Crosslinkable macromers

• US 20030031697A1
• Filed: 06/20/2002
• Published: 02/13/2003
• Est. Priority Date: 03/19/1998
• Status: Active Grant

• Current Assignee: Surmodics Incorporated
• Original Assignee: Surmodics Incorporated
• Inventors: Chudzik, Stephen J., Clapper, David L.
• Granted Patent: US 6,924,370 B2
• Time in Patent Office: Days
• 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 delivering an implant article to a tissue site, the method comprising

a) providing an article selected from the group consisting of tissue implants and prosthetic devices providing a porous surface,

b) providing a crosslinkable macromer system comprising a polymerization initiator and one or more polymers having pendent polymerizable groups,

c) implanting the article within the tissue site with the macromer system positioned between the article and the tissue, and

d) polymerizing the macromer system to form a crosslinked matrix between the article and the tissue site suitable to permit continuous tissue growth through the matrix and between the implant and the native tissue.

2. A method according to claim 1 wherein the macromer system is positioned upon the article prior to implanting the article within the tissue site and is crosslinked before, during or after implanting the article within the tissue site.

3. A method according to claim 1 wherein the macromer system is delivered to the tissue site and crosslinked before, during or after the implant article has been positioned within the tissue site.

4. A method according to claim 1 wherein a first amount of a macromer system is positioned upon the article prior to implanting the article within the tissue site, and a second amount of either the same or different macromer system is delivered to the tissue site, either before or after positioning the implant article within the tissue site, and the first and second amounts are independently crosslinked before, during or after positioning the implant within the tissue site.

5. A method according to claim 1 wherein the macromer system is applied to the tissue site and/or implant article by spraying, dipping, injecting or brushing the macromer system.

6. A method according to claim 1 wherein the polymer having pendent polymerizable groups is prepared by a method that comprises the steps of

a) providing a polymer selected from the group consisting of polysaccharides and polyamino acids, and

b) incorporating polymerizable groups into the polymer by reaction of the polymer with a reactive moiety containing an ethylenically unsaturated group capable of undergoing free radical polymerization,

wherein the reaction between the polymer and reactive moiety is carried out in a medium comprising a polar organic solvent.

7. A method according to claim 6 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.

8. A method according to claim 7 wherein the solvent comprises formamide.

9. A method according to claim 8 wherein the reactive moiety is selected from the group consisting of glycidyl acrylate and acryloyl chloride.

10. A method according to claim 9 wherein the polymer comprises hyaluronic acid or collagen.

11. A method according to claim 1 wherein the initiators comprise polymer-pendent initiators.

12. A method according to claim 1 wherein the macromer system further comprises a polymerization accelerator comprising a N-vinyl compound.

13. A method according to claim 1 wherein the article is selected from joint implants, dental implants, soft tissue cosmetic prostheses, wound dressings, vascular prostheses, and ophthalmic prostheses.

14. A method according to claim 13 wherein the article is a joint implant selected from the group consisting of hip and knee prosthetic devices having porous surfaces.

15. A method according to claim 14 wherein the prosthetic 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.

16. A method according to claim 15 wherein the average pore size is between about 20 microns and about 600 microns in diameter.

17. A method of preparing a polymerizable macromer system comprising the steps of

a) providing a polymer selected from the group consisting of polysaccharides and polyamino acids, and

b) incorporating polymerizable groups into the polymer by reaction of the polymer with a reactive moiety containing an ethylenically unsaturated group capable of undergoing free radical polymerization,

wherein the reaction between the polymer and reactive moiety is carried out in a medium comprising a polar organic solvent.

18. A method according to claim 17 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.

19. A method according to claim 18 wherein the solvent comprises formamide.

20. A method according to claim 19 wherein the reactive moiety is selected from the group consisting of glycidyl acrylate and acryloyl chloride.

21. A method according to claim 20 wherein the polymer comprises hyaluronic acid or collagen.

22. A method according to claim 17 wherein the initiators comprise polymer-pendent initiators.

23. A method according to claim 17 wherein the macromer system further comprises a polymerization accelerator comprising a N-vinyl compound.

24. A polymerizable macromer system comprising a polymer selected from the group consisting of polysaccharides and polyamino acids wherein polymerizable groups have been incorporated into the polymer by reaction of the polymer, in a medium comprising a polar organic solvent, with a reactive moiety containing an ethylenically unsaturated group capable of undergoing free radical polymerization.

25. A macromer system according to 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. A macromer system according to claim 25 wherein the solvent comprises formamide.

