Biohybrid elastomeric scaffolds and methods of use thereof

• US 20080268019A1
• Filed: 07/06/2007
• Published: 10/30/2008
• Est. Priority Date: 07/07/2006
• Status: Active Grant

• Current Assignee: University of Pittsburgh of The Commonwealth System of Higher Education
• Original Assignee: University of Pittsburgh of The Commonwealth System of Higher Education
• Inventors: Stankus, John, Badylak, Stephen F., Gilbert, Thomas W., Wagner, William R., Guan, Jianjun, Freytes, Donald O.
• Granted Patent: US 8,535,719 B2
• Time in Patent Office: Days
• US Class Current: 424/426
• CPC Class Codes: A61L 27/3633 Extracellular matrix [ECM]
• CPC Class Codes: A61L 27/3804 characterised by specific cells or progenitors thereof, e.g. fibroblasts, connective tissue cells, kidney cells
• CPC Class Codes: A61L 27/56 Porous materials, e.g. foams or sponges
• CPC Class Codes: A61L 27/58 Materials at least partially resorbable by the body
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Provided herein is a biohybrid elastomeric scaffold comprising a synthetic polymeric component and a biological polymeric component. The scaffold can be fabricated to have many different forms, non-limiting examples of which include a non-woven fibrous mesh or in a porous composite. Methods of use of the biohybrid elastomeric scaffolds in wound healing and tissue regeneration are also provided.

Claims

1. An elastomeric scaffold comprising a synthetic polymeric component and a biological polymeric component, wherein the scaffold is porous, biodegradable, and biocompatible.

2. The elastomeric scaffold of claim 1, in which the synthetic polymeric component comprises a thermoplastic biodegradable elastomer.

3. The elastomeric scaffold of claim 2, wherein the thermoplastic biodegradable elastomer comprises one or both of a poly(ester urethane) urea elastomer and a poly(ether ester urethane urea) elastomer.

4. The elastomeric scaffold of claim 3, wherein the elastomer comprises a diamine.

5. The elastomeric scaffold of claim 4, wherein the diamine is putrescine.

6. The elastomeric scaffold of claim 4, wherein the diamine is lysine ethyl ester.

7. The elastomeric scaffold of claim 3, wherein the elastomer comprises a polycaprolactone.

8. The elastomeric scaffold of claim 3, wherein the elastomer comprises a polycaprolactone diol.

9. The elastomeric scaffold of claim 3, wherein the elastomer comprises a triblock copolymer comprising polycaprolactone.

10. The elastomeric scaffold of claim 9, wherein the elastomer comprises a polycaprolactone-b-polyethylene glycol-b-polycaprolactone triblock copolymer.

11. The elastomeric scaffold of claim 3, wherein the elastomer is functionalized with an adhesion-promoting peptide.

12. The elastomeric scaffold of claim 11, wherein the adhesion-promoting peptide comprises the oligopeptide RGD.

13. The elastomeric scaffold of claim 3, wherein the elastomer comprises an isocyanate derivative, a polycaprolactone diol, and a diamine chain extender.

14. The elastomeric scaffold of claim 13, wherein the ratio of isocyanate derivative:

polycaprolactone diol;

diamine chain extender is 2;

1;

1.

15. The elastomeric scaffold of claim 3, wherein the elastomer comprises an isocyanate derivative, a triblock copolymer comprising polycaprolactone, and a diamine chain extender.

16. The elastomeric scaffold of claim 15, wherein the ratio of isocyanate derivative:

triblock copolymer;

diamine chain extender is 2;

1;

1.

17. The elastomeric scaffold of claim 1, in which the biological polymeric component comprises an extracellular matrix-derived material.

18. The elastomeric scaffold of claim 17, wherein the extracellular matrix-derived material is isolated from urinary bladder tissue.

19. The elastomeric scaffold of claim 18, wherein the extracellular matrix-derived material comprises epithelial basement membrane and subjacent tunica propria.

20. The elastomeric scaffold of claim 18, wherein the extracellular matrix-derived material comprises tunica submucosa.

21. The elastomeric scaffold of claim 18, wherein the extracellular matrix-derived material comprises epithelial basement membrane, subjacent tunica propria and tunica submucosa.

22. The elastomeric scaffold of claim 17, wherein the extracellular matrix-derived material is isolated from small intestinal submucosa or the dermis of the skin.

