Method and material for enhanced tissue-biomaterial integration

• US 7,897,165 B2
• Filed: 03/07/2006
• Issued: 03/01/2011
• Est. Priority Date: 09/25/2002
• Status: Active Grant

• Current Assignee: Synthasome, Inc.
• Original Assignee: Synthasome, Inc.
• Inventors: Ratcliffe, Anthony, Elisseeff, Jennifer, Wang, Dong-an
• Primary Examiner(s): Weber; Jon P
• Assistant Examiner(s): SCHUBERG, LAURA J
• Application Number:
  US11/369,578
• Publication Number:
  US 20070048291A1
• Time in Patent Office: 1,820 Days
• Field of Search: None
• US Class Current: 424/423
• CPC Class Codes: A61K 35/32 Bones; Osteocytes; Osteoblasts; Tendons; Tenocytes; Teeth; Odontoblasts; Cartilage; Chondrocytes; Synovial membrane
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61L 24/0005 Ingredients of undetermined constitution or reaction products thereof
• CPC Class Codes: A61L 24/0031 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 27/3604 characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
• CPC Class Codes: A61L 27/3616 Blood, e.g. platelet-rich plasma
• CPC Class Codes: A61L 27/3633 Extracellular matrix [ECM]
• CPC Class Codes: A61L 27/3683 subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
• CPC Class Codes: A61L 27/3687 characterised by the use of chemical agents in the treatment, e.g. specific enzymes, detergents, capping agents, crosslinkers, anticalcification agents
• CPC Class Codes: A61L 27/3691 characterised by physical conditions of the treatment, e.g. applying a compressive force to the composition, pressure cycles, ultrasonic/sonication or microwave treatment, lyophilisation
• CPC Class Codes: A61L 27/38 containing added animal cells organs or tissue containing native cells A61L27/36
• CPC Class Codes: A61L 27/50 Materials characterised by their function or physical properties , e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• CPC Class Codes: A61L 27/52 Hydrogels or hydrocolloids
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: C12N 2533/30 Synthetic polymers
• CPC Class Codes: C12N 5/0062 General methods for three-dimensional culture
• CPC Class Codes: C12N 5/0655 Chondrocytes; Cartilage
• CPC Class Codes: C12N 5/0697 Artificial constructs associating cells of different lineages, e.g. tissue equivalents blood vessels C12N5/0691

Abstract

The present invention relates to the covalent binding of a hydrogel to an extracellular matrix (ECM). The integration of the hydrogel with the tissue is superior to that in previous techniques. Moreover, unlike previous techniques, the present invention does not require a photoinitiator. Potential therapeutic applications include tissue repair and delivery of drugs or cells.

The ECM is first exposed, then treated with a priming agent. Then a polymerizable agent is added and crosslinked to the ECM.

Two primary embodiments of methods are disclosed. In the first, the priming agent is an oxidizer which creates tyrosyl radicals in the ECM, which are then bound by acrylate groups in the polymerizable agent. In the second, the priming agent contains aldehydes which bind amino groups in the ECM.

Claims

1. A method of integrating a hydrogel to the extracellular matrix of a bone, comprising the steps of:

(a) priming the surface of a bone by treating the bone with a priming agent to create a primed bone, wherein the priming agent comprises a polysaccharide with at least one produced aldehyde group and a first at least one free radical polymerizable group wherein the aldehyde is produced by treating said polysaccharide with periodate, and the least one produced aldehyde group reacts with the extracellular matrix of the bone to covalently bind the extracellular matrix of the bone and the priming agent;

(b) adding to the primed bone a polymerizable agent, wherein the polymerizable agent comprises a second at least one free radical polymerizable group; and

(c) reacting the primed bone and the polymerizable agent by a radical reaction to create a hydrogel covalently bound to the bone;

wherein the radical reaction is between the first and second free radical polymerizable groups, and the first and second free radical polymerizable groups are each independently selected from the group consisting of an acrylate, diacrylate, oligoacrylate, methacrylate, dimethacrylate, and oligo methacrylate.

2. The method of claim 1, wherein said bone is disposed in a mammal.

3. The method of claim 1, wherein the polysaccharide is chondroitin sulfate.

4. The method of claim 1, wherein said reacting step further comprises exposing said primed bone and said polymerizable agent to ultraviolet radiation.

