Covalently cross linked hydrogels and methods of making and using same

• US 9,987,393 B2
• Filed: 01/18/2017
• Issued: 06/05/2018
• Est. Priority Date: 01/28/2011
• Status: Active Grant

• Current Assignee: The Board of Regents of the University of Colorado (University of Colorado System)
• Original Assignee: The Board of Regents of the University of Colorado (University of Colorado System)
• Inventors: Anseth, Kristi, Fairbanks, Ben, Bowman, Christopher
• Primary Examiner(s): VANHORN, ABIGAIL LOUISE
• Application Number:
  US15/409,392
• Publication Number:
  US 20170232143A1
• Time in Patent Office: 503 Days
• Field of Search: None
• CPC Class Codes: A61L 2430/02 for reconstruction of bones; weight-bearing implants
• CPC Class Codes: A61L 2430/06 for cartilage reconstruction, e.g. meniscus
• CPC Class Codes: A61L 2430/34 for soft tissue reconstruction
• CPC Class Codes: A61L 27/18 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 27/22 Polypeptides or derivatives thereof , e.g. degradation products
• 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 38/00 Homopolymers and copolymers of compounds having one or more carbon-to-carbon triple bonds
• CPC Class Codes: C08G 75/045 from mercapto compounds and unsaturated compounds
• CPC Class Codes: C08G 75/12 Polythioether-ethers C08G75/0245 takes precedence
• CPC Class Codes: C08J 2300/16 Biodegradable polymers
• CPC Class Codes: C08J 2300/20 Polymers characterized by their physical structure
• CPC Class Codes: C08J 2371/02 Polyalkylene oxides
• CPC Class Codes: C08J 3/075 Macromolecular gels
• CPC Class Codes: C08L 101/02 characterised by the presence of specified groups , e.g. terminal or pendant functional groups
• CPC Class Codes: C08L 101/16 the macromolecular compounds being biodegradable
• CPC Class Codes: C08L 81/02 Polythioethers; Polythioether-ethers
• CPC Class Codes: C12N 5/0068 General culture methods using substrates for specific animal cell type C12N5/06

Abstract

A thiol-yne polymeric material and methods for producing said polymers are disclosed. The material is produced by the radically mediated polymerization of monomers having alkyne and thiol functional groups. The alkyne moiety, internal or terminal, may react with one or two thiols. Degradable monomers may be used to form degradable polymers.

Claims

1. A method for producing a composition comprising a biocompatible cross-linked thiol-yne hydrogel, the method comprising:

(a) providing a first monomer comprising at least two thiol moieties and a second monomer comprising an alkyne moiety;

(b) mixing the first and second monomers with a photoinitiator in a solvent wherein the solvent is water and is present at greater than 50% of the mixture of the first and second monomers, photoinitiator and solvent; and

(c) exposing the first and second monomers and photoinitiator to light, thereby producing the composition in less than 20 minutes.

2. The method of claim 1, wherein the photoinitiator is selected from the group consisting of 1-[4-(2-hydroxyethoxy)-phenyl]-2-hydroxy-2-methyl-1-propane-1-one, 1-hydroxy-cyclohexyl-phenyl-ketone and 2,2-dimethoxy -1,2-diphenylethan-1-one.

3. The method of claim 2, wherein the photoinitiator is present in the mixture of the first and second monomers, photoinitiator, and solvent in an amount less than or equal to 0.5% or 1% by weight.

4. The method of claim 1, wherein the light is ultraviolet light.

5. The method of claim 4, wherein the ultraviolet light has a wavelength between 300 and 400 nm.

6. The method of claim 1, wherein the exposure to light lasts for less than two, five or 20 minutes.

7. The method of claim 1, wherein the first monomer comprises two thiol moieties.

8. The method of claim 1, wherein the second monomer comprises at least two alkyne moieties.

9. The method of claim 1, wherein the first monomer comprises a core monomer structure selected from the group consisting of poly(lactic acid) (PLA), polyglycolide (PGA), copolymers of PLA and PGA (PLGA), poly(vinyl alcohol) (PVA), poly(ethylene glycol) (PEG), poly(ethylene oxide), poly(ethylene oxide)-co-poly(propylene oxide) block copolymers (poloxamers, meroxapols), poloxamines, polyanhydrides, polyorthoesters, poly(hydroxy acids), polydioxanones, polycarbonates, polyaminocarbonates, poly(vinyl pyrrolidone), poly(ethyl oxazoline), carboxymethyl cellulose, hydroxyalkylated celluloses, nucleic acids, polypeptides, polysaccharides, heparan sulfate, chondroitin sulfate, heparin, alginate, copolymers thereof, and blends thereof.

10. The method of claim 1, wherein the second monomer comprises a core monomer structure selected from the group consisting of poly(lactic acid) (PLA), polyglycolide (PGA), copolymers of PLA and PGA (PLGA), poly(vinyl alcohol) (PVA), poly(ethylene glycol) (PEG), poly(ethylene oxide), poly(ethylene oxide)-co-poly(propylene oxide) block copolymers (poloxamers, meroxapols), poloxamines, polyanhydrides, polyorthoesters, poly(hydroxy acids), polydioxanones, polycarbonates, polyaminocarbonates, poly(vinyl pyrrolidone), poly(ethyl oxazoline), carboxymethyl cellulose, hydroxyalkylated celluloses, nucleic acids, polypeptides, polysaccharides, heparan sulfate, chondroitin sulfate, heparin, alginate, copolymers thereof, and blends thereof.

11. The method of claim 1, wherein the hydrogel comprises between 50 and 95% water by weight.

12. The method of claim 1, wherein the first or second monomers are degradable.

13. The method of claim 12, wherein the degradable monomer is hydrolytically, chemically or enzymatically degradable.

14. The method of claim 1, wherein the first monomer comprises a peptide.

15. The method of claim 14, wherein the peptide is enzymatically degradable.

16. The method of claim 15, wherein the enzyme is a protease.

17. The method of claim 14, wherein the peptide is selected from the group consisting of adhesion peptides, growth factors, hormones, antihormones, signaling compounds, enzymes, serum proteins, albumins, macroglobulins, globulins, agglutinins, lectins, extracellular matrix proteins, antibodies, and antigens.

18. The method of claim 1, further comprising mixing the first and second monomers with an agent that has a biological function or activity.

19. The method of claim 18, wherein the agent is selected from the group consisting of adhesion peptides, growth factors, hormones, antihormones, signaling compounds, enzymes, serum proteins, albumins, macroglobulins, globulins, agglutinins, lectins, extracellular matrix proteins, antibodies, antigens, analgesics, antipyretics, nonsteriodal antiinflammatory drugs, antiallergics, antibacterial drugs, antianemia drugs, cytotoxic drugs, antihypertensive drugs, dermatological drugs, psychotherapeutic drugs, vitamins, minerals, anorexiants, dietetics, antiadiposity drugs, carbohydrate metabolism drugs, protein metabolism drugs, thyroid drugs, antithyroid drugs, and coenzymes.

20. The method of claim 1, further comprising mixing the first and second monomers with an agricultural chemical.

21. The method of claim 20, wherein the agricultural chemical is selected from the group consisting of fungicides, herbicides, fertilizers, pesticides, carbohydrates, nucleic acids, organic molecules, and inorganic biologically active molecules.