Flexible tissue matrix and methods for joint repair

• US 10,245,306 B2
• Filed: 03/15/2013
• Issued: 04/02/2019
• Est. Priority Date: 11/16/2012
• Status: Active Grant

• Current Assignee: Isto Technologies Ii LLC
• Original Assignee: Isto Technologies Ii LLC
• Inventors: Seyedin, Mitchell S., Ward, Anthony J., Matava, Matthew
• Primary Examiner(s): Hill, Kevin K
• Assistant Examiner(s): Leonard, Arthur S
• Application Number:
  US13/837,849
• Publication Number:
  US 20140142718A1
• Time in Patent Office: 2,209 Days
• Field of Search: None
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 38/18 Growth factors; Growth regulators
• CPC Class Codes: A61K 38/1825 Fibroblast growth factor [FGF]
• CPC Class Codes: A61K 38/1841 Transforming growth factor [TGF]
• CPC Class Codes: A61K 38/1858 Platelet-derived growth factor [PDGF]
• CPC Class Codes: A61K 38/1875 Bone morphogenic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
• CPC Class Codes: A61K 38/193 Colony stimulating factors [CSF]
• CPC Class Codes: A61K 38/20 Interleukins [IL]
• CPC Class Codes: A61K 38/30 Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2 insulin-like growth factor binding protein A61K38/1754
• CPC Class Codes: A61K 38/39 Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
• CPC Class Codes: A61K 38/4886 Metalloendopeptidases (3.4.24), e.g. collagenase
• CPC Class Codes: A61K 38/51 Lyases (4)
• CPC Class Codes: A61L 27/26 Mixtures of macromolecular compounds
• CPC Class Codes: A61L 27/52 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 27/56 Porous materials, e.g. foams or sponges
• CPC Class Codes: A61L 27/58 Materials at least partially resorbable by the body
• CPC Class Codes: C08L 5/08 Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
• CPC Class Codes: C08L 67/04 Polyesters derived from hydroxycarboxylic acids, e.g. lactones C08L67/06 takes precedence

Abstract

A synthetic, flexible tissue matrix and methods for repairing hyaline cartilage defects in a joint using the flexible tissue matrix are described. The flexible tissue matrix includes a high molecular weight polycaprolactone polymer entangled with a polysaccharide such as hyaluronic acid. In the methods, autologous bone mesenchymal stem cells are introduced to a joint by a microfracturing technique, and a membrane made of the flexible matrix is applied to the joint. Cartilage which forms in the joint is hyaline cartilage rather than fibrocartilage.

Claims

1. A tissue matrix for supporting repair of biological tissues comprising total polymers comprising a caprolactone polymer and at least one additional polyester polymer other than a caprolactone polymer which is not copolymerized with the caprolactone polymer, wherein the total polymers are entangled with a polysaccharide following combination of the total polymers and the polysaccharide in a dual solvent emulsion, said dual solvent emulsion being formed by the steps of:

i. dissolving the total polymers in an organic solvent;

ii. dissolving the polysaccharide in an aqueous solvent;

iii. blending the total polymers in the organic solvent with the polysaccharide in an aqueous solvent to form the dual solvent emulsion; and

iv. removing the organic solvent and aqueous solvent from the emulsion to form a flexible matrix comprising the total polymer molecules entangled with polysaccharide polymer molecules;

wherein the weight ratio of the polyester polymer to the caprolactone polymer ranges from about 1;

1 to about 4;

1.

2. A tissue matrix according to claim 1, wherein the caprolactone polymer is selected from polycaprolactone;

a co-polymer of polylactic acid and polycaprolactone;

a co-polymer of polyglycolic acid and polycaprolactone;

a copolymer of polylactic acid, polyglycolic acid, and polycaprolactone;

a co-polymer of polyethylene glycol, polylactic acid and polycaprolactone;

a co-polymer of polyethylene glycol, polyglycolic acid and polycaprolactone; and

a copolymer of polyethylene glycol, polylactic acid, polyglycolic acid, and polycaprolactone.

3. A tissue matrix according to claim 2 comprising a co-polymer selected from a copolymer of polylactic acid and polycaprolactone;

a co-polymer of polyglycolic acid and polycaprolactone;

a copolymer of polylactic acid, polyglycolic acid and polycaprolactone;

a co-polymer of polyethylene glycol, polylactic acid and polycaprolactone;

a co-polymer of polyethylene glycol, polyglycolic acid and polycaprolactone; and

a copolymer of polyethylene glycol, polylactic acid, polyglycolic acid, and polycaprolactone.

