Strain-Promoted Crosslinking of PEG-based Hydrogels via Copper-Free Cycloaddition

• US 20150183988A1
• Filed: 07/31/2013
• Published: 07/02/2015
• Est. Priority Date: 07/31/2012
• Status: Active Grant

• Current Assignee: University of Akron
• Original Assignee: University of Akron
• Inventors: Becker, Matthew, Weiss, Robert A.
• Granted Patent: US 9,758,671 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: C08G 65/325 containing nitrogen
• CPC Class Codes: C08G 65/33389 aromatic
• CPC Class Codes: C08L 2205/02 containing two or more polymers of the same C08L -group
• CPC Class Codes: C08L 71/00 Compositions of polyethers obtained by reactions forming an ether link in the main chain of polyacetals C08L59/00; of epoxy resins C08L63/00; of polythioether-ethers C08L81/02; of polyether-sulfones C08L81/06; Compositions of derivatives of such polymers
• CPC Class Codes: C08L 71/02 Polyalkylene oxides
• CPC Class Codes: C08L 89/00 Compositions of proteins; Compositions of derivatives thereof foodstuff preparations A23J3/00

Abstract

The present invention is directed to a covalently crosslinked hydrogel comprising the strain-promoted reaction product of an 8-member cycloalkyne functionalized polyalkylene glycol and a multi-arm glycerol exytholate triazide and methods for making them. Because the precursor materials can be manipulated without causing crosslinking, provided the strain threshold is not reached, these hydrogels permit mechanical control over when (and where) cross linking occurs and are easier to use than prior strain-activated or temperature-activated systems. These novel hydrogels do not require a catalyst to cross link, thus avoiding the biocompatibility problems common to many catalysts. Nor is the crosslinking process affected by the presence of catalysts or other substances, which have interfered with crosslinking in known strain induced hydrogels. Because of their crosslinking reaction kinetics, these novel hydrogels can encapsulate and transport highly sensitive cells and other biological additives and have no known toxic byproducts.

Claims

1. A covalently crosslinked hydrogel comprising the strain-promoted reaction product of an 8-member cycloalkyne functionalized polyalkylene glycol and a multi-arm glycerol exytholate triazide.

2. The covalently crosslinked hydrogel of claim 1 wherein said 8-member cycloalkyne functionalized polyalkylene glycol is a polymer selected from the group consisting of polyethylene glycol, polypropylene glycol and combinations thereof.

3. The covalently crosslinked hydrogel of claim 1 wherein said 8-member cycloalkyne functionalized polyalkylene glycol has a molecular mass from about 500 Da to about 12000 Da.

4. The covalently crosslinked hydrogel of claim 1 wherein said 8-member cycloalkyne functionalized polyalkylene glycol is dibenzylcyclooctyne functionalized polyethylene glycol.

5. The covalently crosslinked hydrogel of claim 4 wherein said 8-member cycloalkyne functionalized polyalkylene glycol is an aqueous solution comprising from about 1% to about 40% weight percent dibenzylcyclooctyne functionalized polyethylene glycol.

7. The covalently crosslinked hydrogel of claim 1 wherein said multi-arm glycerol exytholate triazide is a glycerol exytholate triazide having from 2 to 5 arms.

9. The covalently crosslinked hydrogel of claim 1 wherein said multi-arm glycerol exytholate triazide is an aqueous solution comprising from about 1% to about 40% weight percent of a 3-arm glycerol exytholate triazide.

11. The covalently crosslinked hydrogel of claim 3 wherein said covalently crosslinked hydrogel is formed by the strain-promoted cycloaddition of said dibenzylcyclooctyne functionalized polyethylene glycol and said multi-arm glycerol exytholate triazide.

13. The covalently crosslinked hydrogel of claim 1 wherein said covalently crosslinked hydrogel is formed by the strain-promoted cycloaddition of a dibenzylcyclooctyne functionalized polyethylene glycol and a 3-arm glycerol exytholate triazide.

14. The covalently crosslinked hydrogel of claim 4 wherein said is dibenzylcyclooctyne functionalized polyethylene glycol has a mass average molecular weight of from about 1,000 to about 20,000.

15. The covalently crosslinked hydrogel of claim 1 having a crosslink density of from about 2 to about 300 mol/m³.

17. The covalently crosslinked hydrogel of claim 1 having a loss factor (tan δ

) of from about 0.10 to about 0.50.

19. The covalently crosslinked hydrogel of claim 1 further comprising an additive selected from the group consisting of cells, collagen, deceullarized tissue, gelatin and combinations thereof.

20. The covalently crosslinked hydrogel of claim 19 wherein said additive is encapsulated with said covalently crosslinked hydrogel.

23. The covalently crosslinked hydrogel of claim 1 wherein said covalently crosslinked hydrogel is from about 40% to about 99.9% water.

25. The covalently crosslinked hydrogel of claim 4 wherein said dibenzylcyclooctyne functionalized polyethylene glycol has the following formula:

26. The covalently crosslinked hydrogel of claim 25 wherein n is 6 or 7.

27. The covalently crosslinked hydrogel of claim 7 wherein said multi-arm glycerol exytholate triazide comprises a 3-arm glycerol exytholate triazide having the formula:

28. The covalently crosslinked hydrogel of claim 1 having the formula:

29. A method of making the covalently crosslinked hydrogel of claim 1, comprising:

A. preparing an aqueous solution containing a 8-member cycloalkyne functionalized polyalkylene glycol;

B. preparing an aqueous solution containing a multi-arm glycerol exytholate triazide; and

C. combining the solution of step A with the solution of step B; and

D. applying a strain to the mixture of step C until covalent crosslinks form between said 8-member cycloalkyne functionalized polyalkylene glycol and said multi-arm glycerol exytholate triazide.

30. The method of claim 29, wherein said 8-member cycloalkyne functionalized polyalkylene glycol is a polymer selected from the group consisting of polyethylene glycols, polypropylene glycols and combinations thereof.

32. The method of claim 29, wherein said 8-member cycloalkyne functionalized polyalkylene glycol is dibenzylcyclooctyne functionalized polyethylene glycol.

33. The method of claim 29, wherein the aqueous solution of Step A contains from about 1% to about 40% weight percent of said 8-member cycloalkyne functionalized polyalkylene glycol.

35. The method of claim 29, wherein said multi-arm glycerol exytholate triazide is a glycerol exytholate triazide having from 2 to 5 arms.

37. The method of claim 29, wherein the aqueous solution of Step B contains from about 1% to about 40% weight percent of said multi-arm glycerol exytholate triazide.

39. The method of claim 32, wherein said dibenzylcyclooctyne functionalized polyethylene glycol has a mass average molecular weight of from about 1,000 to about 20,000.

40. The method of claim 29, further comprising the step of introducing the mixture of step C into a living organism, prior to step D.

43. The method of claim 40, wherein step D occurs in vivo.

46. The method of claim 29, wherein the mixture of step C has a loss factor (tan δ

) greater than or equal to about 1.0.

48. The method of claim 29, further comprising the step of adding an additive selected from the group consisting of cells, collagen, decellularized tissue, gelatin and combinations thereof into one or more of the aqueous solution of step A or the aqueous solution of step B.

49. The method of claim 48, wherein said additive is encapsulated with said covalently crosslinked hydrogel.

52. The method of claim 29, wherein the strain applied in step D is an oscillatory shear strain of from 5% to 15%.

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