Implant coating for control of tissue/implant interactions

• US 6,497,729 B1
• Filed: 11/19/1999
• Issued: 12/24/2002
• Est. Priority Date: 11/20/1998
• Status: Expired due to Term

• Current Assignee: University of Connecticut (State of Connecticut)
• Original Assignee: University of Connecticut (State of Connecticut)
• Inventors: Kreutzer, Donald, Burgess, Diane, Koberstein, Jeffrey, Papadimitrakopoulos, Fotios, Moussy, Francis, Huang, Samuel
• Primary Examiner(s): Prebilic, Paul B.
• Application Number:
  US09/443,857
• Time in Patent Office: 1,131 Days
• Field of Search: 623/11.11, 623/23.57, 623/23.71, 623/23.73, 424/423, 600/365, 600/377
• US Class Current: 623/23.57
• CPC Class Codes: A61B 5/0031 Implanted circuitry
• CPC Class Codes: A61B 5/14532 for measuring glucose, e.g. by tissue impedance measurement
• CPC Class Codes: A61L 2300/00 Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• 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 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: C08L 27/12 containing fluorine atoms
• CPC Class Codes: C08L 33/14 of esters containing halogen, nitrogen, sulfur, or oxygen atoms in addition to the carboxy oxygen
• CPC Class Codes: C08L 39/06 Homopolymers or copolymers of N-vinyl-pyrrolidones
• CPC Class Codes: C08L 89/00 Compositions of proteins; Compositions of derivatives thereof foodstuff preparations A23J3/00

Abstract

A tissue/implant interface, comprising an implant and a bioactive polymer layer adjacent at least a portion of the outer surface of the implant, wherein the polymer layer contains at least one tissue response modifier covalently attached to the polymer layer or entrapped within the polymer layer in a quantity effective to control the tissue response at the site of implantation. Preferably, the at least one tissue response modifier controls inflammation, fibrosis, and/or neovascularization. Exemplary tissue response modifiers include, but are not limited to, steroidal and non-steroidal anti-inflammatory agents, anti-fibrotic agents, anti-proliferative agents, cytokines, cytokine inhibitors, neutralizing antibodies, adhesive ligands, and combinations thereof. Use of the various combinations of tissue response modifiers with bioactive polymers provides a simple, flexible and effective means to control the implant/tissue interphase, improving implant lifetime and function.

Claims

1. An implant having a tissue/implant interface, comprising an implant having an outer surface and a bioactive polymer layer self-assembled with metal cations, wherein the self-assembled polymer layer is adjacent to at least a portion of the outer surface, and wherein the self-assembled bioactive polymer layer provides at least one tissue response modifier to the site of implantation in a quantity effective to control tissue response at the site of implantation.

2. The implant of claim 1, wherein the tissue response modifier is provided in a controlled release form by nanoparticles, emulsions, liposomes, or microspheres.

3. The implant of claim 2, wherein the tissue response modifier is encapsulated within a microsphere, physically entrained within a microsphere, or covalently attached to a microsphere.

4. The implant of claim 1, wherein the tissue response is inflammation, fibrosis, fibroblast formation, fibroblast function, cell proliferation, neovascularization, cell injury, cell death, leukocyte activation, leukocyte adherence, lymphocyte activation, lymphocyte adherence, macrophage activation, macrophage adherence, thrombosis, neoplasia, protein adhesion to the implant, or a combination comprising at least one of the foregoing.

5. The implant of claim 1, wherein the tissue response modifier is an anti-fibrotic agent, steroidal anti-inflammatory agent, non-steroidal anti-inflammatory agent, anti-proliferative agent, cytokine, cytokine inhibitor, growth factor, vascular growth factor, neutralizing antibody, adhesive ligand, hormone, cytotoxic agent, or a combination comprising at least one of the foregoing.

6. The implant of claim 1, comprising a tissue response modifier which affects inflammation.

7. The implant of claim 1, comprising a tissue response modifier which affects neovascularization.

8. The implant of claim 1, comprising first a tissue response modifier which affects inflammation and a second tissue response modifier which affects neovascularization.

