INJECTABLE AND MOLDABLE BONE SUBSTITUTE MATERIALS

• US 20070191963A1
• Filed: 01/19/2007
• Published: 08/16/2007
• Est. Priority Date: 12/12/2002
• Status: Active Grant

• Current Assignee: Warsaw Orthopedic Incorporated (Medtronic Plc)
• Original Assignee: Warsaw Orthopedic Incorporated (Medtronic Plc)
• Inventors: Winterbottom, John, Knaack, David, Bhattacharyya, Subhabrata, Russell, James, Kaes, David, Boyce, Todd, Tunc, Deger
• Granted Patent: US 9,107,751 B2
• Time in Patent Office: Days
• US Class Current: 623/23.5
• CPC Class Codes: A61F 2/28 Bones joints A61F2/30
• CPC Class Codes: A61F 2002/2835 Bone graft implants for filling a bony defect or an endoprosthesis cavity, e.g. by synthetic material or biological material
• CPC Class Codes: A61F 2002/30062 (bio)absorbable, biodegradable, bioerodable, (bio)resorbable, resorptive
• CPC Class Codes: A61F 2002/30677 Means for introducing or releasing pharmaceutical products, e.g. antibiotics, into the body
• CPC Class Codes: A61F 2210/0004 bioabsorbable
• CPC Class Codes: A61F 2310/00293 containing a phosphorus-containing compound, e.g. apatite
• CPC Class Codes: A61F 2310/00359 Bone or bony tissue
• CPC Class Codes: A61F 2310/00365 Proteins; Polypeptides; Degradation products thereof
• CPC Class Codes: A61L 2400/06 Flowable or injectable implant compositions
• CPC Class Codes: A61L 2400/08 Methods for forming porous structures using a negative form which is filled and then removed by pyrolysis or dissolution
• CPC Class Codes: A61L 2430/02 for reconstruction of bones; weight-bearing implants
• 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
• CPC Class Codes: A61L 27/48 with macromolecular fillers
• 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

Abstract

An osteoimplant composite comprising a plurality of particles of an inorganic material, a bone substitute material, a bone-derived material, or any combination thereof; and a polymer material with which the particles are combined. The composite is either naturally moldable or flowable, or it can be made moldable or settable. After implantation, the composite may be set to provide mechanical strength to the implant. The inventive composite have the advantage of being able to fill irregularly shape implantation site while at the same time being settable to provide the mechanical strength required for most orthopedic applications. The invention also provides methods of using and preparing the moldable and flowable composites.

Claims

1. (canceled)

2. A composite osteoimplant comprising:

a plurality of bone-derived particles; and

a polymer with which the particles have been combined;

wherein the composite has an initial phase and a set phase;

wherein the set phase is more resistant to mechanical deformation relative to the initial phase.

7. The composite osteoimplant of claim 2, wherein the polymer has penetrated the pores, spaces, or voids of the particles.

8. The composite osteoimplant of claim 2, wherein the composite is moldable.

9. The composite osteoimplant of claim 2, wherein the composite can be shaped manually.

10. The composite osteoimplant of claim 2, wherein the composite can be shaped using a surgical instrument.

11. The composite osteoimplant of claim 2, wherein the composite can be shaped using a machine.

18. The composite osteoimplant of claim 2, wherein the suitable conditions for setting the composite include changing the temperature of the composite, changing the osmotic pressure of the composite, exposing the composite to electromagnetic radiation, cross-linking the composite, exposing the composite to a chemical agent, changing the water or solvent content of the composite, changing the content of a component of the composite, or changing a diffusion gradient.

19. The composite osteoimplant of claim 2, wherein the suitable conditions for setting the composite include cooling the composite.

20. The composite osteoimplant of claim 2, wherein the suitable conditions for setting the composite includes cooling the composite to body temperature of approximately 37°

C.

25. The composite osteoimplant of claim 2, wherein the suitable conditions for setting the composite include cooling the composite to a temperature below approximately 40°

C.

