Photopolymerizable biodegradable hydrogels as tissue contacting materials and controlled-release carriers

• US 5,626,863 A
• Filed: 01/27/1995
• Issued: 05/06/1997
• Est. Priority Date: 02/28/1992
• Status: Expired due to Term

• 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: Pathak, Chandrashekhar P., Sawhney, Amarpreet S., Desai, Neil P., Hubbell, Jeffrey A., Hill, Jennifer L.
• Primary Examiner(s): Dodson, Shelley A.
• Application Number:
  US08/379,848
• Time in Patent Office: 830 Days
• Field of Search: 424/426, 424/489, 514/772.1, 514/772.3, 514/773, 514/777, 525/54.1, 525/54.2, 525/408, 525/413, 525/415, 528/354, 528/361, 128/898, 427/399, 523/105, 523/112, 523/113, 523/114, 523/115
• US Class Current: 424/426
• CPC Class Codes: A61K 2035/128 capsules, e.g. microcapsules
• CPC Class Codes: A61K 38/47 acting on glycosyl compounds (3.2), e.g. cellulases, lactases
• CPC Class Codes: A61K 38/49 Urokinase; Tissue plasminogen activator
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/1635 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: A61L 2300/424 Anti-adhesion agents
• CPC Class Codes: A61L 2300/602 Type of release, e.g. controlled, sustained, slow
• CPC Class Codes: A61L 24/0031 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 24/0042 Materials resorbable by the body
• CPC Class Codes: A61L 24/046 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds A61L24/043 takes precedence
• CPC Class Codes: A61L 27/34 Macromolecular materials
• CPC Class Codes: A61L 27/36 containing ingredients of undetermined constitution or reaction products thereof , e.g. transplant tissue, natural bone, extracellular matrix isolated natural compounds, e.g. collagen A61L27/24
• CPC Class Codes: A61L 27/38 containing added animal cells organs or tissue containing native cells A61L27/36
• CPC Class Codes: A61L 27/52 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 29/085 Macromolecular materials
• CPC Class Codes: A61L 31/145 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 31/148 Materials at least partially resorbable by the body
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence
• CPC Class Codes: C08F 290/00 : Macromolecular compounds obtained by polymerising monomers on to polymers modified by introduction of aliphatic unsaturated end or side groups
• CPC Class Codes: C08F 290/06 : Polymers provided for in subclass C08G
• CPC Class Codes: C08F 291/00 : Macromolecular compounds obtained by polymerising monomers on to macromolecular compounds according to more than one of the groups C08F251/00 - C08F289/00
• CPC Class Codes: C09D 153/00 : Coating compositions based on block copolymers containing at least one sequence of a polymer obtained by reactions only involving carbon-to-carbon unsaturated bonds; Coating compositions based on derivatives of such polymers
• CPC Class Codes: C12N 11/04 : entrapped within the carrier, e.g. gel or hollow fibres
• CPC Class Codes: C12N 2533/30 : Synthetic polymers thermoreactive polymers, e.g. PNIPAm, C12N2539/10
• CPC Class Codes: C12N 2533/32 : Polylysine, polyornithine
• CPC Class Codes: C12N 2533/40 : Polyhydroxyacids, e.g. polymers of glycolic or lactic acid (PGA, PLA, PLGA); Bioresorbable polymers
• CPC Class Codes: C12N 2533/74 : Alginate
• CPC Class Codes: C12N 5/0012 : Cell encapsulation
• CPC Class Codes: C12N 5/0677 : Three-dimensional culture, tissue culture or organ culture; Encapsulated cells
• CPC Class Codes: C12Y 302/01017 : Lysozyme (3.2.1.17)
• CPC Class Codes: C12Y 304/21068 : Tissue plasminogen activator (3.4.21.68), i.e. tPA

Abstract

Hydrogels of polymerized and crosslinked macromers comprising hydrophilic oligomers having biodegradable monomeric or oligomeric extensions, which biodegradable extensions are terminated on free ends with end cap monomers or oligomers capable of polymerization and cross linking are described. The hydrophilic core itself may be degradable, thus combining the core and extension functions. Macromers are polymerized using free radical initiators under the influence of long wavelength ultraviolet light, visible light excitation or thermal energy. Biodegradation occurs at the linkages within the extension oligomers and results in fragments which are non-toxic and easily removed from the body. Preferred applications for the hydrogels include prevention of adhesion formation after surgical procedures, controlled release of drugs and other bioactive species, temporary protection or separation of tissue surfaces, adhering of sealing tissues together, and preventing the attachment of cells to tissue surfaces.

