Dendritic macroporous hydrogels prepared by crystal templating

• US 8,668,863 B2
• Filed: 02/26/2009
• Issued: 03/11/2014
• Est. Priority Date: 02/26/2008
• Status: Active Grant

• Current Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Original Assignee: Board of Regents of the University of Texas System (University of Texas System)
• Inventors: Zawko, Scott, Schmidt, Christine E.
• Primary Examiner(s): Soroush, Ali
• Application Number:
  US12/919,667
• Publication Number:
  US 20110008442A1
• Time in Patent Office: 1,839 Days
• Field of Search: 264/413, 264/425
• US Class Current: 264/413
• CPC Class Codes: A61L 26/0023 Polysaccharides
• CPC Class Codes: A61L 26/0095 Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
• CPC Class Codes: A61L 27/52 Hydrogels or hydrocolloids
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: B01J 13/0065 containing an organic phase
• CPC Class Codes: C08B 37/0015 Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes
• CPC Class Codes: C08B 37/003 Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof
• CPC Class Codes: C08B 37/0045 alpha-D-Galacturonans, e.g. methyl ester of (alpha-1,4)-linked D-galacturonic acid units, i.e. pectin, or hydrolysis product of methyl ester of alpha-1,4-linked D-galacturonic acid units, i.e. pectinic acid; Derivatives thereof
• CPC Class Codes: C08B 37/0072 Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
• CPC Class Codes: C08B 37/0075 Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
• CPC Class Codes: C08B 37/0084 Guluromannuronans, e.g. alginic acid, i.e. D-mannuronic acid and D-guluronic acid units linked with alternating alpha- and beta-1,4-glycosidic bonds; Derivatives thereof, e.g. alginates
• CPC Class Codes: C08H 1/06 derived from horn, hoofs, hair, skin or leather
• CPC Class Codes: C08J 2201/0424 containing halogen, nitrogen, sulphur or phosphorus atoms
• CPC Class Codes: C08J 2205/022 Hydrogel, i.e. a gel containing an aqueous composition
• CPC Class Codes: C08J 2205/04 characterised by the foam pores
• CPC Class Codes: C08J 2207/10 Medical applications, e.g. biocompatible scaffolds
• CPC Class Codes: C08J 2305/00 Characterised by the use of polysaccharides or of their derivatives not provided for in groups C08J2301/00 or C08J2303/00
• CPC Class Codes: C08J 2305/04 Alginic acid; Derivatives thereof
• CPC Class Codes: C08J 2305/08 Chitin; Chondroitin sulfate; Hyaluronic acid; 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 3/242 : Applying crosslinking or accelerating agent onto compounding ingredients such as fillers, reinforcements
• CPC Class Codes: C08J 3/26 : of latex
• CPC Class Codes: C08J 3/28 : Treatment by wave energy or particle radiation
• CPC Class Codes: C08J 5/10 : characterised by the additives used in the polymer mixture
• CPC Class Codes: C08J 5/18 : Manufacture of films or sheets
• CPC Class Codes: C08J 9/26 : by elimination of a solid phase from a macromolecular composition or article, e.g. leaching out
• CPC Class Codes: C08K 5/0025 : Crosslinking or vulcanising agents; including accelerators
• CPC Class Codes: C08K 5/0083 : Nucleating agents promoting the crystallisation of the polymer matrix
• CPC Class Codes: C08K 5/21 : Urea; Derivatives thereof, e.g. biuret
• CPC Class Codes: C08L 5/00 : Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
• CPC Class Codes: C08L 5/04 : Alginic acid; Derivatives thereof
• CPC Class Codes: C08L 5/06 : Pectin; Derivatives thereof
• CPC Class Codes: C08L 5/08 : Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
• CPC Class Codes: C08L 5/10 : Heparin; Derivatives thereof
• CPC Class Codes: C08L 5/16 : Cyclodextrin; Derivatives thereof
• CPC Class Codes: C08L 89/06 : derived from leather or skin , e.g. gelatin

Abstract

The present invention includes a hydrogel and a method of making a porous hydrogel by preparing an aqueous mixture of an uncrosslinked polymer and a crystallizable molecule; casting the mixture into a vessel; allowing the cast mixture to dry to form an amorphous hydrogel film; seeding the cast mixture with a seed crystal of the crystallizable molecule; growing the crystallizable molecule into a crystal structure within the uncrosslinked polymer; crosslinking the polymer around the crystal structure under conditions in which the crystal structure within the crosslinked polymer is maintained; and dissolving the crystals within the crosslinked polymer to form the porous hydrogel.

Claims

1. A method of making a porous hydrogel comprising:

preparing an aqueous mixture of an uncrosslinked polymer and a crystallizable molecule;

casting the mixture into a vessel to form a cast mixture;

drying the cast mixture to form an amorphous hydrogel film;

growing the crystallizable molecule into a crystal structure within the uncrosslinked polymer;

crosslinking the uncrosslinked polymer around the crystal structure under conditions in which the crystal structure within the crosslinked polymer is maintained; and

dissolving the crystal structure within the crosslinked polymer to form the porous hydrogel.

2. The method of claim 1, wherein the polymer comprises at least one of nucleic acids, amino acids, saccharides, lipids and combinations thereof, in monomeric, dimeric, trimeric, oligomeric, multimeric, or polymeric forms.

3. The method of claim 1, wherein the polymer includes a mixture of alginate and hyaluronic acid.

4. The method of claim 1, wherein the polymer is gelled by a chemical crosslink, a physical crosslink, or a combination thereof;

wherein said crosslink is induced by a UV method, a temperature method, a pH method, an ion, or ion-radical based method or combinations thereof.