4. A tissue matrix according to claim 1 further comprising at least one flexibility agent.

5. A tissue matrix according to claim 4, wherein the weight ratio of caprolactone polymer to flexibility agent is 9:

1 to 99;

1.

6. A tissue matrix according to claim 4, wherein the flexibility agent is selected from the group consisting of triethyl citrate, acetyl tributyl citrate, acetyl triethyl citrate, tributyl citrate, trimethyl citrate, trihexyl citrate, acetyl trihexyl citrate, trioctyl citrate, acetyl trioctyl citrate and any combination thereof.

7. A tissue matrix according to claim 4, wherein the flexibility agent is selected from the group consisting of polyethylene glycol, polyethylene glycol monoalkyl ether, propylene glycol, glycerin, triacetin and any combination thereof.

8. A tissue matrix according to claim 3 comprising a copolymer of polylactic acid and polycaprolactone, wherein the weight ratio of polylactic acid to polycaprolactone is about 95:

5 to 1;

9.

9. A tissue matrix according to claim 3 comprising a copolymer of polylactic acid and polycaprolactone, wherein the weight ratio of polylactic acid to polycaprolactone is about 7:

3.

10. A tissue matrix according to claim 1, wherein the at least one additional polyester polymer other than a caprolactone polymer is selected from polylactic acid, polyglycolic acid, and a copolymer of polylactic acid and polyglycolic acid, which is not copolymerized with the caprolactone polymer.

11. A tissue matrix according to claim 10, wherein the caprolactone polymer comprises a copolymer of polyglycolic acid and polycaprolactone, and wherein the second polymer is polylactic acid.

12. A tissue matrix according to claim 11, wherein the weight ratio of the polylactic acid to the copolymer of polyglycolic acid and polycaprolactone is about 1:

1 to about 4;

1.

13. A tissue matrix according to claim 10 further comprising at least one flexibility agent.

14. A tissue matrix according to claim 13, wherein the polylactic acid and the copolymer of polyglycolic acid and polycaprolactone combined have a total polymer weight, and the weight ratio of the total polymer weight polymer to flexibility agent is 9:

1 to 99;

1.

15. A tissue matrix according to claim 13, wherein the flexibility agent is selected from the group consisting of triethyl citrate, acetyl tributyl citrate, acetyl triethyl citrate, tributyl citrate, trimethyl citrate, trihexyl citrate, acetyl trihexyl citrate, trioctyl citrate, acetyl trioctyl citrate and any combination thereof.

16. A tissue matrix according to claim 13, wherein the flexibility agent is selected from the group consisting of polyethylene glycol, polyethylene glycol monoalkyl ether, propylene glycol, glycerin, triacetin and any combination thereof.

17. A tissue matrix according to claim 1, wherein the polysaccharide comprises hyaluronic acid polymers.

18. A tissue matrix according to claim 17, wherein the hyaluronic acid polymers are oxidized.

19. A tissue matrix according to claim 17, wherein the hyaluronic acid polymers are covalently cross linked.

20. A tissue matrix according to claim 17, wherein the caprolactone polymer and the hyaluronic acid polymers are present in a weight ratio of from 99:

1 to 1;

99.

21. A tissue matrix according to claim 17, wherein the total polymers and the hyaluronic acid polymers are present in a weight ratio from 5:

1 to 10;

1.

22. A tissue matrix according to claim 1, characterized by retention of flexibility, compressive resistance and conformability when manipulated at temperatures of about (15 to 20°

C.), and the ability to support the growth of cells in vivo or ex vivo.

23. A tissue matrix according to claim 1, further comprising at least one growth factor.

24. A tissue matrix according to claim 23, wherein the at least one growth factor comprises a bone morphogenetic protein.

25. A tissue matrix according to claim 23, wherein the at least one growth factor is an isolated growth factor previously isolated from allogenic bone.

26. A tissue matrix according to claim 23, wherein the at least one growth factor is selected from the group consisting of basic fibroblast growth factor (bFGF), transforming growth factor (TGF-β

), BMP-2, ADMP-1, a hedgehog protein, an insulin-like growth factor, a platelet-derived growth factor, an interleukin, a colony-stimulating factor, and an activin.

27. A tissue matrix according to claim 1, further comprising a type I collagen or a type II collagen.

28. A tissue matrix according to claim 1, combined at a defect site in a joint with a demineralized bone matrix (DBM) composition.

29. A tissue matrix according to claim 1, combined at a defect site in a joint with crushed bone.

30. A tissue matrix according to claim 1, combined at a defect site in a joint with allogenic bone.

31. A membrane comprising the tissue matrix of claim 1.

32. A membrane according to claim 31 having a thickness of at least about 0.5 mm up to about 3 mm.