# US 10,245,306 B2 · Flexible tissue matrix and methods for joint repair

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 10,245,306 B2
- Document ID: US10245306B2
- Status: Granted
- Kind: B2
- Application number: 13/837,849
- Filed: 2013-03-15
- Published: 2014-05-22
- Granted: 2019-04-02
- Earliest claimed: 2012-11-16
- Assignees: Isto Technologies II, LLC
- Applicants: ISTO Technologies, Inc.
- Inventors: Mitchell S. Seyedin; Anthony J. Ward; Matthew Matava
- Web page: https://patentgrep.com/patent/US10245306B2

## CPC

- A61K 38/51: Lyases (4)
- A61K 38/18: Growth factors; Growth regulators
- A61K 38/1825: {Fibroblast growth factor [FGF]}
- A61K 38/1841: {Transforming growth factor [TGF]}
- A61K 38/1858: {Platelet-derived growth factor [PDGF]}
- A61K 38/1875: {Bone morphogenic factor; Osteogenins; Osteogenic factor; Bone-inducing factor}
- A61K 38/193: {Colony stimulating factors [CSF]}
- A61K 38/20: Interleukins [IL]
- A61K 38/30: Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2 {(insulin-like growth factor binding protein A61K38/1754)}
- A61K 38/39: Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
- A61K 38/4886: {Metalloendopeptidases (3.4.24), e.g. collagenase}
- A61L 27/26: Mixtures of macromolecular compounds
- A61L 27/52: Hydrogels or hydrocolloids
- A61L 27/56: Porous materials, {e.g. foams or sponges}
- A61L 27/58: Materials at least partially resorbable by the body
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61L: METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES (preservation of bodies or disinfecting characterised by the agents employed A01N; preserving, e.g. sterilising, food or foodstuffs A23; preparations for medical, dental or toiletry purposes A61K)

## 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

### Claim 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.

### Claim 2 (depends on 1)

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.

### Claim 3 (depends on 2)

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.

### Claim 4 (depends on 1)

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

### Claim 5 (depends on 4)

A tissue matrix according to claim 4, wherein the weight ratio of caprolactone polymer to flexibility agent is 9:1 to 99:1.

### Claim 6 (depends on 4)

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.

### Claim 7 (depends on 4)

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.

### Claim 8 (depends on 3)

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.

### Claim 9 (depends on 3)

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.

### Claim 10 (depends on 1)

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.

### Claim 11 (depends on 10)

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.

### Claim 12 (depends on 11)

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.

### Claim 13 (depends on 10)

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

### Claim 14 (depends on 13)

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.

### Claim 15 (depends on 13)

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.

### Claim 16 (depends on 13)

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.

### Claim 17 (depends on 1)

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

### Claim 18 (depends on 17)

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

### Claim 19 (depends on 17)

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

### Claim 20 (depends on 17)

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.

### Claim 21 (depends on 17)

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.

### Claim 22 (depends on 1)

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.

### Claim 23 (depends on 1)

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

### Claim 24 (depends on 23)

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

### Claim 25 (depends on 23)

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

### Claim 26 (depends on 23)

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.

### Claim 27 (depends on 1)

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

### Claim 28 (depends on 1)

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

### Claim 29 (depends on 1)

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

### Claim 30 (depends on 1)

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

### Claim 31 (depends on 1)

A membrane comprising the tissue matrix of claim 1.

### Claim 32 (depends on 31)

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