Gels for encapsulation of biological materials

• US 5,573,934 A
• Filed: 03/01/1993
• Issued: 11/12/1996
• Est. Priority Date: 04/20/1992
• 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., Hossainy, Syed F. A., Hubbell, Jeffrey A., Hill-West, Jennifer L.
• Primary Examiner(s): Lilling, Herbert J.
• Application Number:
  US08/024,657
• Time in Patent Office: 1,352 Days
• Field of Search: 427/213.35, 427/213.3, 427/213.32, 427/2.14, 427/2.21, 424/487, 424/488, 424/499, 424/489, 424/450, 424/451, 424/459-463, 424/477, 424/479, 424/93, 435/177, 435/180, 435/240.2, 435/240.22, 264/4, 264/4.1, 264/4.3, 514/2, 428/402.22, 428/402.24
• US Class Current: 435/177
• CPC Class Codes: A61K 2035/128 capsules, e.g. microcapsules
• CPC Class Codes: A61K 38/42 Haemoglobins; Myoglobins
• CPC Class Codes: A61K 38/44 Oxidoreductases (1)
• CPC Class Codes: A61K 47/645 Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
• CPC Class Codes: A61K 47/6903 the form being semi-solid, e.g. an ointment, a gel, a hydrogel or a solidifying gel
• CPC Class Codes: A61K 47/6927 the form being a solid microparticle having no hollow or gas-filled cores
• 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: A61K 9/5026 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/5031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
• CPC Class Codes: A61K 9/5073 having two or more different coatings optionally including drug-containing subcoatings
• 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 26/0019 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 27/34 Macromolecular materials
• CPC Class Codes: A61L 27/3683 subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
• 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 31/10 : 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: B82Y 5/00 : Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• 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 37/0072 : Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
• 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: 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 290/02 : on to polymers modified by introduction of unsaturated end groups
• CPC Class Codes: C08F 290/06 : Polymers provided for in subclass C08G
• CPC Class Codes: C08F 290/062 : Polyethers
• CPC Class Codes: C08F 290/08 : on to polymers modified by introduction of unsaturated side groups
• CPC Class Codes: C08F 290/10 : Polymers provided for in subclass C08B
• 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: C08L 71/02 : Polyalkylene oxides
• 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: Y10S 530/812 : Peptides or proteins is immobilized on, or in, an organic carrier
• CPC Class Codes: Y10S 530/813 : Carrier is a saccharide
• CPC Class Codes: Y10S 530/815 : Carrier is a synthetic polymer
• CPC Class Codes: Y10S 530/817 : Entrapped within the carrier, e.g. gel, hollow fibre
• CPC Class Codes: Y10T 428/2987 : Addition polymer from unsaturated monomers only
• CPC Class Codes: Y10T 428/2989 : Microcapsule with solid core [includes liposome]

Abstract

Water soluble macromers are modified by addition of free radical polymerizable groups, such as those containing a carbon-carbon double or triple bond, which can be polymerized under mild conditions to encapsulate tissues, cells, or biologically active materials. The polymeric materials are particularly useful as tissue adhesives, coatings for tissue lumens including blood vessels, coatings for cells such as islets of Langerhans, coatings, plugs, supports or substrates for contact with biological materials such as the body, and as drug delivery devices for biologically active molecules.

Claims

1. A method for encapsulating, sealing, coating or supporting a biological material comprising:

a) contacting a solution of a non-toxic free radical polymerization initiator selected from the group consisting of visible or long wavelength ultraviolet light-activatable free radical initiators, thermal activatable free-radical initiators with a biological material selected from the group consisting of mammalian cells, components of mammalian cells, aggregates of mammalian cells, and mammalian tissues, to allow binding of the initiator to the biological material;

b) removing the unbound initiator;

c) adding to the biological material a water soluble biocompatible macromer comprising at least two free radical polymerizable end groups, wherein the macromer is non-toxic and has a molecular weight of at least 400, and

d) exposing the mixture to an agent activating the initator to cause polymerization of the macromers to form a polymeric gel with a degree of polymerization greater than 10.

2. The method of claim 1 further comprising adding to the biocompatible macromer a biologically active molecule selected from the group consisting of peptides of less than one hundred amino acids, proteins of one hundred or more amino acids, polysaccharides, nucleic acids, organic drugs, and inorganic drugs.

3. The method of claim 1 wherein the free-radical polymerizable endgroups contain carbon-carbon double or triple bonds.

4. The method of claim 1 wherein the water soluble macromer is selected from the group consisting of poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol), poly(vinylpyrrolidone), poly(ethyloxazoline), poly(amino acid), polysaccharides, proteins, or a block or random copolymer thereof comprising two or more polymerizable substituents.

5. The method of claim 4 wherein the polysaccharide is selected from the group consisting of alginate, hyaluronic acid, chondroitin sulfate, dextran, dextran sulfate, heparin, heparin sulfate, heparan sulfate, chitosan, gellan gum, xanthan gum, guar gum, and K-carrageenan.

6. The method of claim 4 wherein the protein is selected from the group consisting of gelatin, collagen and albumin.

7. The method of claim 1 wherein the free-radical polymerizable endgroups are selected from the group of macromers containing two or more acrylate groups.

8. The method of claim 1 wherein the polymer is prepared from macromers comprising an acrylate terminated poly(ethylene glycol).

9. The method of claim 1 wherein the polymerization initiator is selected from the group consisting of an eosin dye, riboflavin, acetophenone, a substituted acetophenone, a fluorescein dye camphorquinone, rose bengal, methylene green, methylene blue, acridine orange, xanthine dye, and thioxanthine dyes.

10. The method of claim 1 wherein the polymerization initiator is selected from the group consisting of erythrosin, phloxine, and thionine.

11. The method of claim 1 wherein polymerization is initiated by visible light having a wavelength of less than 800 nm.

12. The method of claim 11 wherein the light has a wavelength of 514 nm.

13. The method of claim 1 wherein the unbound initiator is removed by dilution with the macromer solution such that polymerization occurs only at the surface of the mammalian cell, mammalian cell aggregate, or mammalian tissue.

14. The method of claim 1 wherein polymerization of the macromer solution adheres mammalian tissue to other mammalian tissue or cells.

15. The method of claim 1 wherein the initiator is a photoinitiator which is activated by exposure to visible light, and the water soluble macromer is selected from the group consisting of poly(alkylene glycol), poly(alkylene oxide), poly(vinyl alcohol), poly(vinylpyrrolidone), poly(ethyloxazoline), poly(amino acid), polysaccharides, proteins, or a block or random copolymer thereof comprising two or more polymerizable substituents.

16. The method of claim 15 wherein the macromer is poly(ethylene glycol) and the free radical polymerizable groups contain carbon-carbon double bonds.