Hydrogels and methods of making and using same

• US 6,268,405 B1
• Filed: 05/04/1999
• Issued: 07/31/2001
• Est. Priority Date: 05/04/1999
• Status: Expired due to Term

• Current Assignee: Porex Corporation (FGI Equity LLC)
• Original Assignee: Porex Surgical Incorporated (Stryker Corporation)
• Inventors: Swords, Gregory Alan, Yao, Li
• Primary Examiner(s): Hoke, Veronica P.
• Application Number:
  US09/305,083
• Time in Patent Office: 819 Days
• Field of Search: 523/115, 523/111, 523/113, 523/114, 523/118, 521/141, 623/10, 623/16, 264/28
• US Class Current: 523/113
• CPC Class Codes: A61L 2300/40 characterised by a specific therapeutic activity or mode of action
• CPC Class Codes: A61L 2300/432 Inhibitors, antagonists A61L2300/402 - A61L2300/43 take precedence
• CPC Class Codes: A61L 2300/45 Mixtures of two or more drugs, e.g. synergistic mixtures
• CPC Class Codes: A61L 27/16 obtained by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: C08L 29/04 Polyvinyl alcohol; Partially hydrolysed homopolymers or copolymers of esters of unsaturated alcohols with saturated carboxylic acids

Abstract

The invention is directed to methods of making novel porous and solid polyvinyl alcohol hydrogels. These hydrogels are particularly suited for use in the replacement and augmentation of soft tissue or non-load bearing bone of the face, head and cranium.

Claims

1. A porous poly(vinyl alcohol) freeze-thaw hydrogel having pores, wherein the pores have an average diameter of from about 0.02 mm to about 2.0 mm.

2. The hydrogel of claim 1 wherein the pores have an average diameter of from about 0.05 mm to about 1.0 mm.

3. The hydrogel of claim 2 wherein the pores have an average diameter of from about 0.1 mm to about 0.5 mm.

4. The hydrogel of claim 1 wherein the average pore density is from about 10 to about 10⁵ pores/cm³.

5. The hydrogel of claim 4 wherein the average pore density is from about 10² to about 10⁴ pores/cm³.

6. The hydrogel of claim 5 wherein the average pore density is from about 10² to about 10³ pores/cm³.

7. The hydrogel of claim 1 wherein said hydrogel is substantially free of low molecular weight poly(vinyl alcohol) molecules.

14. The hydrogel of claim 1 or 8 wherein said hydrogel comprises at least one calcification inhibitor.

15. The hydrogel of claim 14 wherein the calcification inhibitor is selected from the group consisting of:

aluminum salts;

iron salts;

magnesium salts;

metallocene dichlorides;

amino acids;

phosphates, polyphosphates, and phosphonates;

sulfates; and

mixtures thereof.

16. The hydrogel of claim 1 or 8 wherein said hydrogel comprises at least one bioactive agent.

17. The hydrogel of claim 16 wherein the bioactive agent is selected from the group consisting of:

heparin;

growth factors;

collagen cross-linking inhibitors such as β

aminopropeonitrile and cis-4-hydroxyproline;

matrix inhibitors;

antibodies;

cytokines;

integrins;

thrombins;

thrombin inhibitors;

proteases;

anticoagulants and glycosaminoglycans.

22. An implant suitable for the replacement or enhancement of soft tissue or non-load bearing bone of the neck, face or cranium, wherein said implant comprises a hydrogel of claim 1, 8, or 18.

23. The implant of claim 22 wherein the soft tissue or non-load bearing bone is soft tissue or non-load bearing bone of the neck, face or cranium.

8. A poly(vinyl alcohol) freeze-thaw hydrogel having pores wherein the hydrogel is substantially free of low molecular weight poly(vinyl alcohol) molecules and the pores have an average diameter of from about 0.02 mm to about 2.0 mm.

9. The hydrogel of claim 8 wherein said hydrogel comprises less than about 0.3 percent by weight of low molecular weight poly(vinyl alcohol).

10. The hydrogel of claim 9 wherein said hydrogel comprises less than about 0.2 percent by weight of low molecular weight poly(vinyl alcohol).

11. The hydrogel of claim 10 wherein said hydrogel comprises less than bout 0.1 percent by weight of low molecular weight poly(vinyl alcohol).

