Multi-phased, biodegradable and osteointegrative composite scaffold for biological fixation of musculoskeletal soft tissue to bone

• US 20060067969A1
• Filed: 03/04/2005
• Published: 03/30/2006
• Est. Priority Date: 03/05/2004
• 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., Dionisio, Kathie, Spalazzi, Jeffrey
• Granted Patent: US 7,767,221 B2
• Time in Patent Office: Days
• US Class Current: 424/423
• 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 2/3094 Designing or manufacturing processes
• CPC Class Codes: A61F 2002/0086 for preferentially controlling or promoting the growth of specific types of cells or tissues of bone tissue onto implantable joints A61F2002/3093
• CPC Class Codes: A61F 2002/30004 the prosthesis being made from materials having different values of a given property at different locations within the same prosthesis
• CPC Class Codes: A61F 2002/30011 differing in porosity
• CPC Class Codes: A61F 2002/30028 differing in tissue ingrowth capacity, e.g. made from both ingrowth-promoting and ingrowth-preventing parts
• CPC Class Codes: A61F 2002/30059 differing in bone mineralization, e.g. made from both mineralized and demineralized adjacent parts
• CPC Class Codes: A61F 2002/30062 (bio)absorbable, biodegradable, bioerodable, (bio)resorbable, resorptive
• CPC Class Codes: A61F 2002/30327 differing in diameter
• CPC Class Codes: A61F 2002/30677 Means for introducing or releasing pharmaceutical products, e.g. antibiotics, into the body
• CPC Class Codes: A61F 2002/3093 for promoting ingrowth of bone tissue
• CPC Class Codes: A61F 2002/30968 Sintering
• CPC Class Codes: A61F 2210/0004 bioabsorbable
• CPC Class Codes: A61F 2240/001 Designing or manufacturing processes
• CPC Class Codes: A61F 2250/0014 having different values of a given property or geometrical feature, e.g. mechanical property or material property, at different locations within the same prosthesis
• CPC Class Codes: A61F 2250/0023 differing in porosity
• CPC Class Codes: A61F 2250/0039 differing in diameter
• CPC Class Codes: A61F 2250/0051 differing in tissue ingrowth capacity, e.g. made from both ingrowth-promoting and ingrowth-preventing parts
• CPC Class Codes: A61F 2250/0067 Means for introducing or releasing pharmaceutical products into the body
• CPC Class Codes: A61F 2310/00293 : containing a phosphorus-containing compound, e.g. apatite
• CPC Class Codes: A61L 2430/30 : for muscle reconstruction
• CPC Class Codes: A61L 2430/34 : for soft tissue reconstruction
• CPC Class Codes: A61L 27/12 : Phosphorus-containing materials, e.g. apatite
• CPC Class Codes: A61L 27/3839 : characterised by the site of application in the body materials for artificial blood vessels A61L27/507; materials for use in artificial skin A61L27/60
• CPC Class Codes: A61L 27/3891 : as distinct cell layers
• CPC Class Codes: A61L 27/446 : with other specific inorganic fillers other than those covered by A61L27/443 or A61L27/46
• CPC Class Codes: A61L 27/46 : with phosphorus-containing inorganic fillers

Abstract

Methods and apparatuses are provided for musculoskeletal tissue engineering. For example, a scaffold apparatus is provided which comprises microspheres of selected sizes and/or composition. The microspheres are layered to have a gradient of microsphere sizes and/or compositions. The scaffold provides a functional interface between multiple tissue types.

Claims

1. A scaffold apparatus for musculoskeletal tissue engineering, said apparatus comprising microspheres of selected sizes and/or composition, wherein the microspheres are layered to have a gradient of microsphere sizes and/or compositions, and the scaffold provides a functional interface between multiple tissue types.

2. The scaffold apparatus of claim 1, wherein the scaffold apparatus promotes growth and maintenance of the multiple tissue types.

3. The scaffold apparatus of claim 1, wherein the scaffold supports growth, maintenance and differentiation of multiple tissue and cell types.

4. The scaffold apparatus of claim 1, further comprising:

a first region comprising composite microspheres of a first size and composition optimized to promote growth, proliferation, and differentiation of a first cell type for integration and growth of a first tissue type;

a second region joined to the first region, said second region comprising at least one of microspheres and a fibrous mesh, said one of microspheres and a fibrous mesh having a second size and a second composition;

a third region joined to the second region, said third region comprising microspheres and/or a fibrous mesh, said microspheres and/or fibrous mesh having a third size and a third composition, and said second and third regions being optimized to promote growth, proliferation and differentiation of a second cell type for integration and formation of a second tissue type; and

a fourth region joined to the third region, said fourth region comprising at least one of microspheres and/or a fibrous mesh, said microspheres and/or fibrous mesh having a composition adapted to promote growth, proliferation, and differentiation of a third cell type for integration and growth of a third tissue type,

wherein said first, second, third and fourth regions are joined together through one of a solid state sintering process and a solvent aggregation process, in which selected growth factors or bioactive agents are incorporated into each region to promote formation, growth and integration of said first, second and third types of tissues.