5. The method of claim 1, wherein the polymerizable agent comprises biologically active material.

6. The method of claim 5, wherein the biologically active material comprises autologous cells.

7. The method of claim 5, wherein the biologically active material comprises a growth factor.

8. A hydrogel produced by a method comprising:

(a) priming the surface of a bone by treating the bone with a priming agent comprising a polysaccharide with at least one produced aldehyde group and a first at least one free radical polymerizable group wherein the aldehyde is produced by treating said polysaccharide with periodate, to create a primed bone, wherein the least one produced aldehyde group reacts with the extracellular matrix of the bone to covalently bind the extracellular matrix of the bone and the priming agent;

(b) adding to the primed bone a polymerizable agent, wherein the polymerizable agent comprises a second at least one free radical polymerizable group; and

(c) reacting the primed bone and the polymerizable agent by a radical reaction to create a hydrogel covalently bound to the bone;

wherein the radical reaction is between the first and second free radical polymerizable groups, and the first and second free radical polymerizable groups are each independently selected from the group consisting of an acrylate, diacrylate, oligoacrylate, methacrylate, dimethacrylate, and oligo methacrylate.

9. The hydrogel of claim 8, wherein said bone is disposed in a mammal.

10. The hydrogel of claim 8, wherein the polysaccharide is chondroitin sulfate.

11. The hydrogel of claim 8, wherein said reacting further comprises exposing said primed bone and said polymerizable agent to ultraviolet radiation.

12. The hydrogel of claim 8, wherein the polymerizable agent comprises biologically active material.

13. The hydrogel of claim 12, wherein the biologically active material comprises autologous cells.

14. The hydrogel of claim 12, wherein the biologically active material comprises a growth factor.

15. A method of integrating a hydrogel to the extracellular matrix of an osteochondral defect, comprising the steps of:

(a) priming the surface of an osteochondral defect by treating the osteochondral defect with a priming agent to create a primed osteochondral defect, wherein the priming agent comprises a polysaccharide with at least one produced aldehyde group and a first at least one free radical polymerizable group wherein the aldehyde is produced by treating said polysaccharide with periodate, and the least one produced aldehyde group reacts with the extracellular matrix of the osteochondral defect to covalently bind the extracellular matrix of the osteochondral defect and the priming agent;

(b) adding to the primed osteochondral defect a polymerizable agent, wherein the polymerizable agent comprises a second at least one free radical polymerizable group; and

(c) reacting the primed osteochondral defect and the polymerizable agent by a radical reaction to create a hydrogel covalently bound to the osteochondral defect;

wherein the radical reaction is between the first and second free radical polymerizable groups, and the first and second free radical polymerizable groups are each independently selected from the group consisting of an acrylate, diacrylate, oligoacrylate, methacrylate, dimethacrylate, and oligo methacrylate.

16. The method of claim 15, wherein said osteochondral defect is disposed in a mammal.

17. The method of claim 15, wherein the polysaccharide is chondroitin sulfate.

18. The method of claim 15, wherein said reacting step further comprises exposing said primed osteochondral defect and said polymerizable agent to ultraviolet radiation.

19. The method of claim 15, wherein the polymerizable agent comprises biologically active material.

20. The method of claim 19, wherein the biologically active material comprises autologous cells.

21. The method of claim 19, wherein the biologically active material comprises a growth factor.

22. A hydrogel produced by a method comprising:

(a) priming the surface of an osteochondral defect by treating the osteochondral defect with a priming agent comprising a polysaccharide with at least one produced aldehyde group and a first at least one free radical polymerizable group wherein the aldehyde is produced by treating said polysaccharide with periodate, to create a primed osteochondral defect, wherein the least one produced aldehyde group reacts with the extracellular matrix of the osteochondral defect to covalently bind the extracellular matrix of the osteochondral defect and the priming agent;

(b) adding to the primed osteochondral defect a polymerizable agent, wherein the polymerizable agent comprises a second at least one free radical polymerizable group; and

(c) reacting the primed osteochondral defect and the polymerizable agent by a radical reaction to create a hydrogel covalently bound to the osteochondral defect;

wherein the radical reaction is between the first and second free radical polymerizable groups, and the first and second free radical polymerizable groups are each independently selected from the group consisting of an acrylate, diacrylate, oligoacrylate, methacrylate, dimethacrylate, and oligo methacrylate.

23. The hydrogel of claim 22, wherein said osteochondral defect is disposed in a mammal.

24. The hydrogel of claim 22, wherein the polysaccharide is chondroitin sulfate.

25. The hydrogel of claim 22, wherein said reacting further comprises exposing said primed osteochondral defect and said polymerizable agent to ultraviolet radiation.

26. The hydrogel of claim 22, wherein the polymerizable agent comprises biologically active material.

27. The hydrogel of claim 26, wherein the biologically active material comprises autologous cells.

28. The hydrogel of claim 26, wherein the biologically active material comprises a growth factor.