23. The elastomeric scaffold of claim 1, wherein the elastomeric scaffold comprises a therapeutic agent.

24. The elastomeric scaffold of claim 23, wherein the therapeutic agent is an antimicrobial agent chosen from one or more of:

isoniazid, ethambutol, pyrazinamide, streptomycin, clofazimine, rifabutin, fluoroquinolones, ofloxacin, sparfloxacin, rifampin, azithromycin, clarithromycin, dapsone, tetracycline, erythromycin, ciprofloxacin, doxycycline, ampicillin, amphotericin B, ketoconazole, fluconazole, pyrimethamine, sulfadiazine, clindamycin, lincomycin, pentamidine, atovaquone, paromomycin, diclazaril, acyclovir, trifluorouridine, foscarnet, penicillin, gentamicin, ganciclovir, iatroconazole, miconazole, Zn-pyrithione, and silver salts such as chloride, bromide, iodide and periodate.

25. The elastomeric scaffold of claim 23, wherein the therapeutic agent is a growth factor chosen from one or more of:

basic fibroblast growth factor (bFGF), acidic fibroblast growth factor (aFGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), insulin-like growth factors 1 and 2 (IGF-1 and IGF-2), platelet derived growth factor (PDGF), stromal derived factor 1 alpha (SDF-1 alpha), nerve growth factor (NGF), ciliary neurotrophic factor (CNTF), neurotrophin-3, neurotrophin-4, neurotrophin-5, pleiotrophin protein (neurite growth-promoting factor

     1), midkine protein (neurite growth-promoting factor

     2), brain-derived neurotrophic factor (BDNF), tumor angiogenesis factor (TAF), corticotrophin releasing factor (CRF), transforming growth factors α and

β

(TGF-α and

TGF-β

), interleukin-8 (IL-8), granulocyte-macrophage colony stimulating factor (GM-CSF), interleukins, and interferons.

26. The elastomeric scaffold of claim 23, wherein the therapeutic agent is in the form of cells.

27. The elastomeric scaffold of claim 26, wherein the cells are one or more of stem cells, precursor stem cells, smooth muscle cells, skeletal myoblasts, myocardial cells, endothelial cells, and genetically modified cells.

28. The elastomeric scaffold of claim 1, wherein the elastomeric scaffold is produced by suspending a synthetic polymeric component and a biological polymeric component in a solvent to form a mixture;

and electrospinning the mixture to form an elastomeric scaffold.

29. The elastomeric scaffold of claim 1, wherein the elastomeric scaffold is produced by suspending a synthetic polymeric component in a solvent to form a solution, suspending a biological polymeric component in another solvent to form a solution;

and independently electrospinning the solutions to form an elastomeric scaffold.

30. The elastomeric scaffold of claim 1, wherein the elastomeric scaffold is produced by casting a polymer composition comprising a synthetic polymeric component and a biological polymeric component in a mold.

31. The elastomeric scaffold of claim 30, wherein the elastomeric scaffold is prepared by one or both of thermally induced phase separation and solvent casting.

32. The elastomeric scaffold of claim 31, wherein the elastomeric scaffold is prepared by thermally induced phase separation.

33. The elastomeric scaffold of claim 31, wherein the elastomeric scaffold is prepared by solvent casting.

34. The elastomeric scaffold of claim 31, further comprising electrospinning a solution containing a polymeric component to form a fiber coating onto or around the elastomeric scaffold.

41. A method of promoting wound healing or tissue generation or regeneration in a patient comprising implanting the elastomeric scaffold of claim 1 at or near a site for wound healing or tissue generation or regeneration in the patient.

42. A method of promoting wound healing or tissue generation or regeneration in a patient, comprising

a) contacting the elastomeric scaffold of claim 1 with cells in vitro;

b) culturing the cells in vitro so that the cells grow in and/or on the scaffold;

c) implanting the elastomeric scaffold at or near a site for wound healing or tissue generation or regeneration in the patient.

43. The method of claim 41, wherein the elastomeric scaffold comprises a therapeutic agent.

44. The method of claim 43, wherein the therapeutic agent is an antimicrobial agent chosen from one or more of isoniazid, ethambutol, pyrazinamide, streptomycin, clofazimine, rifabutin, fluoroquinolones, ofloxacin, sparfloxacin, rifampin, azithromycin, clarithromycin, dapsone, tetracycline, erythromycin, ciprofloxacin, doxycycline, ampicillin, amphotericin B, ketoconazole, fluconazole, pyrimethamine, sulfadiazine, clindamycin, lincomycin, pentamidine, atovaquone, paromomycin, diclazaril, acyclovir, trifluorouridine, foscarnet, penicillin, gentamicin, ganciclovir, iatroconazole, miconazole, Zn-pyrithione, and silver salts such as chloride, bromide, iodide and periodate.

