Polymerizable emulsions for tissue engineering

• US 7,651,682 B2
• Filed: 10/29/2004
• Issued: 01/26/2010
• Est. Priority Date: 10/29/2003
• Status: Expired due to Fees

• Current Assignee: Gentis, Inc.
• Original Assignee: Gentis, Inc.
• Inventors: Cohen, Charles, Ducheyne, Paul, Devore, David
• Primary Examiner(s): Foley; Shanon A
• Application Number:
  US10/977,521
• Publication Number:
  US 20050112186A1
• Time in Patent Office: 1,915 Days
• Field of Search: 424/450, 424/487, 424/78.31
• US Class Current: 424/78.08
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/74 Synthetic polymeric materials
• CPC Class Codes: A61L 2300/256 Antibodies, e.g. immunoglobulins, vaccines
• CPC Class Codes: A61L 2300/414 Growth factors
• CPC Class Codes: A61L 2300/43 Hormones, e.g. dexamethasone
• CPC Class Codes: A61L 2300/64 Animal cells
• CPC Class Codes: A61L 27/26 Mixtures of macromolecular compounds
• CPC Class Codes: A61L 27/38 containing added animal cells organs or tissue containing native cells A61L27/36
• CPC Class Codes: A61L 27/50 Materials characterised by their function or physical properties , e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• CPC Class Codes: A61L 27/52 Hydrogels or hydrocolloids
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: C08F 290/048 Polymers of monomers having two or more carbon-to-carbon double bonds as defined in group C08F36/00

Abstract

Provided are biocompatible viscoelastic solid materials derived from polymerization of fluid water-in-oil emulsions, along with methods of their preparation and methods for their use for tissue engineering applications, including for reforming diseased, damaged or degenerated intervertebral discs by acceptably non-invasive means.

Claims

1. A biocompatible, non toxic, viscoelastic material for tissue engineering having two discrete organic and aqueous phases comprising a polymerized emulsion having:

a) a continuous hydrophobic organic phase comprised of polymerized ethylenically unsaturated acrylate monomers; and

b) a discontinuous aqueous phase comprising water;

wherein the viscoelastic material is prepared by polymerization of ethylenically unsaturated acrylate monomers in an inverse (“

water-in-oil”

) fluid emulsion, said fluid emulsion also comprising two distinct phases,

wherein the aqueous phase is present in the fluid emulsion in an amount of about 0.5% to about 90% weight/weight of the organic phase.

2. The viscoelastic material of claim 1, wherein at least one of the reactive, ethylenically unsaturated, polymerizable acrylate monomers is selected from the group consisting of methyl acrylate;

methyl methacrylate;

ethyl acrylate;

ethyl methacrylate;

stearyl acrylate and methacrylate;

lauryl acrylate and methacrylate;

ethoxylated and/or propoxylated acrylates and methacrylates;

alkoxylated acrylates and methacrylates;

allyl acrylates and methacrylates;

tetrahdrofurfturyl methacrylate;

isodecyl acrylate or methacrylate;

octyldecyl acrylate and methacrylate;

phenoxyethyl acrylate and methacrylate;

glycidyl acrylate and methacrylate;

isobomyl acrylate;

caprolactone acrylate;

ethoxylated nonyl phenol acrylates and methacrylates;

propylene glycol acrylate and methacrylate;

alkoxylated nonyl phenol acrylates and methacrylates;

alkoxylated diol diacrylates;

alkoxylated bisphenol diacrylates;

ethylene glycol diacrylate;

butylene glycoldiacrylate and dimethacrylate;

butanediol diacrylate and dimethacrylate;

neopentylglycol diacrylate and dimethacrylate;

polyethyleneglycol diacrylate and dimethacrylate;

ethoxylated bisphenol diacrylates;

saturated and unsaturated (C36) dimer diol diacrylates;

polyethyleneglycol diacrylate and dimethacrylate;

polybutadiene diacrylate and dimethacrylate;

polybuadiene urethane diacrylate;

triethylene glycol dimethacrylate;

acrylamide and methacrylamide.

3. The viscoelastic material of claim 1, wherein at least one of the reactive, ethylenically unsaturated, polymerizable acrylate monomers is pre-polymerized.

4. The viscoelastic material of claim 3, wherein the pre-polymerized monomer is lauryl acrylate, and it replaces a fraction of the monomer in the organic phase of the emulsion.

5. The viscoelastic material of claim 1, wherein the aqueous phase of the fluid emulsion further comprises at least one additive selected from the group consisting of stabilizers, stabilizing salts, diluents, solubilizers, lubricants, suspending agents, encapsulating materials, solvents, thickeners, dispersants, buffers, anti-oxidants, preservatives, low molecular weight peptides, proteins immunoglobulins, hydrophilic polymers, amino acids, monosaccharides, disaccharides, carbohydrates, cellulose or its derivatives, glucose, mannose, dextrines, chelating agents, sugar alcohols, counter-ions, and non-ionic surfactants.

6. The viscoelastic material of claim 1, wherein the organic phase of the fluid emulsion further comprises at least one polymer.

7. The viscoelastic material of claim 1, wherein an activator-controlled polymerization initiator is used that is a photoinitiator.

8. The viscoelastic material of claim 7, wherein the photoinitiator is 2-hydroxy-1-[4-(2-hydroxyethoxyphenyl]-2-methyl-1-propane or bisacyl phosphine oxide.

9. The viscoelastic material of claim 1, wherein the fluid emulsion further comprises particles, solutions or dispersions of at least one inert, bioactive or biological material.

