Biomimmetic nanofiber scaffold for soft tissue and soft tissue-to-bone repair, augmentation and replacement

• US 20110066242A1
• Filed: 08/24/2010
• Published: 03/17/2011
• Est. Priority Date: 02/12/2007
• Status: Active Grant

• Current Assignee: Trustees Of Columbia University In The City Of New York (Columbia University)
• Original Assignee: Trustees Of Columbia University In The City Of New York (Columbia University)
• Inventors: Levine, William N., Moffat, Kristen L., Spalazzi, Jeffrey, Lu, Helen H.
• Granted Patent: US 8,864,843 B2
• Time in Patent Office: Days
• US Class Current: 623/13.14
• CPC Class Codes: A61F 2/08 Muscles; Tendons; Ligaments sutures A61B17/04
• CPC Class Codes: A61F 2/0811 Fixation devices for tendons or ligaments
• CPC Class Codes: A61F 2002/0858 Fixation of tendon or ligament between anchor and bone, e.g. interference screws, wedges
• CPC Class Codes: A61F 2210/0004 bioabsorbable
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 35/32 Bones; Osteocytes; Osteoblasts; Tendons; Tenocytes; Teeth; Odontoblasts; Cartilage; Chondrocytes; Synovial membrane
• CPC Class Codes: A61K 38/18 Growth factors; Growth regulators
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61L 2430/10 for reconstruction of tendons or ligaments
• 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: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: B29C 67/04 Sintering combined with compression B29C43/00

Abstract

An implantable device is provided for soft-tissue or soft tissue-to-bone repair, fixation, augmentation, or replacement that includes a biomimetic and biodegradable nanofiber scaffold. Also provided is a fully synthetic implantable multiphased scaffold which includes, in a single continuous construct, a plurality of phases to mimic the natural anatomy of a tendon or ligament and their insertion sites. Also provided are scaffold apparatuses for musculoskeletal tissue engineering.

Claims

1. An implantable device for soft-tissue or soft tissue-to-bone fixation, repair, augmentation, or replacement comprising a biomimetic and biodegradable nanofiber scaffold, which scaffold comprises one or more continuous phases.

2. The implantable device according to claim 1, wherein the nanofiber scaffold comprises a plurality of nanofibers made from a biodegradable polymer.

3. The implantable device according to claim 2, wherein the biodegradable polymer is selected from the group consisting of aliphatic polyesters, poly(amino acids), modified proteins, polydepsipeptides, copoly(ether-esters), polyurethanes, polyalkylenes oxalates, polyamides, poly(iminocarbonates), polyorthoesters, polyoxaesters, polyamidoesters, poly(ε

-caprolactone)s, polyanhydrides, polyarylates, polyphosphazenes, polyhydroxyalkanoates, polysaccharides, modified polysaccharides, polycarbonates, polytyrosinecarbonates, polyorthocarbonates, poly(trimethylene carbonate), poly(phosphoester)s, polyglycolide, polylactides, polyhydroxybutyrates, polyhydroxyvalerates, polydioxanones, polyalkylene oxalates, polyalkylene succinates, poly(malic acid), poly(maleic anhydride), polyvinylalcohol, polyesteramides, polycyanoacrylates, polyfumarates, poly(ethylene glycol), polyoxaesters containing amine groups, poly(lactide-co-glycolides), poly(lactic acid)s, poly(glycolic acid)s, poly(dioxanone)s, poly(alkylene alkylate)s, biopolymers, collagen, silk, chitosan, alginate, and a blend of two or more of the preceding polymers.

4. The implantable device according to claim 3, wherein the polymer comprises at least one of poly(lactide-co-glycolide), poly(lactide), and poly(glycolide).

5. The implantable device according to claim 3, wherein the polymer is a copolymer.

6. The implantable device according to claim 5, wherein the copolymer is poly(D,L-lactide-co-glycolide (PLGA).

7. The implantable device according to claim 6, wherein the ratio of polymers in the PLGA copolymer is between about 25:

75 to about 95;

5.

8. The implantable device according to claim 7, wherein the ratio of polymers in the PLGA copolymer is between about 85:

15.

9. The implantable device according to claim 2, wherein the nanofibers are aligned.

10. The implantable device according to claim 2, wherein the nanofibers are unaligned.

11. The implantable device according to claim 2, wherein the nanofiber scaffold comprises both aligned and unaligned nanofibers.

12. The implantable device according to claim 2, wherein the nanofiber alignment and orientation mimics the anatomy of a soft-tissue or a soft tissue-to-bone interface to be repaired, augmented, fixated, or replaced.

13. The implantable device according to claim 12, wherein the soft tissue is a ligament or tendon.

14. The implantable device according to claim 2, wherein the nanofiber alignment and orientation mimics the anatomy of a tendon-to-bone interface.