12. The hydrogel of claim 8 wherein said hydrogel is solid.

13. The hydrogel of claim 8 wherein said hydrogel is porous.

18. A porous poly(vinyl alcohol) freeze-thaw hydrogel having an average pore diameter of from about 0.02 mm to about 2.0 mm and a pore density of from about 10 to about 10⁵ pores/cm³.

19. The hydrogel of claim 18 wherein said hydrogel comprises less than about 0.3 percent by weight of low molecular weight poly(vinyl alcohol).

20. The hydrogel of claim 19 wherein said hydrogel comprises a calcification inhibitor and/or a bioactive agent.

21. The freeze-thaw poly(vinyl alcohol) hydrogel according to claim 18, further comprising at least one dopant selected from the group consisting of salts, sugars, water soluble natural proteins, complex carbohydrates, and polymers.

24. A method of making a porous freeze-thaw poly(vinyl alcohol) hydrogel which comprises:

(a) forming a mixture comprising a solvent, poly(vinyl alcohol) in a concentration of from about 8 to about 40 weight percent, and at least one dopant selected from the group consisting of salts, sugars, water soluble natural proteins, complex carbohydrates, and polymers,

(b) transferring the mixture to a mold by high-pressure injection;

(c) cooling the mold to a temperature of from about −

60°

C. to about −

20°

C.;

(d) heating the mold to a temperature of from about 25°

C. to about 60°

C.;

(e) repeating steps (c) and (d) from about 1 to about 20 times to form a hydrogel;

(f) removing the hydrogel from the mold; and

(g) washing or soaking the hydrogel such that at least part of the dopant is removed to form a porous freeze-thaw poly(vinyl alcohol) hydrogel having pores with an average diameter of from about 0.02 mm to about 2.0 mm.

26. A hydrogel formed by the method of claim 24 or 25.

25. A method of making a poly(vinyl alcohol) freeze-thaw hydrogel which is substantially free of low molecular weight poly(vinyl alcohol) molecules which comprises:

(a) forming a high molecular weight poly(vinyl alcohol) mixture by removing low-molecular weight polymers from a poly(vinyl alcohol) mixture using supercritical extraction;

(b) forming a second mixture comprising a solvent and the high molecular weight poly(vinyl alcohol) mixture in a concentration of from about 8 to about 40 weight percent;

(c) transferring the second mixture to a mold by high-pressure injection;

(d) cooling the mold to a temperature of from about −

60°

C. to about −

20°

C.;

(e) heating the mold to a temperature of from about 25°

C. to about 60°

C.; and

(f) repeating steps (d) and (e) from about 1 to about 20 times to form a freeze-thaw hydrogel to form a porous freeze-thaw poly(vinyl alcohol) hydrogel having pores with an average diameter of from about 0.02 mm to about 2.0 mm.

27. A method of augmenting or replacing soft tissue or non-load bearing bone which comprises implanting in a patient a porous poly(vinyl alcohol) freeze-thaw hydrogel having pores with an average diameter of from about 0.02 mm to about 2.0 mm.

28. The method of claim 27 wherein the pore density of said hydrogel is from about 10 to about 10⁵ pores/cm³.

29. The method of claim 27 wherein the hydrogel is substantially free of low molecular weight poly(vinyl alcohol).

31. The method of claim 27 or 30 wherein said method is selected from the group consisting of:

temporal fossa augmentation after temporalis muscle transfer or atrophy;

volume augmentation after split calvarial graft harvest;

forehead, malar, paranasal, nasal dorsum, nasal valve, nasal tip, pre-maxillary, mental (chin), pre-jowl, and mandible augmentation;

orbital floor blowout repair;

orbital (enucleation and evisceration) implants;

enophthalmos correction;

eyelid support;

ear construction and reconstruction nasolabial fold augmentation;

lip augmentation; and

cerebro spinal fluid obstruction.

30. A method of augmenting or replacing soft tissue or non-load bearing bone which comprises implanting in a patient a poly(vinyl alcohol) freeze-thaw hydrogel substantially free of low molecular weight poly(vinyl alcohol) and having pores with an average diameter of from about 0.02 mm to about 2.0 mm.