10. The viscoelastic material of claim 9, wherein the inert, bioactive or biological material is selected from the group consisting of biological cells or cell fragments, tissue fragments derived from in vitro or in vivo cell culture, biological cell or tissue growth factors, agents to facilitate cell delivery or cell growth and their delivery, antibodies, antibody fragments, hormones, cell targeting moieties, inert ceramics, inert glasses, bioactive ceramics and bioactive glasses.

11. The viscoelastic material of claim 9, wherein the aqueous phase comprises droplets having a size of ≧

1 micron.

12. The viscoelastic material of claim 1, wherein the fluid emulsion further comprises an emulsifier.

13. The viscoelastic material of claim 12, wherein the emulsifier is present in an amount of about 0.1% to about 5.0% by weight of the emulsion.

14. The viscoelastic material of claim 1, wherein the aqueous phase of the fluid emulsion further comprises at least one polymer selected from the group consisting of polyelectrolytes, polysaccharides, proteins, proteoglycans, nucleic acids, hydroxyethylcellulose, and carboxymethylcellulose.

15. The viscoelastic material of claim 1, further comprising at least one filler selected from the group consisting of radio-opacifiers, polymeric microspheres, glass, sugar crystals, and proteins.

16. The viscoelastic material of claim 1, further comprising at least one medicament.

17. The viscoelastic material of claim 16, wherein the medicament is an anesthetic.

18. The viscoelastic material of claim 17, wherein the anesthetic is selected from the group consisting of lidocaine, xylocaine, novocaine, benzocaine, prilocaine, ripvacaine, and propofol.

19. The viscoelastic material of claim 16, wherein the medicament is selected from the group consisting of antibiotics, steroids, fibronectins, cytokines, growth factors, analgesics, antiseptics, glucagons, polynucleotides, proteins, peptides, cell attachment mediators, and osteoinductive substances.

20. The viscoelastic material of claim 19, wherein the polynucleotide is cDNA or DNA.

21. The viscoelastic material of claim 16, wherein the medicament is selected from the group consisting of alpha-, beta, or gamma-interferon, erythropoietin, calcitonin, heparin, interleukin-1, interleukin-2, filgrastim, HGH, luteinizing hormone, atrial natriuretic factor, Factor VIII, Factor IX, follicle-stimulating hormone, acyclovir, cephradine, malfalen, procaine, ephedrine, adriomycin, daunomycin, plumbagin, atropine, quanine, digoxin, quinidine, cephalothin, proline, cis-hydroxy-L-proline, penicillin V, aspirin, ibuprofen, nicotinic acid, chemodeoxycholic acid, chlorambucil, bone morphogenic proteins, epidermal growth factor, fibroblast growth factor, platelet-derived growth factor, insulin-like growth factor, and transforming growth factor-beta.

22. The viscoelastic material of claim 16, further comprising at least one carrier selected from the group consisting of saline, starch, hydrogel, polyvinylpyrrolidone, polysaccharide, hyaluronic acid ester, and plasma.

26. The viscoelastic material of claim 1, wherein an activator-controlled polymerization initiator is used that is a chemical initiator.

27. The viscoelastic material of claim 26, wherein the chemical initiator is a peroxide or a redox catalyst.

28. The viscoelastic material of claim 26, wherein the chemical initiator is a combination of benzoyl peroxide and a tertiary amine.

29. The viscoelastic material of claim 1, wherein the fluid emulsion further comprises inert glass.

23. A biocompatible, non toxic, inverse (“

water-in-oil”

) fluid emulsion for tissue engineering, comprising two discrete phases;

a continuous hydrophobic organic phase comprising lauryl acrylate, bisacyl phosphine oxide, bisphenol A diglycidylether, and an inert glass filler, and

a discontinuous aqueous phase comprising water,

wherein the aqueous phase is a solution that contains about 1% hydroxypropyl methyl cellulose and is present in an amount of about 5% weight/weight of the organic phase, which when the fluid emulsion is polymerized in situ, forms a solid viscoelastic material comprising;

a) a continuous hydrophobic organic phase comprised of polymerized ethylenically unsaturated acrylate monomers; and

b) a discontinuous aqueous (“

water”

) phase comprising water.

24. A kit for tissue engineering comprising a dual component cartridge having first and second individual compartments, wherein

the first compartment contains (i) benzoyl peroxide and (ii) a biocompatible, non toxic, inverse (“

water-in-oil”

) fluid emulsion for tissue engineering, comprising two discrete phases;

a continuous hydrophobic organic phase comprising lauryl acrylate, bisphenol A diglycidylether, and an inert glass filler, and a discontinuous aqueous phase comprising water, wherein the aqueous phase is a solution that contains about 1% hydroxypropyl methyl cellulose and is present in an amount of about 5% weight/weight of the organic phase,

the second compartment contains (i) a tertiary amine and (ii) a biocompatible, non toxic, inverse (“

water-in-oil”

) fluid emulsion for tissue engineering, comprising two discrete phases;

a continuous hydrophobic organic phase comprising lauryl acrylate, bisphenol A diglycidylether, and an inert glass filler, and a discontinuous aqueous phase comprising water, wherein the aqueous phase is a solution that contains about 1% hydroxypropyl methyl cellulose and is present in an amount of about 5% weight/weight of the organic phase, and

when the contents of the first and second compartments are combined, the emulsion polymerizes in situ to form a solid viscoelastic material comprising;

a) a continuous hydrophobic organic phase comprised of polymerized ethylenically unsaturated acrylate monomers; and

b) a discontinuous aqueous (“

water”

) phase.

25. The kit of claim 24, wherein the tertiary amine is N,N-diethyl-p-toluidine.