9. The implant of claim 8, wherein the tissue response modifier is 2-(3-benzophenyl)propionic acid, 9-alpha-fluoro-16-alpha-methylprednisolone, methyl prednisone, fluoroxyprednisolone, 17-hydroxycorticosterone, cyclosporin, (+)-6-methoxy-α

-methyl-2-naphthalene acetic acid, 4-isobutyl-α

-methylphenyl acetic acid, Mitomicyin C, transforming growth factor alpha, anti-transforming growth factor beta, epidermal growth factor, vascular endothelial growth factor, anti-transforming growth factor beta antibody, anti-fibroblast antibody, anti-transforming growth factor beta receptor antibody, arginine-glycine-aspartic acid, REDV, or a combination thereof.

10. The implant of claim 1, wherein the tissue response modifier is covalently attached to the self-assembled bioactive polymer layer, is entrapped within the self-assembled bioactive polymer layer, is associated with an outer surface of the self-assembled bioactive polymer layer, or a combination thereof.

11. The implant of claim 1, wherein the self-assembled bioactive polymer layer is a synthetic polymer.

12. The implant of claim 1, wherein the self-assembled bioactive polymer layer further comprises covalently bound poly(ethylene oxide), phosphatidyl choline, polyvinyl alcohol, polyethylene imine, an adhesive ligand, or a combination thereof.

13. The implant of claim 1, wherein the self-assembled bioactive polymer layer is a mussel adhesive protein.

14. The implant of claim 1, wherein the self-assembled bioactive polymer layer is assembled from humic acid.

15. The implant of claim 1, wherein the self-assembled bioactive polymer layer is assembled from glutamic acid.

16. The implant of claim 1, wherein the metal cations are Fe³⁺ or Ca²⁺.

17. The implant of claim 1, wherein the site of implantation is the gastrointestinal tract, biliary tract, urinary tract, genital tract, central nervous system or endocrine system.

18. The implant of claim 1, wherein the site of implantation is at blood vessels, bones, joints, tendons, nerves, muscles, the head, the neck, or organs.

19. The implant of claim 1, wherein the implant is a material, a prosthesis, an artificial organ, a repair device, an implantable drug delivery system, or a biosensor.

20. The implant of claim 1, wherein the implant further comprises an additional bioactive polymer layer.

21. The implant of claim 20, wherein the additional bioactive polymer layer is a hydrogel.

22. The implant of claim 1, further comprising a bioactive polymer layer formed by the polymerization of 2-hydroxyethyl methacrylate, a fluorinated acrylate, acrylic acid, methacrylic acid, or a combination comprising one of the foregoing monomers with an ethylenically unsaturated co-monomer.

23. The implant of claim 22, wherein the bioactive polymer layer is formed by co-polymerization of 2-hydroxyethyl methacrylate with hydroxypropyl methacrylate, N-vinyl pyrrolidinone, 2-hydroxyethyl acrylate, glycerol methacrylate, n-isopropyl acrylamide, N,N-dimethylacrylamide, glycidyl methacrylate, or a combination thereof.

24. The implant of claim 22, wherein the bioactive polymer layer is formed by co-polymerization of 2-hydroxyethyl methacrylate, N-vinyl pyrrolidinone, and 2-N-ethylperflourooctanesulfanamido ethyl acrylate in the presence of EGDMA.

25. An implant having a tissue/implant interface, comprising an implant having an outer surface and a self-assembled poly(anion)/poly(cation) film, wherein the film comprises at least one poly(anion) layer and one poly(cation) layer, the film being adjacent to at least a portion of the outer surface, and wherein the film provides at least one tissue response modifier to the site of implantation in a quantity effective to control tissue response at the site of implantation.

26. The implant of claim 25, wherein the poly(anion) is poly(glutamic acid) or copolymers thereof, and the poly(cation) is poly(lysine) or copolymers thereof.

27. The implant of claim 25, wherein the tissue response modifier is provided in a controlled release form by nanoparticles, emulsions, liposomes, or microspheres.