45. The method of claim 43, wherein the therapeutic agent is a growth factor chosen from one or more of basic fibroblast growth factor (bFGF), acidic fibroblast growth factor (aFGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), insulin-like growth factors 1 and 2 (IGF-1 and IGF-2), platelet derived growth factor (PDGF), stromal derived factor 1 alpha (SDF-1 alpha), nerve growth factor (NGF), ciliary neurotrophic factor (CNTF), neurotrophin-3, neurotrophin-4, neurotrophin-5, pleiotrophin protein (neurite growth-promoting factor 1), midkine protein (neurite growth-promoting factor 2), brain-derived neurotrophic factor (BDNF), tumor angiogenesis factor (TAF), corticotrophin releasing factor (CRF), transforming growth factors α

and β

(TGF-α and

TGF-β

), interleukin-8 (IL-8), granulocyte-macrophage colony stimulating factor (GM-CSF), interleukins, and interferons.

46. The method of claim 42, the elastomeric scaffold comprises a therapeutic agent.

47. The method of claim 46, wherein the therapeutic agent is an antimicrobial agent chosen from one or more of isoniazid, ethambutol, pyrazinamide, streptomycin, clofazimine, rifabutin, fluoroquinolones, ofloxacin, sparfloxacin, rifampin, azithromycin, clarithromycin, dapsone, tetracycline, erythromycin, ciprofloxacin, doxycycline, ampicillin, amphotericin B, ketoconazole, fluconazole, pyrimethamine, sulfadiazine, clindamycin, lincomycin, pentamidine, atovaquone, paromomycin, diclazaril, acyclovir, trifluorouridine, foscarnet, penicillin, gentamicin, ganciclovir, iatroconazole, miconazole, Zn-pyrithione, and silver salts such as chloride, bromide, iodide and periodate.

48. The method of claim 46, wherein the therapeutic agent is a growth factor chosen from one or more of basic fibroblast growth factor (bFGF), acidic fibroblast growth factor (aFGF), vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), insulin-like growth factors 1 and 2 (IGF-1 and IGF-2), platelet derived growth factor (PDGF), stromal derived factor 1 alpha (SDF-1 alpha), nerve growth factor (NGF), ciliary neurotrophic factor (CNTF), neurotrophin-3, neurotrophin-4, neurotrophin-5, pleiotrophin protein (neurite growth-promoting factor 1), midkine protein (neurite growth-promoting factor 2), brain-derived neurotrophic factor (BDNF), tumor angiogenesis factor (TAF), corticotrophin releasing factor (CRF), transforming growth factors α

and β

(TGF-α and

TGF-β

), interleukin-8 (IL-8), granulocyte-macrophage colony stimulating factor (GM-CSF), interleukins, and interferons.

35. A method of producing a medical device comprising an elastomeric scaffold comprising forming a porous, biodegradable, and biocompatible elastomeric scaffold from a synthetic polymeric component and a biological polymeric component.

36. The method of claim 35, wherein the elastomeric scaffold is formed by one or more of electrospinning and casting.

37. The method of claim 35, comprising forming an elastomeric scaffold by casting to form a casted elastomeric scaffold and then electrospinning a polymer-containing solution onto and/or around the casted elastomeric scaffold, wherein the elastomeric scaffold comprises a synthetic polymeric component and a biological polymeric component.

38. The method of claim 35, wherein the elastomeric scaffold is formed by one or more of electrospinning, thermally induced phase separation and solvent casting.

39. The method of claim 35, in which the elastomeric scaffold is produced by suspending a synthetic polymeric component in a solvent to form a solution, suspending a biological polymeric component in another solvent to form a solution;

and independently electrospinning the solutions together to form an elastomeric scaffold.

40. The method of claim 35, in which the elastomeric scaffold is produced by suspending a synthetic polymeric component and a biological polymeric component in a solvent to form a mixture;

injecting the mixture into a pre-formed mold, subsequently cooling the pre-formed mold and extracting the solvent to form an elastomeric scaffold.