15. The implantable device according to claim 13, wherein the soft tissue is a rotator cuff.

16. The implantable device according to claim 1, wherein the scaffold is designed to mimic soft tissue and comprises a preformed interface region.

17. The implantable device according to claim 1, wherein the nanofiber scaffold is multiphasic and the scaffold is continuous from phase-to-phase.

18. The implantable device according to claim 17, wherein the phases are layered along a vertical axis.

19. The implantable device according to claim 17, wherein each phase is aligned along a horizontal axis.

20. The implantable device according to claim 17, wherein at least two phases are layered along a vertical axis and at least two phases are aligned along a horizontal axis.

21. The implantable device according to claim 17, wherein the nanofiber scaffold is biphasic.

22. The implantable device according to claim 21, wherein at least one of the phases comprises more than one layer and each layer is composed of the same or different nanofiber polymer and/or biocompatible ceramic, nanofiber orientation, and coating.

23. The implantable device according to claim 21, which comprises a first phase comprising nanofibers made from a biodegradable polymer and a second phase coupled to the first phase, which second phase comprises nanofibers made from a biodegradable polymer and a biocompatible ceramic, and the first phase is continuous with the second phase.

24. The implantable device according to claim 23, wherein the biocompatible ceramic is selected from the group consisting of silicon nitride-based ceramics, Pseudowollastonite ceramics (β

-CaSiO₃), bredigite (Ca₇MgSi₄O₁₆) ceramics, monophase ceramics of monticellite (CaMgSiO(4)), akermanite ceramics (Ca₂MgSi₂O₇), tricalcium silicate (Ca(3)SiO(5)), hydroxyapatite, bio-active glass, calcium phosphate, dense calcium sulfate (DCaS), porous silicated calcium phosphate (Si—

CaP), tricalcium phosphate (TCP), calcium pyrophosphate (CPP), and combinations thereof.

25. The implantable device according to claim 23, wherein at least one of the phases further comprises a bioactive agent selected from the group consisting of an anti-infective, an extracellular matrix component, an antibiotic, bisphosphonate, a hormone, an analgesic, an anti-inflammatory agent, a growth factor, an angiogenic factor, a chemotherapeutic agent, an anti-rejection agent, an RGD peptide, and combinations thereof.

26. The implantable device according to claim 25, wherein the growth factor is selected from the group consisting of a member of the Transforming Growth Factor (TGF) super family, a vascular endothelial growth factor (VEGF), a platelet-derived growth factor (PDGF), an insulin-derived growth factor (IGF), a modulator of a growth factor, and combinations thereof.

27. The implantable device according to claim 26, wherein a member of the TGF super family is selected from the group consisting of TGF-β

, bone morphogenetic proteins (BMPs), growth differentiation factors (GDFs), Activin A and Activin B, lnhibin A, lnhibin B, anti-mullerian hormone, Nodal, and combinations thereof.

28. The implantable device according to claim 27, wherein the TGF-β

is selected from the group consisting of TGF-β

1, TGF-β

2, TGF-β

3, and combinations thereof.

29. The implantable device according to claim 27, wherein the BMP is selected from the group consisting of BMP 1-20 and combinations thereof.

30. The implantable device according to claim 27, wherein the GDFs are selected from the group consisting of GDF1-15 and combinations thereof.

31. The implantable device according to claim 26, wherein the IGF is selected from the group consisting of IGF1, IGF2, insulin growth factor binding proteins 1-6 (IGFBP1-6), and combinations thereof.

32. The implantable device according to claim 26, wherein a modulator of a growth factor is a SMAD (small mothers against decapentaplegic) selected from the group consisting of SMAD1-9 and combinations thereof.

33. The implantable device according to claim 23, further comprising a hydrogel disposed on at least a portion of one or both of the phases.

34. The implantable device according to claim 33, wherein the hydrogel is composed of a material selected from the group consisting of agarose, carrageenan, polyethylene oxide, polyethylene glycol, tetraethylene glycol, triethylene glycol, trimethylolpropane ethoxylate, pentaerythritol ethoxylate, hyaluronic acid, thiosulfonate polymer derivatives, polyvinylpyrrolidone-polyethylene glycol-agar, collagen, dextran, heparin, hydroxyalkyl cellulose, chondroitin sulfate, dermatan sulfate, heparan sulfate, keratan sulfate, dextran sulfate, pentosan polysulfate, chitosan, alginates, pectins, agars, glucomannans, galactomannans, maltodextrin, amylose, polyalditol, alginate-based gels cross-linked with calcium, polymeric chains of methoxypoly(ethylene glycol) monomethacrylate, chitin, poly(hydroxyalkyl methacrylate), poly(electrolyte complexes), poly(vinylacetate) cross-linked with hydrolysable bonds, water-swellable N-vinyl lactams, carbomer resins, starch graft copolymers, acrylate polymers, polyacrylamides, polyacrylic acid, ester cross-linked polyglucans, and derivatives and combinations thereof.