5. The scaffold apparatus of claim 1, wherein the scaffold provides a functional interface between soft tissue and bone.

6. The scaffold apparatus of claim 5, wherein the scaffold has multiple phases including a first phase for supporting growth and maintenance of the soft tissue, a second phase for supporting growth and maintenance of the bone, and a third phase as an interfacial zone supporting growth of fibrocartilage between said first and second phases.

7. The scaffold apparatus of claim 6, wherein the first phase for supporting growth and maintenance of the soft tissue is seeded with at least one of fibroblasts, chondrocytes and stem cells.

8. The scaffold apparatus of claim 6, wherein the first phase of the scaffold includes a fiber mesh.

9. The scaffold apparatus of claim 8, wherein said fiber mesh is electrospun.

10. The scaffold apparatus of claim 6, wherein the second phase for supporting growth and maintenance of the bone is seeded with at least one of osteoblasts, osteoblast-like cells and stem cells.

11. The scaffold apparatus of claim 10, wherein said second phase contains at least one of osteogenic agents, osteogenic materials, osteoinductive agents, osteoinductive materials, osteoconductive agents, osteoconductive materials, growth factors and chemical factors.

12. The scaffold apparatus of claim 6, wherein the third phase includes at least some of said microspheres.

13. The scaffold apparatus of claim 12, wherein the third phase includes a gradient of microsphere sizes.

14. The scaffold apparatus of claim 12, wherein the third phase includes a gradient of microsphere compositions.

15. The scaffold apparatus of claim 12, wherein the microspheres in the third phase are joined by sintering in at least one stage.

16. The scaffold apparatus of claim 12, wherein the second phase of the scaffold further includes additional microspheres.

17. The scaffold apparatus of claim 16, wherein the at least some of said microspheres of the third phase are in a first range of diameters, and the additional microspheres of the second phase are in a second range of diameters, the second range being nonoverlapping with the first range.

18. The scaffold apparatus of claim 6, wherein said scaffold apparatus is integrated in a graft collar.

19. The scaffold apparatus of claim 18, wherein said graft collar is adapted for hamstring tendon-to-bone healing.

20. The scaffold apparatus of claim 18, wherein said graft collar is adapted for peridontal ligament repair.

21. The scaffold apparatus of claim 18, wherein said graft collar is adapted for spinal repair.

22. The scaffold apparatus of claim 6, wherein said first phase is seeded with human hamstring tendon fibroblasts.

23. The scaffold apparatus of claim 6, wherein at least one of said first phase and said second phase is seeded with one or more agents by using a microfluidic system.

24. The scaffold apparatus of claim 1, wherein the scaffold has multiple phases joined by a gradient of properties.

25. The scaffold apparatus of claim 24, wherein the multiple phases of the scaffold are processed through one or more sintering stages.

26. The scaffold apparatus of claim 24, wherein the gradient of properties across the multiple phases of the scaffold includes mechanical properties.

27. The scaffold apparatus of claim 24, wherein the gradient of properties across the multiple phases of the scaffold includes chemical properties.

28. The scaffold apparatus of claim 24, wherein the gradient of properties across the multiple phases of the scaffold includes mineral content.

29. The scaffold apparatus of claim 24, wherein the gradient of properties across the multiple phases of the scaffold includes structural properties.

30. The scaffold apparatus of claim 24, wherein the gradient of properties across the multiple phases of the scaffold includes porosity.

31. The scaffold apparatus of claim 24, wherein the gradient of properties across the multiple phases of the scaffold includes geometry.

32. The scaffold apparatus of claim 1, wherein a first phase of the microspheres comprises polymer and a second phase of the microspheres comprises one of bioactive glass and calcium phosphate.

33. The scaffold apparatus of claim 32, wherein the calcium phosphate is selected from a group comprising tricalcium phosphate, hydroxyapatite, and a combination thereof.

34. The scaffold apparatus of claim 32, wherein the polymer is selected from a group comprising aliphatic polyesters, poly(amino acids), copoly(ether-esters), polyalkylenes oxalates, polyamides, poly(iminocarbonates), polyorthoesters, polyoxaesters, polyamidoesters, poly(E-caprolactone)s, polyanhydrides, polyarylates, polyphosphazenes, polyhydroxyalkanoates, polysaccharides, and biopolymers, and a blend of two or more of the preceding polymers.

