Degradable thiol-ene polymers

• US 10,189,952 B2
• Filed: 03/16/2017
• Issued: 01/29/2019
• Est. Priority Date: 10/10/2001
• 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: Bowman, Christopher, Anseth, Kristi, Hacioglu, Bilge, Nuttelman, Charlie
• Primary Examiner(s): Zimmer, Marc S
• Application Number:
  US15/460,939
• Publication Number:
  US 20170247541A1
• Time in Patent Office: 684 Days
• Field of Search: None
• CPC Class Codes: A01N 25/04 Dispersions, emulsions, suspoemulsions, suspension concentrates or gels foams A01N25/16
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61L 2300/62 Encapsulated active agents, e.g. emulsified droplets
• CPC Class Codes: A61L 27/16 obtained by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 27/18 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• 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 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: C05G 5/23 Solutions
• CPC Class Codes: C05G 5/37 layered or coated with a polymer
• CPC Class Codes: C08G 2261/126 block
• CPC Class Codes: C08G 75/045 from mercapto compounds and unsaturated compounds
• CPC Class Codes: C08G 81/00 Macromolecular compounds obtained by interreacting polymers in the absence of monomers, e.g. block polymers involving only carbon-to-carbon unsaturated bond reactions C08F299/00 ; polyester-amides C08G69/44; polyester-imides C08G73/16; polyamides-imides C08G73/14; block- or graft polymers containing polysiloxane sequences C08G77/42
• CPC Class Codes: C08G 81/025 containing polyether sequences
• CPC Class Codes: C08G 81/027 containing polyester or polycarbonate sequences
• CPC Class Codes: C08J 2329/04 Polyvinyl alcohol; Partially hydrolysed homopolymers or copolymers of esters of unsaturated alcohols with saturated carboxylic acids
• CPC Class Codes: C08J 2367/04 Polyesters derived from hydroxy carboxylic acids, e.g. lactones C08J2367/06 takes precedence
• CPC Class Codes: C08J 2371/02 Polyalkylene oxides
• CPC Class Codes: C08J 3/075 Macromolecular gels
• CPC Class Codes: C08L 2205/05 containing polymer components which can react with one another
• CPC Class Codes: C08L 2666/22 : Macromolecular compounds not provided for in C08L2666/16 - C08L2666/20
• CPC Class Codes: C08L 71/02 : Polyalkylene oxides
• CPC Class Codes: C08L 81/02 : Polythioethers; Polythioether-ethers
• CPC Class Codes: C08L 83/00 : Compositions of macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon only; Compositions of derivatives of such polymers
• CPC Class Codes: C08L 89/00 : Compositions of proteins; Compositions of derivatives thereof foodstuff preparations A23J3/00
• CPC Class Codes: Y10S 524/916 : Hydrogel compositions
• CPC Class Codes: Y10S 525/936 : Encapsulated chemical agent

Abstract

A thiol-ene polymeric material is disclosed. The material is produced by the photopolymerization of reactants having thiol and olefin moieties. The material can incorporate encapsulated components, including cells. Additionally, the material can be derivatized by reacting the polymeric material with components such as proteins.

Claims

1. A method for producing a hydrogel comprising a biocompatible cross-linked degradable thiol-ene polymer, the method comprising:

subjecting a polymerization reaction mixture comprising at least one thiol compound and at least one olefin compound to a radical polymerization reaction under conditions sufficient to produce the biocompatible cross-linked degradable thiol-ene polymer, wherein

(a) the at least one thiol compound comprises m number of reactive thiol groups;

(b) the at least one olefin compound comprises n number of reactive ene groups, wherein at least one of the ene groups is a norbornene moiety; and

(c) each of n and m is an integer of at least 2, provided that the sum of n+m is at least 5.

2. The method of claim 1, wherein the at least one olefin compound comprises a polymeric moiety selected from the group consisting of poly(lactic acid) (PLA);

polyglycolide (PGA);

a copolymer of PLA and PGA (PLGA);

poly(vinyl alcohol) (PVA);

poly(ethylene glycol) (PEG);

poly(ethylene oxide);

a poly(ethylene oxide)-co-poly(propylene oxide) block copolymer;

a poloxamine;

a polyanhydride;

a polyorthoester;

a poly(hydroxy acids);

a polydioxanone;

a polycarbonate;

a polyaminocarbonate;

a poly(vinyl pyrrolidone);

a poly(ethyl oxazoline);

a carboxymethyl cellulose;

a hydroxyalkylated cellulose;

a polypeptide;

a polysaccharide;

a carbohydrate;

heparan sulfate;

chondroitin sulfate;

heparin, alginate; and

a combination thereof.