5. The method of claim 1, wherein the crystallizable molecule comprises a small organic molecule selected from a salt, urea, beta cyclodextrin, glycine and guanidine.

6. The method of claim 1, wherein the crystallizable molecule comprises potassium dihydrogen phosphate.

7. The method of claim 1, further comprising adding a cross-linking agent to the mixture, the crosslinking agent selected from group consisting of p-Azidobenzoyl hydrazide, N-5-Azido-2-nitrobenzoyloxsuccinimide, disuccinimidyl glutamate, dimethyl pimelimidate-(2)HCl, dimethyl suberimidate-2HCl, disuccinimidyl suberate, bis[sulfosuccinimidyl suberate], 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide-HCl, isocyanate, aldehyde, glutaraldehyde, paraformaldehyde and derivatives thereof.

8. The method of claim 1, wherein the crystal structure forms a lattice structure and supports the polymer during the crosslinking step.

9. The method of claim 1, further comprising the step of seeding the crystallizable molecule.

10. The method of claim 1, wherein the step of growing occurs by spontaneous crystal formation.

11. The method of claim 1, wherein the step of growing occurs by spontaneous crystal formation during the step of drying the cast mixture.

26. The method of claim 1 wherein the porous hydrogel includes a tissue scaffold.

12. A method comprising:

growing a crystal structure within a hydrogel that includes an uncrosslinked polymer;

crosslinking the uncrosslinked polymer around the crystal structure under conditions in which the crystal structure within the crosslinked polymer is maintained; and

dissolving the crystal structure to form a porous hydrogel;

wherein the uncrosslinked polymer includes a mixture of alginate and hyaluronic acid.

13. The method of claim 12, wherein the crosslinking is induced by at least one of a UV, temperature, pH, ion, and ion-radical based method.

14. The method of claim 12, wherein the crystal structure includes at least one of a salt, urea, beta cyclodextrin, glycine, and guanidine.

15. The method of claim 12, wherein the crystal structure includes potassium dihydrogen phosphate.

16. The method of claim 12, wherein the crosslinking includes adding a cross-linking agent to the hydrogel, the crosslinking agent including at least one of p-Azidobenzoyl hydrazide, N-5-Azido-2-nitrobenzoyloxsuccinimide, disuccinimidyl glutamate, dimethyl pimelimidate-(2)HCl, dimethyl suberimidate-2HCl, disuccinimidyl suberate, bis[sulfosuccinimidyl suberate], 1-ethyl-3-[3-dimethylaminopropyl]carbodiimide-HCl, isocyanate, aldehyde, glutaraldehyde, paraformaldehyde, and derivatives thereof.

17. The method of claim 12, wherein the crystal structure forms a lattice structure and supports the polymer during the crosslinking.

18. The method of claim 12 comprising seeding the hydrogel with a crystal.

19. The method of claim 12 wherein growing the crystal structure occurs by spontaneous crystal formation.

20. The method of claim 12 including drying the hydrogel, wherein growing the crystal structure occurs by spontaneous crystal formation while drying the hydrogel.

21. The method of claim 12, wherein the porous hydrogel comprises:

first and second opposing ends;

a continuous pore network, connecting the first and second ends, including first and second pore portions parallel to one another; and

a compressed fiber including a ridge compressed between the first and second pore portions.

22. The method of claim 21, wherein the compressed fiber is included in a plurality of compressed fibers formed among alternating valleys and ridges.

23. The method of claim 12 wherein the crosslinking includes crosslinking the hyaluronic acid.

24. The method of claim 12 wherein the crosslinking includes crosslinking the alginate.

25. The method of claim 12 wherein the porous hydrogel includes a continuous pore network that is templated, in situ, by the crystal structure.

27. The method of claim 12 wherein the porous hydrogel includes a tissue scaffold.

28. A method of making a porous hydrogel comprising:

preparing an aqueous mixture of an uncrosslinked polymer and a crystallizable molecule;

drying the mixture to form a hydrogel film;

seeding the crystallizable molecule;

growing the crystallizable molecule into a crystal structure within the uncrosslinked polymer;

crosslinking the uncrosslinked polymer around the crystal structure under conditions in which the crystal structure within the crosslinked polymer is maintained; and

dissolving the crystal structure within the crosslinked polymer to form the porous hydrogel.

29. The method of claim 28, wherein the polymer comprises at least one of nucleic acids, amino acids, saccharides, lipids and combinations thereof.

30. The method of claim 28, wherein the polymer is selected from the group consisting of collagen, chitosan, gelatin, pectins, alginate, hyaluronic acid, heparin and mixtures thereof.

31. The method of claim 28, wherein the crosslinking is induced by at least one method selected from the group comprising UV, temperature, pH, ion, and ion-radical based methods.

32. The method of claim 28, wherein the crystallizable molecule comprises at least one of a salt, urea, beta cyclodextrin, glycine and guanidine.

33. The method of claim 28, wherein the crystal structure forms a lattice structure and supports the polymer during the crosslinking.

34. The method of claim 28, wherein the growing occurs by spontaneous crystal formation.

35. The method of claim 28, wherein the growing occurs by spontaneous crystal formation during the drying.

36. The method of claim 28, wherein the seeding comprises adding a crystallizable molecule in addition to the crystallizable molecule included in the aqueous mixture.

37. The method of claim 28, wherein the seeding comprises seeding the hydrogel film with the crystallizable molecule.