35. The scaffold apparatus of claim 34, wherein the polymer comprises at least one of poly(lactide-co-glycolide), poly(lactide) and poly(glycolide).

36. The scaffold apparatus of claim 6, wherein the first phase of the scaffold includes a fiber mesh, and the fiber mesh of the first phase and the microspheres of said third phase are sintered together.

37. The scaffold apparatus of claim 1, wherein the microspheres are processed through one or more sintering stages.

38. The scaffold apparatus of claim 1, wherein the scaffold includes a composite of said microspheres and a fiber mesh.

39. The scaffold apparatus of claim 38, wherein the fiber mesh is a degradable polymer.

40. The scaffold apparatus of claim 38, wherein said fiber mesh is electrospun.

41. The scaffold apparatus of claim 38, wherein at least one of bioactive agents and peptides coat the surface of the mesh.

42. The scaffold apparatus of claim 41, wherein the bioactive agents and peptides enhance differentiation, proliferation and attachment of cells and specific cell types.

43. The scaffold apparatus of claim 31, wherein at least one of bioactive agents and peptides are directly incorporated into the mesh.

44. The scaffold apparatus of claim 1, wherein the apparatus is biomimetic.

45. The scaffold apparatus of claim 1, wherein the apparatus is biodegradable.

46. The scaffold apparatus of claim 1, wherein the apparatus is osteointegrative.

47. The scaffold apparatus of claim 1, wherein the microspheres are degradable.

48. The scaffold apparatus of claim 1, wherein at least one of bioactive agents and peptides coat the surface of at least some of the microspheres.

49. The scaffold apparatus of claim 48, wherein the bioactive agents and peptides enhance at least one of differentiation, proliferation and attachment of cells and specific cell types.

50. The scaffold apparatus of claim 1, wherein at least one of bioactive agents and peptides are directly incorporated into at least some of the microspheres.

51. The scaffold apparatus of claim 1, wherein the microspheres additionally include one or more agents selected from a group comprising antiinfectives, hormones, analgesics, anti-inflammatory agents, growth factors, chemotherapeutic agents, anti-rejection agents and RGD peptides.

52. The scaffold apparatus of claim 6, wherein the second phase comprises one of polymeric and composite microspheres including a range of diameters or a gradient of diameter.

53. The scaffold apparatus of claim 6, wherein the second phase comprises polymeric hydrogels of one of polyethylene glycol and hydroxyethyl methacrylate.

54. The scaffold apparatus of claim 53, wherein the hydrogel comprises one or more of poly(ethylene glycol), agarose, alginate, 2-hydroxyethyl methacrylate and polyacrylamide.

55. The scaffold apparatus of claim 6, wherein the second phase comprises collagen gels with varied mineral content.

56. The scaffold apparatus of claim 1, wherein varying concentrations of calcium phosphate are incorporated into the microspheres.

57. A scaffold apparatus for soft tissue-to-bone interface tissue engineering comprising:

a first region comprising composite microspheres of a first size and composition optimized to promote growth, proliferation, and differentiation of a first cell type for integration and growth of a first tissue type;

a second region joined to the first region, said second region comprising microspheres and/or a fibrous mesh, said microspheres and/or fibrous mesh having a second size and a second composition;

a third region joined to the second region, said third region comprising microspheres and/or a fibrous mesh, said microspheres and/or fibrous mesh having a third size and a third composition, and said second and third regions being optimized to promote growth, proliferation and differentiation of a second cell type for integration and formation of a second tissue type; and

a fourth region joined to the third region, said fourth region comprising at least one of a microsphere and a fibrous mesh, said one of a microsphere and a fibrous mesh having a composition adapted to promote growth, proliferation, and differentiation of a third cell type for integration and growth of a third tissue type.

58. The scaffold apparatus of claim 57, wherein said first, second, third and fourth regions are joined together through one of a solid state sintering process and a solvent aggregation process, in which selected growth factors or bioactive agents are incorporated into each region to promote formation, growth and integration of said first, second and third types of tissues.

59. The scaffold apparatus of claim 57, wherein said composite microspheres of said first region include a range of sizes.

60. The scaffold apparatus of claim 57, wherein said at least one of microspheres and a fibrous mesh of said second region include a range of sizes.

61. The scaffold apparatus of claim 57, wherein said at least one of microspheres and a fibrous mesh of said second region include a gradient of sizes.

62. The scaffold apparatus of claim 57, wherein said at least one of microspheres and a fibrous mesh of said second region include a gradient of compositions.

63. The scaffold apparatus of claim 57, wherein said at least one of a microsphere and a fibrous mesh of said third region include a range of sizes.

64. The scaffold apparatus of claim 57, wherein said at least one of a microsphere and a fibrous mesh of said third region include a gradient of sizes.