35. The implantable device according to claim 33 further comprising fibroblasts, chondrocytes, osteoblasts, osteoblast-like cells, stem cells, and combinations thereof.

36. The implantable device according to claim 33, wherein fibroblasts, chondrocytes, stem cells, and combinations thereof are disposed on at least a portion of the first phase.

37. The implantable device according to claim 33, wherein chondrocytes, osteoblasts, osteoblast-like cells, stem cells, and combinations thereof are disposed on at least a portion of the second phase.

38. The implantable device according to claim 33, wherein fibroblasts, stem cells, and chondrocytes are disposed on at least a portion of the first phase and chondrocytes, osteoblasts, osteoblast-like cells, stem cells, and combinations thereof are disposed on at least a portion of the second phase.

39. The implantable device according to claim 35, wherein the stem cells are undifferentiated.

40. The method according to claim 35, wherein the stem cells are pre-differentiated prior to disposition on the implantable device.

41. The implantable device of claim 1, wherein the nanofiber scaffold has a fiber diameter of between about 568 to about 615 nm, a pore diameter of about 4.2 to about 4.9 μ

m, a porosity of about 80.7 to about 81.8%, and a permeability of about 5.7 to about 7.9×

10<sup>−

12</sup> m⁴/Ns.

42. An implantable biphasic biomimetic and biodegradable nanofiber device for soft-tissue or soft tissue-to-bone interface fixation, repair, augmentation, or replacement comprising a first phase comprising nanofibers made from a biodegradable polymer and a second phase coupled to the first phase, which second phase comprises nanofibers made from a biodegradable polymer and a biocompatible ceramic, wherein the first and second phases are continuous.

44. The implantable device according to claim 42, wherein the biodegradable polymer is selected from the group consisting of aliphatic polyesters, poly(amino acids), modified proteins, polydepsipeptides, copoly(ether-esters), polyurethanes, polyalkylenes oxalates, polyamides, poly(iminocarbonates), polyorthoesters, polyoxaesters, polyamidoesters, poly(ε

-caprolactone)s, polyanhydrides, polyarylates, polyphosphazenes, polyhydroxyalkanoates, polysaccharides, modified polysaccharides, polycarbonates, polytyrosinecarbonates, polyorthocarbonates, poly(trimethylene carbonate), poly(phosphoester)s, polyglycolide, polylactides, polyhydroxybutyrates, polyhydroxyvalerates, polydioxanones, polyalkylene Oxalates, polyalkylene succinates, poly(malic acid), poly(maleic anhydride), polyvinylalcohol, polyesteramides, polycyanoacrylates, polyfumarates, poly(ethylene glycol), polyoxaesters containing amine groups, poly(lactide-co-glycolides), poly(lactic acid)s, poly(glycolic acid)s, poly(dioxanone)s, poly(alkylene alkylate)s, biopolymers, collagen, silk, chitosan, alginate, and a blend of two or more of the preceding polymers.

45. The implantable device according to claim 42, wherein the biocompatible ceramic is selected from the group consisting of silicon nitride-based ceramics, Pseudowollastonite ceramics (β

-CaSiO₃), bredigite (Ca₇MgSi₄O₁₆) ceramics, mono-phase ceramics of monticellite (CaMgSiO(4)), akermanite ceramics (Ca₂MgSi₂O₇), tricalcium silicate (Ca(3)SiO(5)), hydroxyapatite, bio-active glass, calcium phosphate, dense calcium sulfate (DCaS), porous silicated calcium phosphate (Si—

CaP), tricalcium phosphate (TCP), calcium pyrophosphate (CPP), and combinations thereof.

46. The implantable device according to claim 42, wherein at least one of the phases further comprises a bioactive agent selected from the group consisting of an anti-infective, an extracellular matrix component, an antibiotic, bisphosphonate, a hormone, an analgesic, an anti-inflammatory agent, a growth factor, an angiogenic factor, a chemotherapeutic agent, an anti-rejection agent, an RGD peptide, and combinations thereof.

47. The implantable device according to claim 46, wherein the growth factor is selected from the group consisting of a member of the Transforming Growth Factor (TGF) super family, a vascular endothelial growth factor (VEGF), a platelet-derived growth factor (PDGF), an insulin-derived growth factor (IGF), a modulator of a growth factor, and combinations thereof.