3. The method of claim 1, wherein the at least one thiol compound comprises a polymeric moiety selected from the group consisting of poly(lactic acid) (PLA);

polyglycolide (PGA);

a copolymer of PLA and PGA (PLGA);

poly(vinyl alcohol) (PVA);

poly(ethylene glycol) (PEG);

poly(ethylene oxide);

a poly(ethylene oxide)-co-poly(propylene oxide) block copolymer;

a poloxamine;

a polyanhydride;

a polyorthoester;

a poly(hydroxy acids);

a polydioxanone;

a polycarbonate;

a polyaminocarbonate;

a poly(vinyl pyrrolidone);

a poly(ethyl oxazoline);

a carboxymethyl cellulose;

a hydroxyalkylated cellulose;

a polypeptide;

a polysaccharide;

a carbohydrate;

heparan sulfate;

chondroitin sulfate;

heparin, alginate; and

a combination thereof.

4. The method of claim 1, wherein the at least one thiol compound is a branched thiol compound.

5. The method of claim 1, wherein the at least at least one olefin compound is a branched olefin compound.

6. The method of claim 1, wherein the polymerization reaction mixture further comprises a chemical initiator.

7. The method of claim 1, wherein the polymerization reaction mixture further comprises a biologically active component.

8. The method of claim 7, wherein the biologically active component is selected from the group consisting of cells, tissues, and tissue aggregates.

9. The method of claim 7, wherein the biologically active component is selected from the group consisting of chondrocytes, immortalized cell lines, stem cells, hormone-producing cells and fibroblasts.

10. The method of claim 7, wherein the biologically active component is selected from the group consisting of a protein, a pharmacologically active agent, and an agricultural chemical.

11. The method of claim 10, wherein the biologically active component is a protein selected from the group consisting of an adhesion peptide, growth factor, hormone, antihormone, signaling compound, enzyme, serum protein, albumin, macroglobulin, globulin, agglutinin, lectin, extracellular matrix protein, antibody, antigen, and a combination thereof.

12. The method of claim 10, wherein the biologically active component is a pharmacologically active agent selected from the group consisting of an analgesic, antipyretic, nonsteriodal antiinflammatory drug, antiallergic, antibacterial drug, antianemia drug, cytotoxic drug, antihypertensive drug, dermatological drug, psychotherapeutic drug, vitamin, mineral, anorexiant, dietetic, antiadiposity drug, carbohydrate metabolism drug, protein metabolism drug, thyroid drug, antithyroid drug, coenzymes, and a combination thereof.

13. The method of claim 10, wherein the biologically active component is an agricultural chemical selected from the group consisting of a fungicide, herbicide, fertilizer, pesticide, carbohydrate, nucleic acid, organic molecule, inorganic biologically active molecule, and a combination thereof.

14. The method of claim 7, wherein the radical polymerization reaction encapsulates the biologically active component within the biocompatible cross-linked degradable thiol-ene polymer.

15. The method of claim 2, wherein the polymeric moiety has a molecular weight ranging from about 30 Da to about 50,000 Da.

16. The method of claim 3, wherein the polymeric moiety has a molecular weight ranging from about 30 Da to about 50,000 Da.

17. The method of claim 2, wherein the polymeric moiety is biodegradable.

18. The method of claim 3, wherein the polymeric moiety is biodegradable.

19. The method of claim 2, wherein the polymeric moiety selected from the group consisting of poly(lactic acid) (PLA), poly(vinyl alcohol) (PVA), and poly(ethylene glycol) (PEG), and a combination thereof.

20. The method of claim 3, wherein the polymeric moiety selected from the group consisting of poly(lactic acid) (PLA), poly(vinyl alcohol) (PVA), and poly(ethylene glycol) (PEG), and a combination thereof.

21. A method for producing a biocompatible thiol-ene hydrogel, the method comprising

subjecting a polymerization reaction mixture comprising at least one thiol compound and at least one olefin compound to a radical polymerization reaction under conditions sufficient to produce the biocompatible thiol-ene hydrogel, wherein:

(a) the at least one thiol compound comprises m number of reactive thiol groups;

(b) the at least one olefin compound comprises n number of reactive ene groups; and

(c) each of n and m is an integer of at least 2, provided the sum of n+m is at least 5.

22. The method of claim 21 wherein the at least one thiol compound comprises a polymeric moiety selected from the group consisting of poly(lactic acid) (PLA), polyglycolide (PGA), a copolymer of PLA and PGA (PLGA), poly(vinyl alcohol) (PVA), poly(ethylene glycol) (PEG), poly(ethylene oxide), a poly(ethylene oxide)-co-poly(propylene oxide) block copolymer, a poloxamine, a polyanhydride, a polyorthoester, a poly(hydroxy acids), a polydioxanone, a polycarbonate, a polyaminocarbonate, a poly(vinyl pyrrolidone), a poly(ethyl oxazoline), a carboxymethyl cellulose, a hydroxyalkylated cellulose, a polypeptide, a polysaccharide, a carbohydrate, heparan sulfate, chondroitin sulfate, heparin, alginate, hyaluronic acid, gelatin, and a combination thereof.

