Crosslinkable macromers

• US 7,094,418 B2
• Filed: 11/17/2004
• Issued: 08/22/2006
• Est. Priority Date: 03/19/1998
• Status: Expired due to Fees

• Current Assignee: Surmodics Incorporated
• Original Assignee: Surmodics Incorporated
• Inventors: Chudzik, Stephen J., Clapper, David L.
• Primary Examiner(s): Russel, Jeffrey E.
• Application Number:
  US10/990,582
• Publication Number:
  US 20050136091A1
• Time in Patent Office: 643 Days
• Field of Search: None
• US Class Current: 424/423
• CPC Class Codes: A61K 2035/128 capsules, e.g. microcapsules
• CPC Class Codes: A61K 38/1875 Bone morphogenic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
• CPC Class Codes: A61K 9/1641 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61L 24/0031 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 24/0042 Materials resorbable by the body
• CPC Class Codes: A61L 27/34 Macromolecular materials
• CPC Class Codes: A61L 29/085 Macromolecular materials
• CPC Class Codes: A61L 31/148 Materials at least partially resorbable by the body
• CPC Class Codes: Y10S 623/92 Method or apparatus for preparing or treating prosthetic
• CPC Class Codes: Y10S 623/921 Blood vessel
• CPC Class Codes: Y10S 623/923 Bone
• CPC Class Codes: Y10S 623/926 Synthetic

Abstract

A crosslinkable macromer system and related methods of preparing the system and using the system in the form of a crosslinked matrix between a tissue site and an implant article such as a tissue implant or on the porous surface of a prosthetic device. The macromer system includes two or more polymer-pendent polymerizable groups and one or more initiator groups (e.g., polymer-pendent initiator groups). The polymerizable groups and the initiator group(s), when polymer-pendent, can be pendent on the same or different polymeric backbones. The macromer system provides advantages over the use of polymerizable macromers and separate, low molecular weight initiators, including advantages with respect to such properties as nontoxicity, efficiency, and solubility. A macromer system of the invention can be used as an interface between the tissue site and implant article in a manner sufficient to permit tissue growth through the crosslinked matrix and between the tissue site and implant. In a preferred embodiment, polymers with pendent polymerizable groups, for use in the macromer system, are prepared by reacting a polysaccharide polymer with a reactive moiety in an organic, polar solvent such as formamide.

Claims

1. A method of reducing immediate and chronic adverse reactions to an implanted medical device, comprising:

providing a medical device,

providing a matrix-forming system comprising a polymerization initiator and a crosslinkable macromer comprising one or more polymer backbones having pendent polymerizable groups,

implanting the medical device within a tissue site with the matrix-forming system positioned between the medical device and the tissue,

polymerizing the matrix-forming system to form a crosslinked matrix between the medical device and the tissue site, and

covalently bonding the matrix to a surface of the medical device.

2. The method of claim 1, wherein the adverse reactions are reduced by increasing tissue ingrowth.

3. The method of claim 1, wherein the adverse reactions comprise fibrosis.

4. The method of claim 1, wherein the adverse reactions comprise the accumulation of fluid.

5. The method of claim 1, wherein the adverse reactions comprise the accumulation of undesirable cells.

6. The method of claim 1, wherein the adverse reactions comprise restenosis.

7. The method of claim 1, wherein the matrix-forming system is positioned upon the medical device prior to implanting the medical device within the tissue site.

8. The method of claim 7, wherein the matrix-forming system is crosslinked prior to implanting the medical device within the tissue site.

9. The method of claim 7, wherein the matrix-forming system is crosslinked after implanting the medical device within the tissue site.

10. The method of claim 1, wherein the matrix-forming system is positioned within the tissue site after the medical device has been positioned within the tissue site.

11. The method of claim 1, wherein the matrix-forming system is crosslinked prior to implanting the medical device within the tissue site.

12. The method of claim 1, wherein the matrix-forming system is croslinked after implanting the medical device within the tissue site.

13. The method of claim 1, wherein a first amount of the matrix-forming system is positioned upon the medical device prior to implanting the medical device within the tissue site, and a second amount of the matrix-forming system is delivered to the tissue site after positioning the medical device within the tissue site, and the first and second amounts are independently crosslinked.

14. The method of claim 1, wherein the matrix-forming system further comprises a polymerization accelerator comprising a N-vinyl compound.

15. The method of claim 1, wherein the initiator comprises a polymer-pendent initiator.

16. The method of claim 15, wherein the polymer-pendent initiator includes an initiator group pendent on one or more polymeric backbones selected from the group consisting of polysaccharides, polyamino acids and combinations thereof.

17. The method of claim 16, wherein the polysaccharides are selected from the group consisting of hyaluronic acid, starch, dextran, heparin, chondroitin sulfate, dermatan sulfate, heparan sulfate, keratan sulfate, dextran sulfate, pentosan polysulfate and chitosan, and the polyamino acids are selected from the group consisting of gelatin, collagen, fibronectin, laminin, albumin, elastin, and active peptide domains thereof.