48. The implantable device according to claim 47, wherein a member of the TGF super family is selected from the group consisting of TGF-β

, bone morphogenetic proteins (BMPs), growth differentiation factors (GDFs), Activin A and Activin B, lnhibin A, lnhibin B, anti-mullerian hormone, Nodal, and combinations thereof.

49. The implantable device according to claim 48, wherein the TGF-β

is selected from the group consisting of TGF-β

1, TGF-β

2, TGF-β

3, and combinations thereof.

50. The implantable device according to claim 48, wherein the BMP is selected from the group consisting of BMP1-20 and combinations thereof.

51. The implantable device according to claim 48, wherein the GDFs are selected from the group consisting of GDF1-15 and combinations thereof.

52. The implantable device according to claim 47, wherein the IGF is selected from the group consisting of IGF1, IGF2, insulin growth factor binding proteins 1-6 (IGFBP1-6), and combinations thereof.

53. The implantable device according to claim 47, wherein a modulator of a growth factor is a SMAD (small mothers against decapentaplegic) selected from the group consisting of SMAD1-9 and combinations thereof.

54. The implantable device according to claim 42, further comprising a hydrogel disposed on at least a portion of one or both of the phases.

55. The implantable device according to claim 54, wherein the hydrogel is composed of a material selected from the group consisting of agarose, carrageenan, polyethylene oxide, polyethylene glycol, tetraethylene glycol, triethylene glycol, trimethylolpropane ethoxylate, pentaerythritol ethoxylate, hyaluronic acid, thiosulfonate polymer derivatives, polyvinylpyrrolidone-polyethylene glycol-agar, collagen, dextran, heparin, hydroxyalkyl cellulose, chondroitin sulfate, dermatan sulfate, heparan sulfate, keratan sulfate, dextran sulfate, pentosan polysulfate, chitosan, alginates, pectins, agars, glucomannans, galactomannans, maltodextrin, amylose, polyalditol, alginate-based gels cross-linked with calcium, polymeric chains of methoxypoly(ethylene glycol) monomethacrylate, chitin, poly(hydroxyalkyl methacrylate), poly(electrolyte complexes), poly(vinylacetate) cross-linked with hydrolysable bonds, water-swellable N-vinyl lactams, carbomer resins, starch graft copolymers, acrylate polymers, polyacrylamides, polyacrylic acid, ester cross-linked polyglucans, and derivatives and combinations thereof.

56. The implantable device according to claim 55 further comprising fibroblasts, chondrocytes, osteoblasts, osteoblast-like cells, stem cells, and combinations thereof.

57. The implantable device according to claim 56, wherein fibroblasts, stem cells, chondrocytes, and combinations thereof are disposed on at least a portion of the first phase.

58. The implantable device according to claim 56, wherein chondrocytes, osteoblasts, osteoblast-like cells, stem cells, and combinations thereof are disposed on at least a portion of the second phase.

59. The implantable device according to claim 56, wherein fibroblasts, stem cells, and chondrocytes are disposed on at least a portion of the first phase and chondrocytes, osteoblasts, osteoblast-like cells, stem cells, and combinations thereof are disposed on at least a portion of the second phase.

60. The implantable device according to claim 56, wherein the stem cells are undifferentiated.

61. The method according to claim 56, wherein the stem cells are pre-differentiated prior to disposition on the implantable device.

62. The implantable device according to claim 42, which is about 0.2 to about 2.0 mm thick.

63. The implantable device according to claim 62, which is about 5.0 cm in length and about 5.0 cm in width.

64. The implantable device according to claim 62, which has a diameter of about 10 cm.

43. An implantable device for fixation, repair, augmentation, or replacement of a rotator cuff or a tendon-to-bone interface thereof comprising a biphasic, biomimetic, and biodegradable nanofiber scaffold having a first phase comprising nanofibers whose anisotropy mimics that of a tendon and non-mineralized fibrocartilage, which nanofibers are made from a biodegradable polymer and a second phase coupled to the first phase, which second phase comprises nanofibers whose anisotropy mimics that of mineralized fibrocartilage and bone, which nanofibers are made from a biodegradable polymer and a biocompatible ceramic, wherein the first and second phases are continuous.

65. A method for fixating, repairing, augmenting, or replacing a damaged soft tissue or soft tissue-to-bone interface in a patient comprising affixing a biomimetic, biodegradable, continuous multiphasic nanofiber scaffold to a surgically relevant site in order to repair, augment, or replace the damaged soft tissue or soft tissue-to-bone interface.

66. A method for fixating, repairing, augmenting, or replacing a damaged rotator cuff in a patient comprising affixing a biomimetic and biodegradable continuous multiphase nanofiber scaffold to a surgically relevant site in order to repair, augment, or replace the damaged rotator cuff.

67-155. -155. (canceled)