27. A macromer system according to claim 26 wherein the reactive moiety is selected from the group consisting of glycidyl acrylate and acryloyl chloride.

28. A macromer system according to claim 27 wherein the polymer comprises hyaluronic acid or collagen.

29. A macromer system according to claim 24 wherein the initiators comprise polymer-pendent initiators.

30. A macromer system according to claim 24 wherein the macromer system further comprises a polymerization accelerator comprising a N-vinyl compound.

31. An implantable combination comprising

a) an implant article selected from the group consisting of tissue implants and prosthetic devices providing a porous surface, and

b) a macromer system positioned upon the article and comprising a polymerization initiator and one or more polymers having pendent polymerizable groups.

32. A combination according to claim 31 wherein the macromer system is crosslinked to form a matrix suitable to permit continuous tissue growth through the matrix and between the implant and the native tissue.

33. An implanted combination within a tissue site, the combination comprising

a) an implant article selected from the group consisting of tissue implants and prosthetic devices providing a porous surface, and

b) a crosslinked matrix positioned between the article and the tissue site, the matrix prepared by crosslinking a macromer system comprising a polymerization initiator and one or more polymers having pendent polymerizable groups,

wherein the combination is positioned within and/or in apposition to a tissue site.

34. An implanted combination within a tissue site, the combination comprising

a) an implant article selected from the group consisting of tissue implants and prosthetic devices providing a porous surface,

b) a crosslinked matrix positioned between the article and the tissue site, the matrix prepared by crosslinking a macromer system comprising a polymerization initiator and one or more polymers having pendent polymerizable groups, wherein the combination is positioned within and/or in apposition to a tissue site, and wherein continuous tissue ingrowth is present through the matrix and between the tissue site and the implant article.

35. A crosslinkable macromer system comprising one or more polymers providing pendent polymerizable and pendent initiator groups wherein the system is adapted to be polymerized in order to form a matrix suitable for in vivo application, and wherein either:

(a) the polymerizable groups and initator group(s) are pendent on different polymers and the initiator groups are independently selected from the group consisting of long wave ultraviolet activatable molecules selected from the group consisting of benzophenone, thioxanthones, and benzoin ethers;

visible light activatable molecules selected from the group consisting of ethyl eosin, eosin Y, rose bengal, camphorquinone and erythrosin; and

thermally activatable molecules selected from the group consisting of 4,4′

azobis(4-cyanopentanoic) acid, and 2,2-azobis[2-(2-imidazolin-2-yl) propane] dihydrochloride, and benzoyl peroxide; and

the pendent polymerizable groups are selected from the group consisting of vinyl groups, acrylate groups, methacrylate groups, ethacrylate groups, 2-phenyl acrylate groups, acrylamide groups, methacrylamide groups, itaconate groups, and styrene groups, or

(b) the polymerizable groups and the initiator group(s) are pendent on the same polymer and the initiator groups are independently selected from the group consisting of long wave ultraviolet activatable molecules selected from the group consisting of thioxanthones, and benzoin ethers;

visible light activatable molecules selected from the group consisting of ethyl eosin, eosin Y, rose bengal, camphorquinone and erythrosin; and

thermally activatable molecules selected from the group consisting of 4,4′

azobis(4-cyanopentanoic) acid, and 2,2-azobis[2-(2-imidazolin-2-yl) propane] dihydrochloride, and benzoyl peroxide; and

the pendent polymerizable groups are selected from the group consisting of vinyl groups, acrylate groups, methacrylate groups, ethacrylate groups, 2-phenyl acrylate groups, acrylamide groups, methacrylamide groups, itaconate groups, and styrene groups;

or

(c) the polymerizable groups and the initiator group(s) are pendent on the same polymer and the initiator groups are independently selected from the group consisting of long wave ultraviolet activatable molecules selected from the group consisting of benzophenone, thioxanthones, and benzoin ethers;

visible light activatable molecules selected from the group consisting of ethyl eosin, eosin Y, rose bengal, camphorquinone and erythrosin; and

thermally activatable molecules selected from the group consisting of 4,4′

azobis(4-cyanopentanoic) acid, and 2,2-azobis[2-(2-imidazolin-2-yl) propane] dihydrochloride, and benzoyl peroxide; and

the pendent polymerizable groups are selected from the group consisting of acrylate groups, methacrylate groups, ethacrylate groups, 2-phenyl acrylate groups, acrylamide groups, methacrylamide groups, itaconate groups, and styrene groups,

wherein the macromer system further comprises a polymerization accelerator comprising a N-vinyl compound.