Photocrosslinked biodegradable hydrogel

• US 9,642,914 B2
• Filed: 08/31/2012
• Issued: 05/09/2017
• Est. Priority Date: 12/30/2008
• Status: Active Grant

• Current Assignee: Case Western Reserve University
• Original Assignee: Case Western Reserve University
• Inventors: Alsberg, Eben, Jeon, Oju
• Primary Examiner(s): Pallay, Michael B
• Application Number:
  US13/600,715
• Publication Number:
  US 20130230493A1
• Time in Patent Office: 1,712 Days
• CPC Class Codes: A61K 35/32 Bones; Osteocytes; Osteoblasts; Tendons; Tenocytes; Teeth; Odontoblasts; Cartilage; Chondrocytes; Synovial membrane
• CPC Class Codes: A61K 38/1825 Fibroblast growth factor [FGF]
• CPC Class Codes: A61K 38/1841 Transforming growth factor [TGF]
• CPC Class Codes: A61K 38/1866 Vascular endothelial growth factor [VEGF]
• CPC Class Codes: A61K 38/1875 Bone morphogenic factor; Osteogenins; Osteogenic factor; Bone-inducing factor
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61L 27/38 containing added animal cells organs or tissue containing native cells A61L27/36
• CPC Class Codes: A61L 27/3817 Cartilage-forming cells, e.g. pre-chondrocytes
• CPC Class Codes: A61L 27/52 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 27/58 Materials at least partially resorbable by the body
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C08J 2300/16 Biodegradable polymers
• CPC Class Codes: C08J 2305/04 Alginic acid; Derivatives thereof
• CPC Class Codes: C08J 2305/10 Heparin; Derivatives thereof
• CPC Class Codes: C08J 3/075 Macromolecular gels
• CPC Class Codes: C08J 3/24 Crosslinking, e.g. vulcanising, of macromolecules mechanical aspects B29C35/00; crosslinking agents C08K
• CPC Class Codes: C08J 3/28 Treatment by wave energy or particle radiation
• CPC Class Codes: C08K 5/175 containing COOH-groups; Esters or salts thereof

Abstract

A photocrosslinked biodegradable hydrogel includes a plurality of natural polymer macromers cross-linked with a plurality of hydrolyzable acrylate cross-links. The hydrogel is cytocompatible and produces substantially non-toxic products upon degradation.

Claims

1. A photocrosslinked biodegradable hydrogel comprising:

a plurality of alginate and heparin macromers cross-linked with a plurality of hydrolyzable acrylate cross-links that can be hydrolyzed in vivo, at least one cell dispersed within or on the photocrosslinked biodegradable hydrogel, and a bioactive agent that modulates a function and/or characteristic of the cell, the hydrogel being cytocompatible and, upon degradation, producing substantially non-toxic products.

2. The photocrosslinked biodegradable hydrogel of claim 1, each of the hydrolyzable acrylate cross-links comprising at least one of a hydrolyzable ester or hydrolyzable amide.

3. The photocrosslinked biodegradable hydrogel of claim 1 further including at least one attachment molecule coupling the at least one cell to the photocrosslinked biodegradable hydrogel.

4. The photocrosslinked biodegradable hydrogel of claim 1, release of the bioactive agent from the hydrogel being dependent on the degradation rate of the hydrogel, diffusion rate of the bioactive agent, and/or affinity interactions between the bioactive agent and a component of the hydrogel.

5. The photocrosslinked biodegradable hydrogel of claim 1 further including a separate carrier material dispersed on or within the hydrogel, the carrier material including the bioactive agent for modulating a function and/or characteristic of a cell.

6. The photocrosslinked biodegradable hydrogel of claim 1, the hydrogel further comprising calcium phosphate or polymer microparticles or nanoparticles.

7. The photocrosslinked biodegradable hydrogel of claim 1, wherein the cross-links are provided in at least one concentration gradient in the hydrogel to define at least one gradient release profile bioactive agents in the hydrogel.

8. A photocrosslinked biodegradable hydrogel comprising:

a plurality of natural polymer macromers cross-linked with a plurality of cross-links that are degradable in vivo, at least one cell dispersed within or on the photocrosslinked biodegradable hydrogel, and a bioactive agent that modulates a function and/or characteristic of the cell, the hydrogel being cytocompatible and upon degradation, producing substantially non-toxic products, wherein the cross-links are provided in at least one concentration gradient in the hydrogel to define at least one gradient release profile bioactive agents in the hydrogel.