65. The scaffold apparatus of claim 57, wherein said at least one of a microsphere and a fibrous mesh of said third region include a gradient of compositions.

66. The scaffold apparatus of claim 57, wherein said fibrous mesh is electrospun.

67. The scaffold apparatus of claim 57, wherein said scaffold apparatus is integrated in a graft collar.

68. A multi-phased scaffold apparatus for providing a functional interface between bone and soft tissue, comprising:

microspheres as one phase of the scaffold; and

a mesh as another phase of the scaffold,

wherein the microspheres and the mesh are sintered or solvent casted together.

69. The multi-phased scaffold apparatus of claim 68, wherein said mesh is electrospun.

70. The multi-phased scaffold apparatus of claim 68, wherein said multi-phased scaffold apparatus is integrated in a graft collar.

71. A method for preparing a scaffold for musculoskeletal tissue engineering, said method comprising the steps of:

(a) processing a plurality of microspheres, including incorporating calcium phosphate into the microspheres;

(b) laying the microspheres processed in step (a) in a mold, the microspheres in the mold presenting a gradient of microsphere sizes and/or compositions; and

(c) sintering together the microspheres in the mold above a glass transition temperature.

72. The method of claim 71, further comprising sintering a fiber mesh onto the microsphere construct prepared in step (c), to provide a functional interface between multiple tissue types.

73. The method of claim 72, further comprising the step of electrospinning said fiber mesh prior to attaching the fiber mesh onto the microsphere construct.

74. The method of claim 71, wherein varying concentrations of calcium phosphate are incorporated into the microspheres in step (a).

75. The method of claim 71, wherein the calcium phosphate incorporated into the microspheres includes hydroxyapatite.

76. The method of claim 71, wherein the particulate phase of the microspheres includes bioactive glass.

77. The method of claim 76, wherein varying porosity of bioactive glass are incorporated into the microspheres in step (a).

78. The method of claim 76, wherein varying concentrations of bioactive glass are incorporated into the microspheres in step (a).

79. The method of claim 71, further comprising applying a particle reinforcement process to the microspheres.

80. The method of claim 71, further comprising incorporating particulates in the microspheres prior to step (c) to strengthen the microspheres.

81. A method for preparing a multi-phase scaffold for musculoskeletal tissue engineering, said method comprising the steps of:

(a) processing a plurality of microspheres, including incorporating at least one of calcium phosphate and bioactive glass into the microspheres;

(b) laying the microspheres processed in step (a) in a mold, wherein the microspheres in the mold presenting a gradient of microsphere sizes for a first phase and a second phase of the multi-phase scaffold, with microspheres of the first phase being in a first range of sizes, and with microspheres of the second phase being in a second range of sizes larger than the first range of sizes;

(c) sintering together the microspheres in the mold above a glass transition temperature; and

(d) attaching a fiber mesh, as a third phase of the multi-phase scaffold, onto the microsphere construct prepared in step (c).

82. The method of claim 81, further comprising seeding the third phase with at least one of fibroblasts, chondrocytes and stem cells, for supporting growth and maintenance of soft tissue.

83. The method of claim 81, further comprising seeding the first phase with at least one of osteoblasts, osteoblast-like cells and stem cells, for supporting growth and maintenance of bone.

84. The method of claim 81, wherein the first phase supports growth and maintenance of bone, the third phase supports growth and maintenance of soft tissue, and the second phase serves as an interfacial zone between said first and third phases for growth and maintenance of fibrocartilage.

85. The method of claim 81, further comprising the step of seeding the third phase with human hamstring tendon fibroblasts.

86. The method of claim 81, further comprising the step of seeding at least one of said first, second and phases with one or more agents by using a microfluidic system.

87. The method of claim 81, further comprising the step of electrospinning said fiber mesh prior to attaching the electrospun fiber mesh onto the microsphere construct.

88. The method of claim 81, further comprising the steps of:

seeding the first phase with first cells, for supporting growth and maintenance of the bone;

seeding the third phase with second cells for supporting growth and maintenance of the soft tissue; and

allowing at least some of said first cells and said second cells to migrate to the second phase.

89. A method for preparing a multi-phase scaffold for musculoskeletal tissue engineering, said method comprising the steps of:

(a) forming a mesh scaffold by sintering together a plurality of mesh segments as a first phase of the multi-phase scaffold;

(b) forming a second scaffold by sintering together a plurality of poly-lactide-co-glycolide microspheres as a second phase of the multi-phase scaffold; and

(c) forming a third scaffold by sintering together a plurality of microspheres formed of a composite of poly-lactide-co-glycolide and bioactive glass as a third phase of the multi-phase scaffold; and

(d) sintering together said mesh scaffold, said second scaffold and said third scaffold.