23. The method of claim 22, wherein the at least one thiol compound comprises a polymeric moiety selected from the group consisting of hyaluronic acid and gelatin.

24. The method of claim 23, wherein the polymeric moiety of the at least one thiol compound is hyaluronic acid.

25. The method of claim 23, wherein the polymeric moiety of the at least one thiol compound is gelatin.

26. The method of claim 21, wherein the at least one olefin compound comprises a polymeric moiety selected from the group consisting of poly(lactic acid) (PLA), polyglycolide (PGA), a copolymer of PLA and PGA (PLGA), poly(vinyl alcohol) (PVA), poly(ethylene glycol) (PEG), poly(ethylene oxide), a poly(ethylene oxide)-co-poly(propylene oxide) block copolymer, a poloxamine, a polyanhydride, a polyorthoester, a poly(hydroxy acids), a polydioxanone, a polycarbonate, a polyaminocarbonate, a poly(vinyl pyrrolidone), a poly(ethyl oxazoline), a carboxymethyl cellulose, a hydroxyalkylated cellulose, a polypeptide, a polysaccharide, a carbohydrate, heparan sulfate, chondroitin sulfate, heparin, alginate, and a combination thereof.

27. The method of claim 26, wherein the at least one olefin compound comprises a polymeric moiety selected from the group consisting of polypeptide, poly(lactic acid) (PLA), poly(vinyl alcohol) (PVA), and poly(ethylene glycol) (PEG), and a combination thereof.

28. The method of claim 27, wherein the polymeric moiety of the at least one olefin compound is poly(ethylene glycol) (PEG).

29. The method of claim 21, wherein the at least one olefin compound comprises an ene group selected from the group consisting of a vinyl moiety, a vinyl ether moiety, an allyl moiety, an acrylate moiety, a methacrylate moiety, a maleimide moiety, and a norbornene moiety.

30. The method of claim 21, wherein the at least one thiol compound is a branched thiol compound.

31. The method of claim 21, wherein the at least at least one olefin compound is a branched olefin compound.

32. The method of claim 21, wherein the ene group is a norbornene moiety.

33. The method of claim 21, wherein the molecular weight of the at least one thiol compound is from about 30 Da to about 50 kDa.

34. The method of claim 21, wherein the molecular weight of the at least one olefin compound is from about 30 Da to about 50 kDa.

35. The method of claim 21, wherein the at least one thiol compound is biodegradable.

36. The method of claim 21, wherein the at least one olefin compound is biodegradable.

37. The method of claim 21, wherein the polymerization reaction mixture further comprises a chemical initiator.

38. The method of claim 21, wherein the polymerization reaction mixture further comprises a biologically active component.

39. The method of claim 38, wherein the biologically active component is selected from the group consisting of cells, tissues, and tissue aggregates.

40. The method of claim 39, wherein the biologically active component is selected from the group consisting of chondrocytes, immortalized cell lines, stem cells, hormone-producing cells and fibroblasts.

41. The method of claim 39, wherein the biologically active component is selected from the group consisting of a protein, a pharmacologically active agent, and an agricultural chemical.

42. The method of claim 41, wherein the biologically active component is a protein selected from the group consisting of an adhesion peptide, growth factor, hormone, antihormone, signaling compound, enzyme, serum protein, albumin, macroglobulin, globulin, agglutinin, lectin, extracellular matrix protein, antibody, antigen, and a combination thereof.

43. The method of claim 41, wherein the biologically active component is a pharmacologically active agent selected from the group consisting of an analgesic, antipyretic, nonsteriodal antiinflammatory drug, antiallergic, antibacterial drug, antianemia drug, cytotoxic drug, antihypertensive drug, dermatological drug, psychotherapeutic drug, vitamin, mineral, anorexiant, dietetic, antiadiposity drug, carbohydrate metabolism drug, protein metabolism drug, thyroid drug, antithyroid drug, coenzymes, and a combination thereof.

44. The method of claim 41, wherein the biologically active component is an agricultural chemical selected from the group consisting of a fungicide, herbicide, fertilizer, pesticide, carbohydrate, nucleic acid, organic molecule, inorganic biologically active molecule, and a combination thereof.

45. The method of claim 38, wherein the radical polymerization reaction encapsulates the biologically active component within the biocompatible thiol-ene hydrogel.