9. The photocrosslinked biodegradable hydrogel of claim 8, the cross-links being degradable by hydrolysis of the cross-links.

10. The photocrosslinked biodegradable hydrogel of claim 8, the cross-links comprising hydrolyzable acrylate cross-links.

11. The photocrosslinked biodegradable hydrogel of claim 10, each of the hydrolyzable cross-links comprising at least one of a hydrolyzable ester or hydrolyzable amide.

12. The photocrosslinked biodegradable hydrogel of claim 11, each of the hydrolyzable cross-links having Formula I:

13. The photocrosslinked biodegradable hydrogel of claim 11, each of the hydrolyzable cross-links comprising a hydrolyzable methacrylate cross-link having Formula II:

14. The photocrosslinked biodegradable hydrogel of claim 12, each of R₁ and R₂ comprising an alginate main chain.

15. The photocrosslinked biodegradable hydrogel of claim 13, R₁ comprising an alginate main chain and R₂ comprising a heparin main chain.

16. The photocrosslinked biodegradable hydrogel of claim 8, the at least one cell comprising a progenitor cell.

17. The photocrosslinked biodegradable hydrogel of claim 8 further including at least one attachment molecule coupling the at least one cell to the photocrosslinked biodegradable hydrogel.

18. The photocrosslinked biodegradable hydrogel of claim 17, the at least one attachment molecule being acrylated or methacrylated.

19. The photocrosslinked biodegradable hydrogel of claim 8, the bioactive agent including any agent capable of regulating a cell behavior and/or targeting a specific disease state.

20. The photocrosslinked biodegradable hydrogel of claim 8, release of the bioactive agent from the hydrogel being dependent on the degradation rate of the hydrogel, diffusion rate of the bioactive agent, and/or affinity interactions between the bioactive agent and a component of the hydrogel.

21. The photocrosslinked biodegradable hydrogel of claim 8 further including a separate carrier material dispersed on or within the hydrogel, the carrier material including the bioactive agent for modulating a function and/or characteristic of a cell.

22. The photocrosslinked biodegradable hydrogel of claim 8, the hydrogel further comprising calcium phosphate or polymer microparticles or nanoparticles.

23. A photocrosslinked biodegradable hydrogel comprising:

a plurality of natural polymer macromers cross-linked with a plurality of cross-links that are degradable in vivo, a plurality of cells within or on the photocrosslinked biodegradable hydrogel, a bioactive agent that modulates a function and/or characteristic of the cells, and at least one acrylated or methacrylated attachment molecule coupling the cells to the photocrosslinked biodegradable hydrogel, the hydrogel being cytocompatible and upon degradation, producing substantially non-toxic products.

24. The photocrosslinked biodegradable hydrogel of claim 23, the cross-links being degradable by hydrolysis of the cross-links.

25. The photocrosslinked biodegradable hydrogel of claim 23, the cross-links comprising hydrolyzable acrylate cross-links.

26. The photocrosslinked biodegradable hydrogel of claim 25, each of the hydrolyzable cross-links comprising at least one of a hydrolyzable ester or hydrolyzable amide.

27. The photocrosslinked biodegradable hydrogel of claim 25, each of the hydrolyzable cross-links having Formula I:

28. The photocrosslinked biodegradable hydrogel of claim 26, each of the hydrolyzable cross-links comprising a hydrolyzable methacrylate cross-link having Formula II:

29. The photocrosslinked biodegradable hydrogel of claim 28, each of R₁ and R₂ comprising an alginate main chain.

30. The photocrosslinked biodegradable hydrogel of claim 28, R₁ comprising an alginate main chain and R₂ comprising a heparin main chain.

31. The photocrosslinked biodegradable hydrogel of claim 23, the cells comprising progenitor cells.

32. The photocrosslinked biodegradable hydrogel of claim 23, the bioactive agent including any agent capable of regulating a cell behavior and/or targeting a specific disease state.

33. The photocrosslinked biodegradable hydrogel of claim 23, release of the bioactive agent from the hydrogel being dependent on the degradation rate of the hydrogel, diffusion rate of the bioactive agent, and/or affinity interactions between the bioactive agent and a component of the hydrogel.

34. The photocrosslinked biodegradable hydrogel of claim 23 further including a carrier material dispersed on or within the hydrogel, the carrier material including the bioactive agent for modulating a function and/or characteristic of a cell.

35. The photocrosslinked biodegradable hydrogel of claim 23, the hydrogel further comprising calcium phosphate or polymer microparticles or nanoparticles.