Polymerizable emulsions for tissue engineering

• US 20050112186A1
• Filed: 10/29/2004
• Published: 05/26/2005
• Est. Priority Date: 10/29/2003
• Status: Active Grant

• Current Assignee: Gentis, Inc.
• Original Assignee: Gentis, Inc.
• Inventors: Cohen, Charles, Ducheyne, Paul, Devore, David
• Granted Patent: US 7,651,682 B2
• Time in Patent Office: Days
• US Class Current: 424/450
• 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, inverse (water-in-oil) fluid emulsion for tissue engineering, comprising two discrete organic and aqueous phases, wherein the organic phase comprises one or more reactive, ethylenically unsaturated monomers, oligomers or mixtures thereof, which when said emulsion is polymerized in situ, forms a strong, cohesive viscoelastic material comprising two discrete organic and aqueous phases.

2. The composition of claim 1, wherein at least one of the one or more reactive, ethylenically unsaturated monomers, oligomers or mixtures thereof comprises an acrylate.

3. The composition of claim 1, wherein at least one of the one or more reactive, ethylenically unsaturated monomers, oligomers or mixtures thereof 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;

as well as homopolymers of said monomers, and copolymerization of mixtures of said monomers.

4. The composition of claim 1, wherein at least one of the one or more reactive, ethylenically unsaturated monomers, oligomers or mixtures thereof is pre-polymerized.

5. The composition of claim 1, wherein the pre-polymerized monomer is lauryl acrylate, and it replaces a fraction of the monomer in the organic phase of the emulsion.

6. The composition of claim 1, wherein the aqueous phase comprises water, and may further comprise a carrier selected from the group consisting of saline, starch, hydrogel, polyvinylpyrrolidone, polysaccharide, hyaluronic acid ester, and plasma.

7. The composition of claim 6, further comprising one or more additives 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, non-ionic surfactants and therapeutic compositions.

8. The composition of claim 7, wherein the therapeutic additive compositions are further selected from the group consisting of one or more peptides, tissue regeneration agents, antibiotics, a steroids, fibronectins, cytokines, growth factors, osteoinductive substances, bone morphogenic proteins (BMP), epidermal growth factor (EGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), insulin-like growth factor (IGF-I and II), TGF-beta, analgesics, anesthetics, antiseptics, alpha-, beta, or gamma-interferons, erythropoietin, glucagons, calcitonins, heparin, interleukin-1, interleukin-2, filgrastim, cDNAs, DNAs, proteins, HGH, luteinizing hormones, atrial natriuretic factor, Factor VIII, Factor IX, stimulating hormones, and one or medicaments selected from the group consisting of acyclovir, cephradine, malfalen, procaine, ephedrine, adriomycin, daunomycin, plumbagin, atropine, quanine, digoxin, quinidine, biologically active peptides, cephalothin, proline and proline analogues, penicillin V, aspirin, ibuprofen, steroids, nicotinic acid, chemodeoxycholic acid, chlorambucil, cell attachment mediators, and biologically active ligands.

9. The composition of claim 1, wherein polymerization of the emulsion comprises initiation by thermal, chemical or photoinitiation means.

10. The composition of claim 1, wherein the organic phase of the emulsion comprises at least one high molecular weight polymer.

11. The composition of claim 10, wherein the organic phase of the emulsion comprises at least one initiator or accelerator of a polymerization reaction.

12. The composition of claim 11, wherein the at least one initiator or accelerator comprises at least one photoinitiator of the polymerization reaction.

13. The composition of claim 1, wherein the emulsion further comprises in either the organic or aqueous phase, particles, solutions or dispersions of one or more inert, bioactive or biological materials.

14. The composition of claim 13, wherein the one or more inert, bioactive or biological materials 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.

15. A method of preparing a strong, biocompatible viscoelastic material for tissue engineering, said material having two discrete organic and aqueous phases, said method comprising

preparing a biocompatible, non toxic, inverse (water-in-oil) fluid emulsion comprising two discrete phases (organic and aqueous), wherein the organic phase comprises one or more reactive, ethylenically unsaturated monomers, oligomers or mixtures thereof;

and

polymerizing said emulsion in situ.

16. The method of claim 15, wherein at least one of the one or more reactive, ethylenically unsaturated monomers, oligomers or mixtures thereof comprises an acrylate.

17. The method of claim 15, further comprising selecting and adding at least one of the one or more reactive, ethylenically unsaturated monomers, oligomers or mixtures thereof 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;

tetrahdrofurfuryl methacrylate;

isodecyl acrylate or methacrylate;

octyldecyl acrylate and methacrylate;

phenoxyethyl acrylate and methacrylate;

glycidyl acrylate and methacrylate;

isobornyl 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;

as well as homopolymers of said monomers, and copolymerization of mixtures of said monomers.

