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

• US 8,864,843 B2
• Filed: 08/24/2010
• Issued: 10/21/2014
• 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: Lu, Helen H., Moffat, Kristen L., Levine, William N.
• Primary Examiner(s): STEWART, ALVIN J
• Application Number:
  US12/806,912
• Publication Number:
  US 20110066242A1
• Time in Patent Office: 1,519 Days
• Field of Search: 623 1311- 132, 623/14.12, 623 2372- 2376, 623/11.11, 623/18.11, 530353-357
• US Class Current: 623/23.72
• 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 scaffold, said scaffold being biphasic and continuous from a first phase to a second phase, wherein fibers in the first phase have at least one of different alignment, different orientation, different composition and different coating as compared to fibers in the second phase, and wherein the fibers in the first phase are made from a polymer and the second phase is coupled to the first phase, the fibers in the second phase are composite fibers, each of the composite fibers of the second phase is made from a combination of a polymer and a biocompatible ceramic.

2. The implantable device according to claim 1, 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.

3. The implantable device according to claim 1, 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.

4. The implantable device according to claim 3, 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.

5. The implantable device according to claim 4, 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.

6. The implantable device according to claim 5, wherein the TGF-β

is selected from the group consisting of TGF-β

1, TGF-β

2, TGF-β

3, and combinations thereof.

7. The implantable device according to claim 5, wherein the BMP is selected from the group consisting of BMP 1-20 and combinations thereof.

8. The implantable device according to claim 5, wherein the GDFs are selected from the group consisting of GDF1-15 and combinations thereof.

9. The implantable device according to claim 4, wherein the IGF is selected from the group consisting of IGF1, IGF2, insulin growth factor binding proteins 1-6 (IGFBP1-6), and combinations thereof.

10. The implantable device according to claim 4, 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.

11. The implantable device according to claim 1, further comprising a hydrogel disposed on at least a portion of one or both of the phases.

12. The implantable device according to claim 11, 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.

13. The implantable device according to claim 11 further comprising fibroblasts, chondrocytes, osteoblasts, osteoblast-like cells, stem cells, and combinations thereof.

14. The implantable device according to claim 13, wherein fibroblasts, chondrocytes, stem cells, and combinations thereof are disposed on at least a portion of the first phase.

15. The implantable device according to claim 13, wherein chondrocytes, osteoblasts, osteoblast-like cells, stem cells, and combinations thereof are disposed on at least a portion of the second phase.

16. The implantable device according to claim 13, 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.

17. The implantable device according to claim 13, wherein the stem cells are undifferentiated.

18. The implantable device according to claim 13, wherein the stem cells are pre-differentiated prior to disposition on the implantable device.

19. The implantable device according to claim 1, wherein the fibers in the first phase include nanofibers and the fibers in the second phase include nanofibers.

20. The implantable device according to claim 1, wherein the second phase further comprises particles or nanoparticles made from a biocompatible ceramic.

21. An implantable biphasic biomimetic device for soft-tissue or soft tissue-to-bone interface fixation, repair, augmentation, or replacement, comprising a first phase comprising fibers made from a polymer and a second phase coupled to the first phase, said second phase comprising composite fibers, and each of the composite fibers of the second phase is made from a combination of a polymer and a biocompatible ceramic, wherein the first and second phases are continuous.

22. The implantable device according to claim 21, wherein the 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.

23. The implantable device according to claim 21, 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.

24. The implantable device according to claim 21, 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.

25. The implantable device according to claim 24, 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.

26. The implantable device according to claim 25, 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.

27. The implantable device according to claim 26, wherein the TGF-β

is selected from the group consisting of TGF-β

1, TGF-β

2, TGF-β

3, and combinations thereof.

28. The implantable device according to claim 26, wherein the BMP is selected from the group consisting of BMP1-20 and combinations thereof.

29. The implantable device according to claim 26, wherein the GDFs are selected from the group consisting of GDF1-15 and combinations thereof.

30. The implantable device according to claim 25, wherein the IGF is selected from the group consisting of IGF1, IGF2, insulin growth factor binding proteins 1-6 (IGFBP1-6), and combinations thereof.

31. The implantable device according to claim 25, 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.

32. The implantable device according to claim 21, further comprising a hydrogel disposed on at least a portion of one or both of the phases.

33. The implantable device according to claim 32, 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.

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

35. The implantable device according to claim 34, wherein fibroblasts, stem cells, chondrocytes, and combinations thereof are disposed on at least a portion of the first phase.

36. The implantable device according to claim 34, wherein chondrocytes, osteoblasts, osteoblast-like cells, stem cells, and combinations thereof are disposed on at least a portion of the second phase.

37. The implantable device according to claim 34, 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.

38. The implantable device according to claim 34, wherein the stem cells are undifferentiated.

39. The implantable device according to claim 34, wherein the stem cells are pre-differentiated prior to disposition on the implantable device.

40. The implantable device according to claim 21, which is about 0.2 to about 2.0 mm thick.

41. The implantable device according to claim 40, which is about 5.0 cm in length and about 5.0 cm in width.

42. The implantable device according to claim 40, which has a diameter of about 10 cm.

43. The implantable device according to claim 21, wherein the fibers in the first phase include nanofibers and the fibers in the second phase include nanofibers.

44. The implantable device according to claim 21, wherein the second phase further comprises particles or nanoparticles made from a biocompatible ceramic.

45. An implantable device for fixation, repair, augmentation, or replacement of a rotator cuff or a tendon-to bone interface thereof comprising a biphasic and biomimetic scaffold having a first phase comprising fibers whose anisotropy mimics that of a tendon and non-mineralized fibrocartilage, said fibers having been made from a polymer, and a second phase coupled to the first phase, said second phase comprising composite fibers whose anisotropy mimics that of mineralized fibrocartilage and bone, each of said composite fibers is made from a combination of a polymer and a biocompatible ceramic, wherein the first and second phases are continuous.

46. The implantable device according to claim 45, wherein the fibers in the first phase include nanofibers and the fibers in the second phase include nanofibers.

47. The implantable device according to claim 45, wherein the second phase further comprises particles or nanoparticles made from a biocompatible ceramic.

48. An implantable device for soft-tissue or soft tissue-to-bone fixation, repair, augmentation, or replacement comprising a biomimetic scaffold, said scaffold comprising at least two adjacent continuous phases, wherein a first phase includes fibers having at least one of different alignment, different orientation, different composition and different coating as compared to fibers in a second phase, wherein the first phase comprises composite fibers, each composite fiber is made from a combination of a polymer and a biocompatible ceramic, the second phase is coupled to the first phase, said second phase comprising fibers made from a polymer, and further comprising a third phase coupled to the second phase, which third phase comprises composite fibers, each composite fiber is made from a combination of a polymer and a biocompatible ceramic, wherein the first, second and third phases are continuous.

49. The implantable device according to claim 48, wherein the fibers in the first phase include nanofibers and the fibers in the second phase include nanofibers.

50. The implantable device according to claim 48, wherein the first phase, the third phase or both the first and the third phase further comprises particles or nanoparticles made from a biocompatible ceramic.