizing moiety, wherein the calcification inhibiting moiety is formed by treating the implantable bioprosthesis with a calcification inhibitor and the glucosoaminoglycan stabilizing moiety is formed by treating the implantable bioprosthesis with a glucosoaminoglycan stabilizing reagent.

26. The implantable bioprosthesis of claim 25, wherein the calcification inhibitor is a member selected from the group consisting of an Al⁺³ salt, a Fe⁺³ salt, and aminobisphosphonate.

27. The implantable bioprosthesis of claim 25, wherein the glucosoaminoglycan stabilizing reagent is a member selected from the group consisting of carbodiimide and glutaraldehyde.

28. A method of making the implantable bioprosthesis of claim 2, the method comprising:

providing an untreated bioprosthesis comprising biomolecules having reactive groups;

providing at least two molecules of a linking agent;

providing a spacing agent; and

reacting the linking agent, the spacing agent and the biomolecules, so that the biodegradable cross-linking moiety is formed between the biomolecules to provide cross-linking and thereby make the implantable bioprosthesis.

29. The method of claim 28, wherein the linking agent is represented by at least one of polyepoxy amine, aldehyde, and carbodidimide.

30. The method of claim 29, wherein the linking agent is triglycidyl amine.

31. The method of claim 28, wherein the spacing agent is represented by a formula:

wherein A¹ and A² each comprise at least one carbon atom, and Z¹ and Z² are nucleophilic groups capable of opening an epoxy ring.

32. The method of claim 31, wherein at least one of the nucleophilic groups is a member selected from the group consisting of an amino group, an alkylthio group, a derivative of imidazole, derivative of pyrazole, and derivative of pyridine.

33. The method of claim 31 wherein the spacing agent is cystamine.

34. The method of claim 28, wherein the spacing agent is represented by a formula:

35. The method of claim 28, further comprising reacting the linking agent and the biomolecules to form the non-biodegradable cross-linking moiety, wherein the non-biodegradable cross-linking moiety cross-links biomolecules.

36. The method of claim 28, wherein the linking agent and the spacing agent are provided at a molar ratio of about 1 to about 10.

37. A method of using the implantable bioprosthesis of claim 2, the method comprising:

providing the implantable bioprosthesis;

providing an organism comprising an enzyme capable of degrading the spacer;

contacting the implantable bioprosthesis with the enzyme; and

degrading the implantable bioprosthesis and thereby permitting expansion of the implantable bioprosthesis.

38. The method of claim 37, wherein degrading of the implantable bioprosthesis proceeds at a biodegradation rate and wherein the biodegradation rate is affected by the amount of the spacer.