Claims

1. A method of forming a polymeric, biocompatible material on tissue or cells, the method comprising applying to the tissue or cells a solution of biodegradable, polymerizable macromer having a solubility of at least about 1 g/100 ml in an aqueous solution comprising at least one water soluble region, at least one degradable region which is hydrolyzable under in vivo conditions, and free radical polymerizable end groups having the capacity to form additional covalent bonds resulting in macromer interlinking, wherein the polymerizable end groups are separated from each other by at least one degradable region, in the presence of a free radical initiator, and polymerizing the macromer.

2. The method of claim 1 wherein the tissue is coated with the polymerized macromer to inhibit the formation of adhesions.

3. The method of claim 1 wherein the method further comprises applying the macromer solution to tissue surfaces in the presence of free radical initiator and polymerizing the macromer to adhere the tissue surfaces.

4. The method of claim 1 further comprising providing with the macromer solution biologically active materials selected from the group consisting of proteins, carbohydrates, nucleic acids, inorganic biologically active materials, cells, tissues, and tissue aggregates.

7. The method of claim 1 further comprising providing with the macromer solution biologically active molecules selected from the group consisting of enzymes, antibiotics, antineoplastic agents, local anesthetics, hormones, antiangiogenic agents, antibodies, neurotransmitters, psychoactive drugs, drugs affecting reproductive organs, and antisense oligonucleotides.

8. The method of claim 1 wherein the macromer comprises a water soluble core region, at least two degradable extensions on the core, and an end cap on at least two of the degradable extensions, wherein

the core comprises poly(ethylene glycol);

each extension comprises biodegradable poly(α

-hydroxy acid); and

each end cap comprises an acrylate oligomer or monomer.

9. The method of claim 8 wherein the poly(ethylene glycol) has a molecular weight between about 400 and 30,000 Da;

the poly(α

-hydroxy acid) oligomer has a molecular weight between about 200 and 1200 Da; and

the acrylate oligomer or monomer has a molecular weight between about 50 and 200 Da.

10. The method of claim 1 wherein the degradable region is selected from the group consisting of poly(α

-hydroxy acids), poly(lactones), poly(amino acids), poly(anhydrides), poly(orthoesters), poly(orthocarbonates) and poly(phosphoesters).

11. The method of claim 10 wherein the poly(α

-hydroxy acid) is selected from the group consisting of poly(glycolic acid), poly(DL-lactic acid) and poly(L-lactic acid).

12. The method of claim 10 wherein the poly(lactone) is selected from the group consisting of poly(ε

-caprolactone), poly(δ

-valerolactone), and poly(gamma-butyrolactone).

13. The method of claim 1 wherein the water soluble region is selected from the group consisting of poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol), poly(vinylpyrrolidone), poly(ethyloxazoline), poly(ethylene oxide)-co-poly(propyleneoxide) block copolymers, polysaccharides, carbohydrates, proteins, and combinations thereof.

14. The method of claim 1 wherein the polymerizable end groups contain a carbon-carbon double bond capable of cross-linking and polymerizing the macromers.

15. The method of claim 1 wherein the macromer is polymerized to form a coating on the tissue thereby to inhibit restenosis.

16. The method of claim 1 wherein the macromer is polymerized to form a coating on the tissue thereby to form a sealant on the tissue.

17. The method of claim 1, wherein the macromer is characterized in that the water soluble region is attached to a degradable region, at least one polymerizable end group is attached to the water soluble region, and at least one polymerizable end group is attached to the degradable region.

18. The method of claim 1, wherein the macromer is characterized in that the water soluble region forms a central core, at least two degradable regions are attached to the core, and at least two polymerizable end groups are attached to the degradable regions.

19. The method of claim 1, wherein the macromer is characterized in that the degradable region is a central core, at least two water soluble regions are attached to the core, and at least one polymerizable end group is attached to each water soluble region.

20. The method of claim 1, wherein the macromer is characterized in that the water soluble region is a macromer backbone, the degradable region is a branch or graft attached to the macromer backbone, and at least two polymerizable end groups are attached to the degradable regions.