18. The method of claim 15, further comprising pre-polymerizing at least one of the one or more reactive, ethylenically unsaturated monomers, oligomers or mixtures thereof.

19. The method of claim 15, wherein the pre-polymerized monomer is lauryl acrylate, and it replaces a fraction of the monomer in the organic phase of the emulsion.

20. The method of claim 15, further comprising including water in the aqueous phase of the emulsion, and further comprising selecting and adding a carrier from the group consisting of saline, starch, hydrogel, polyvinylpyrrolidone, polysaccharide, hyaluronic acid ester, and plasma.

21. The method of claim 20, further comprising selecting and adding one or more additives 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, non-ionic surfactants and therapeutic compositions.

22. The method of claim 21, comprising further selecting and adding at least one therapeutic additive composition from the group consisting of one or more peptides, tissue regeneration agents, antibiotics, a steroids, fibronectins, cytokines, growth factors, osteoinductive substances, bone morphogenic proteins (BMP), epidermal growth factor (EGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), insulin-like growth factor (IGF-I and II), TGF-beta, analgesics, anesthetics, antiseptics, alpha-, beta, or gamma-interferons, erythropoietin, glucagons, calcitonins, heparin, interleukin-1, interleukin-2, filgrastim, cDNAs, DNAs, proteins, HGH, luteinizing hormones, atrial natriuretic factor, Factor VIII, Factor IX, stimulating hormones, and one or medicaments selected from the group consisting of acyclovir, cephradine, malfalen, procaine, ephedrine, adriomycin, daunomycin, plumbagin, atropine, quanine, digoxin, quinidine, biologically active peptides, cephalothin, proline and proline analogues, penicillin V, aspirin, ibuprofen, steroids, nicotinic acid, chemodeoxycholic acid, chlorambucil, cell attachment mediators, and biologically active ligands.

23. The method of claim 15, comprising initiating polymerization of the emulsion by thermal, chemical or photoinitiation means.

24. The method of claim 23, further comprising adding to the emulsion at least one initiator or accelerator of a polymerization reaction.

25. The method of claim 24, wherein the added initiator or accelerator comprises at least one photoinitiator of the polymerization reaction.

26. The method of claim 25, further comprising exposing the emulsion in situ to electromagnetic radiation, including ultraviolet, visible, or infrared light and microwaves.

27. The method of claim 23, wherein the at least one initiator or accelerator comprises at least one chemical initiator of the polymerization reaction.

28. The method of claim 15, further comprising selecting and adding to either the organic or aqueous phase, particles, solutions or dispersions of one or more inert, bioactive or biological materials.

29. The method of claim 15, further comprising

separating the emulsion into two parts, one of which comprises a peroxide free radical generator, while the other comprises an amine catalyst;

and

combining the two emulsion components to initiate polymerization into the viscoelastic material.

30. The strong, biocompatible viscoelastic material for tissue engineering, having two discrete organic and aqueous phases, said material produced by the method of claim 15.

31. A method of using the viscoelastic material of claim 30, said method comprising forming the emulsion into tissue implants, scaffolds for cell growth, or bioadhesives for joining or repairing living tissue.

32. The method of claim 31, comprising delivering the emulsion to a site in need of repair, regeneration or tissue engineering in a mammal, and polymerizing the emulsion into the viscoelastic material in situ.

33. The method of claim 32, further comprising delivering the emulsion by acceptably noninvasive means to the site in need of repair, regeneration or tissue engineering in the mammal.

34. The method of claim 33, wherein the delivery is effected by injection of the emulsion means to the site in need of repair, regeneration or tissue engineering in the mammal.

35. The method of claim 32, further comprising replacing or repairing at least one intervertebral disc in the spinal column of the mammal

36. The method of claim 35, further comprising

delivering the emulsion into an evacuated region of a nucleous pulposus of the intervertebral disc of the mammal;

and

polymerizing the emulsion in situ to form the viscoeleastic material, thereby forming an implant in the mammal.

37. The method of claim 36, further comprising

fully or partially evacuating a degenerated nucleus pulposus from the intervertebral disc of the mammal by minimally invasive surgical means prior to the step of delivering the emulsion to the nucleus pulposus.

38. The method of claim 29, further comprising including in the delivered composition at least one initiator or accelerator comprising at least one chemical initiator of the polymerization reaction.

39. The method of claim 38, further comprising selecting and adding to the emulsion, in either the organic or aqueous phase, particles, solutions or dispersions of one or more inert, bioactive or biological materials.

40. The method of claim 39, further comprising selecting and adding to the emulsion, one or more inert, bioactive or biological materials 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.