18. The method of claim 1, wherein the medical device is selected from joint implants, dental implants, soft tissue cosmetic prostheses, wound dressings, vascular prostheses, and ophthalmic prostheses.

19. The method of claim 18, wherein the medical device is a joint implant selected from the group consisting of hip and knee prosthetic devices having porous surfaces.

20. The method of claim 19, wherein the medical device is fabricated from synthetic materials and the porous surface provides a three-dimensional structure having interconnected passages, with pores having an average pore size of between about 5 microns and about 1 mm in diameter.

21. The method of claim 1, wherein the backbone comprises polyethylene glycol.

22. The method of claim 21, wherein the polymerizable groups comprise acrylates.

44. The method of claim 1, wherein the matrix is covalently bonded to the surface of the medical device prior to implanting the medical device within the tissue site.

45. The method of claim 1, wherein the initiator is selected from the group consisting of analogs of benzophenone and thioxanthone.

23. A coated medical device comprising:

a medical device, and

a crosslinked matrix covalently bonded to a surface of the medical device, the crosslinked matrix formed by a matrix-forming system including a polymerization initiator and a polymer backbone having pendent polymerizable groups.

24. The device of claim 23, wherein the polymerization initiator includes an initiator group pendent on a polymeric backbone selected from the group consisting of polysaccharides, polyamino acids and combinations thereof.

25. The device of claim 24, wherein the polysaccharides are selected from the group consisting of hyaluronic acid, starch, dextran, heparin, chondroitin sulfate, dermatan sulfate, heparan sulfate, keratan sulfate, dextran sulfate, pentosan polysulfate, and chitosan, and the polyamino acids are selected from the group consisting of gelatin, collagen, fibronectin, laminin, albumin, elastin, and active peptide domains thereof.

26. The device of claim 23, wherein the matrix-forming system further comprises a polymerization accelerator comprising a N-vinyl compound.

27. The device of claim 23, wherein the medical device is selected from joint implants, dental implants, soft tissue cosmetic prostheses, wound dressings, vascular prostheses, and ophthalmic prostheses.

28. The device of claim 27, wherein the medical device is a joint implant selected from the group consisting of hip and knee prosthetic devices having porous surfaces.

29. The device of claim 28, wherein the medical device comprises synthetic materials and the porous surface provides a three-dimensional structure having interconnected passages, with pores having an average pore size of between about 5 microns and about 1 mm in diameter.

30. The device of claim 23, wherein the backbone comprises polyethylene glycol.

31. The device of claim 30, wherein the polymerizable groups comprise acrylates.

46. The coated medical device of claim 23, wherein the initiator is selected from the group consisting of analogs of benzophenone and thioxanthone.

32. A method of coating a medical device with a matrix, comprising:

providing a medical device,

applying a polymerization initiator to the surface of the medical device,

providing a polymer backbone with pendent polymerizable groups, and

activating the initiator to polymerize the polymerizable groups to form a crosslinked matrix encapsulating the medical device and covalently bonded to a surface of the medical device.

33. The method of claim 32, wherein the backbone comprises polyethylene glycol.

34. The method of claim 33, wherein the polymerizable groups comprise acrylates.

35. The method of claim 34, wherein the medical device is suspended in a solution comprising the polyethylene glycol and acrylates after the initiator has been applied.

36. The method of claim 35, wherein the initiator is activated by illumination.

37. The method of claim 36, further including the step of controlling the thickness of the matrix by adjusting the illumination duration.

38. The method of claim 32 wherein the matrix further comprises a polymerization accelerator comprising an N-vinyl compound.

39. The method of claim 36, wherein the medical device is selected from joint implants, dental implants, soft tissue cosmetic prostheses, wound dressings, vascular prostheses, and ophthalmic prostheses.

40. The method of claim 39, wherein the medical device is a joint implant selected from the group consisting of hip and knee prosthetic devices having porous surfaces.

41. The method of claim 40, wherein the medical device is fabricated from synthetic materials and the porous surface provides a three-dimensional structure having interconnected passages, with pores having an average pore size of between about 5 microns and about 1 mm in diameter.

42. The method of claim 32, wherein the initiator is pendent on a polymeric backbone selected from the group of polysaccharides and polyamino acids.

43. The method of claim 42, wherein the polysaccharides are selected from the group consisting of hyaluronic acid, starch, dextran, heparin, chondroitin sulfate, dermatan sulfate, heparan sulfate, keratan sulfate, dextran sulfate, pentosan polysulfate and chitosan, and the polyamino acids are selected from the group consisting of gelatin, collagen, fibronectin, laminin, albumin, elastin, and active peptide domains thereof.

47. The method of claim 32, wherein the initiator is selected from the group consisting of analogs of benzophenone and thioxanthone.