28. The implant of claim 25, wherein the tissue response modifier is encapsulated within a microsphere, physically entrained within a microsphere, or covalently attached to a microsphere.

29. The implant of claim 25, wherein the tissue response is inflammation, fibrosis, fibroblast formation, fibroblast function, cell proliferation, neovascularization, cell injury, cell death, leukocyte activation, leukocyte adherence, lymphocyte activation, lymphocyte adherence, macrophage activation, macrophage adherence, thrombosis, neoplasia, protein adhesion to the implant, or a combination comprising at least one of the foregoing.

30. The implant of claim 25, wherein the tissue response modifier is an anti-fibrotic agent, steroidal anti-inflammatory agent, non-steroidal anti-inflammatory agent, anti-proliferative agent, cytokine, cytokine inhibitor, growth factor, vascular growth factor, neutralizing antibody, adhesive ligand, hormone, cytotoxic agent, or a combination comprising at least one of the foregoing.

31. The implant of claim 25, comprising a tissue response modifier which affects inflammation.

32. The implant of claim 25, comprising a tissue response modifier which affects neovascularization.

33. The implant of claim 25, comprising first a tissue response modifier which affects inflammation and a second tissue response modifier which affects neovascularization.

34. The implant of claim 25, wherein the tissue response modifier is 2-(3-benzophenyl)propionic acid, 9-alpha-fluoro-16-alpha-methylprednisolone, methyl prednisone, fluoroxyprednisolone, 17-hydroxycorticosterone, cyclosporin, (+)-6-methoxy-α

-methyl-2-naphthalene acetic acid, 4-isobutyl-α

-methylphenyl acetic acid, Mitomicyin C, transforming growth factor alpha, anti-transforming growth factor beta, epidermal growth factor, vascular endothelial growth factor, anti-transforming growth factor beta antibody, anti-fibroblast antibody, anti-transforming growth factor beta receptor antibody, arginine-glycine-aspartic acid, REDV, or a combination thereof.

35. The implant of claim 25, wherein the tissue response modifier is covalently attached to the self-assembled bioactive polymer layer, is entrapped within the self-assembled bioactive polymer layer, is associated with an outer surface of the self-assembled bioactive polymer layer, or a combination thereof.

36. The implant of claim 25, wherein the self-assembled poly(anion)/poly(cation) film further comprises covalently bound poly(ethylene oxide), phosphatidyl choline, polyvinyl alcohol, polyethylene imine, an adhesive ligand, or a combination thereof.

37. The implant of claim 25, wherein the implant further comprises a hydrogel.

38. The implant of claim 25, further comprising a bioactive polymer layer formed by the polymerization of 2-hydroxyethyl methacrylate, 2-hydroxyethyl methacrylate, fluorinated acrylates, acrylic acid, and methacrylic acid, and combinations thereof with ethylenically unsaturated co-monomers.

39. The implant of claim 38, wherein the bioactive polymer layer is formed by co-polymerization of 2-hydroxyethyl methacrylate with hydroxypropyl methacrylate, N-vinyl pyrrolidinone, 2-hydroxyethyl acrylate, glycerol methacrylate, n-isopropyl acrylamide, N,N-dimethylacrylamide, glycidyl methacrylate, and combinations thereof.

40. The implant of claim 38, wherein the self assembled bioactive polymer layer is formed by co-polymerization of 2-hydroxyethyl methacrylate, N-vinyl pyrrolidinone, and 2-N-ethylperflourooctanesulfanamido ethyl acrylate in the presence of EGDMA.

41. The implant of claim 25, wherein the site of implantation is the gastrointestinal tract, biliary tract, urinary tract, genital tract, central nervous system or endocrine system.

42. The implant of claim 25, wherein the site of implantation is at blood vessels, bones, joints, tendons, nerves, muscles, the head, the neck, or organs.

43. The implant of claim 25, wherein the implant is a material, a prostheses, an artificial organ, a repair device, an implantable drug delivery system, or a biosensor.