21. The method of claim 1, wherein the macromer is characterized in that the degradable region is a macromer backbone, the water soluble region is a branch or graft attached to the degradable backbone, and two or more polymerizable end groups are attached to the water soluble branches or grafts.

22. The method of claim 1, wherein the macromer is characterized in that the water soluble region is a star backbone, the degradable region is a branch or graft attached to the water soluble star backbone, and at least two polymerizable end groups are attached to a degradable branch or graft.

23. The method of claim 1, wherein the macromer is characterized in that the degradable region is a star backbone, the water soluble region is a branch or graft attached to the degradable star backbone, and two or more polymerizable end groups are attached to the water soluble branch or graft.

24. The method of claim 1, wherein the macromer is characterized in that the water soluble region is also the degradable region.

25. The method of claim 1, wherein the macromer is characterized in that the water soluble region is also the degradable region, and one or more additional degradable regions are grafts or branches upon the water soluble region.

26. The method of claim 1 wherein crosslinking and polymerization of the macromer can be initiated by a light-sensitive free-radical polymerization initiator with or without a cocatalyst, further comprising a free radical polymerization initiator.

27. The method of claim 26 wherein the initiator is selected from the group consisting of xanthine dyes, acridine dyes, thiazine dyes, phenazine dyes, camphorquinone dyes, and acetophenone dyes.

28. The method of claim 26 wherein the initiator is selected from the group consisting of an eosin dye with triethanolamine, 2,2-dimethyl-2-phenyl acetophenone, and 2-methoxy-2-phenyl acetophenone.

29. The method of claim 1 wherein crosslinking or polymerizations are initiated in situ by light having a wavelength of 320 nm or longer.

30. The method of claim 1 wherein the initiator is a thermal initiator.

31. The method of claim 1, wherein the initiator further comprises an initiator mixture.

32. The method of claim 1, wherein the polymerized macromer forms a barrier on the cells or tissue.

33. The method of claim 1, wherein the tissue or cell is encapsulated by the polymerized macromer.

34. The method of claim 1, wherein the polymerized macromer comprises a tissue support.

35. The method of claim 34, wherein the support forms a shaped article within the body to serve a mechanical function.

36. The method of claim 35, wherein the support is selected from the group consisting of organ sealants, bone defect sealants, space-fillers for aneurysms, blood vessel interior coatings, vessels, tubes and organ holding strictures.

37. The method of claim 2, for inhibiting adhesions of the peritoneal cavity.

38. The method of claim 1, further comprising providing with the macromer solution biologically active organic molecules.

5. A method of forming a polymeric, biocompatible material on tissue, the method comprising:

applying a free radical initiator at a tissue site; and

applying to the tissue site a solution of biodegradable, polymerizable, and at least substantially water soluble macromer comprising at least one water soluble region, at least one degradable region, and at least two free radical polymerizable regions, wherein the polymerizable regions are separated from each other by at least one degradable region, and polymerizing the macromer in the presence of the free radical initiator.

6. A method of forming a polymeric, biocompatible material on tissue, the method comprising:

applying a free radical initiator to a tissue site, permitting the initiator to bind to the tissue, and removing unbound initiator;

applying to the tissue site, after removal of the unbound initiator, a solution of biodegradable, polymerizable, and at least substantially water soluble macromer comprising at least one water soluble region, at least one degradable region, and at least two free radical polymerizable regions, wherein the polymerizable regions are separated from each other by at least one degradable region, and polymerizing the macromer in the presence of the free radical initiator.

39. A method of forming a polymeric, biocompatible material on a surface, the method comprising:

applying to the surface a solution of a biodegradable, polymerizable macromer, having a solubility of at least about 1 g/100 ml in an aqueous solution, and comprising at least one water soluble region, at least one degradable region which is hydrolyzable under in vivo conditions, and free radical polymerizable end groups, wherein the polymerizable end groups are separated from each other by at least one degradable region, in the presence of a free radical initiator, and polymerizing the macromer.

40. The method of claim 39 wherein the surface comprises glass.

41. The method of claim 39, further comprising contacting the surface with cells or tissue.

42. The method of claim 41, wherein polymerized macromer forms a coating on the surface which inhibits adhesion to the surface.

43. The method of claim 42 wherein the adhesion of protein, cells or tissue to the surface is inhibited.