27. The composite osteoimplant of claim 2, wherein the suitable conditions for setting the composite include irradiating the composite with electromagnetic radiation.

32. The composite osteoimplant of claim 2, wherein the particles are fibers.

33. The composite osteoimplant of claim 2, wherein the particles are elongated particles.

42. The composite osteoimplant of claim 2, wherein the particle are between approximately 100 microns and approximately 1000 microns in their greatest dimension.

47. The composite osteoimplant of claim 2, wherein a particle size distribution of the particles with respect to a median value is such that 80 weight percent of the particles are plus and minus about 90% or less of the median.

48. The composite osteoimplant of claim 2, wherein a particle size distribution of the particles with respect to a median value is such that 80 weight percent of the particles are plus and minus about 50% or less of the median.

49. The composite osteoimplant of claim 2, wherein a particle size distribution of the particles with respect to a median value is such that 80 weight percent of the particles are plus and minus about 20% or less of the median.

51. The composite osteoimplant of claim 2, wherein the polymer is selected from the group consisting of poly(L-lactide-co-D,L-lactide), polyglyconate, poly(arylates), poly(anhydrides), poly(hydroxy acids), polyesters, poly(ortho esters), poly(alkylene oxides), polycarbonates, poly(propylene fumarates), poly(propylene glycol-co fumaric acid), poly(caprolactones), polyamides, polyesters, polyethers, polyureas, polyamines, polyamino acids, polyacetals, poly(orthoesters), poly(pyrolic acid), poly(glaxanone), poly(phosphazenes), poly(organophosphazene), polylactides, polyglycolides, poly(dioxanones), polyhydroxybutyrate, polyhydroxyvalyrate, polyhydroxybutyrate/valerate copolymers, poly(vinyl pyrrolidone), polycyanoacrylates, polyurethanes, and polysaccharides.

52. The composite osteoimplant of claim 2, wherein the polymer comprises poly(caprolactone).

53. The composite osteoimplant of claim 2, wherein the polymer comprises poly(lactide), poly(glycolide), poly(lactide-co-glycolide), and/or combination thereof.

54. The composite osteoimplant of claim 53, wherein the polymer comprises poly(lactide-co-glycolide),

wherein the percentage of lactide in the co-polymer ranges from approximately 45% to approximately 80%;

and

wherein the percentage of glycolide in the co-polymer ranges from approximately 55% to approximately 20%.

55. The composite osteoimplant of claim 53, wherein the polymer comprises poly(lactide-co-glycolide),

wherein the percentage of lactide in the co-polymer is approximately 75%;

and

wherein the percentage of glycolide in the co-polymer is approximately 25%.

56. The composite osteoimplant of claim 53, wherein the polymer comprises poly(lactide-co-glycolide),

wherein the percentage of lactide in the co-polymer is approximately 80%;

and

wherein the percentage of glycolide in the co-polymer is approximately 20%.

57. The composite osteoimplant of claim 53, wherein the polymer comprises poly(lactide-co-glycolide),

wherein the percentage of lactide in the co-polymer is approximately 50%;

and

wherein the percentage of glycolide in the co-polymer is approximately 50%.

58. The composite osteoimplant of claim 53, wherein the lactide is D,L-lactide.

59. The composite osteoimplant of claim 53, wherein the lactide is L-lactide.

61. The composite osteoimplant of claim 2, wherein the polymer is resorbed within approximately 1 month to approximately 6 years.

63. The composite osteoimplant of claim 2, wherein the polymer is resorbed within approximately 6 month to approximately 1 year.

64. The composite osteoimplant of claim 2, wherein the polymer is resorbed within approximately 1 year to approximately 3 years.

65. The composite osteoimplant of claim 2, further comprising a plasticizer.

66. The composite osteoimplant of claim 65, wherein the plasticizer is selected from the group consisting of bis(2-ethylhexyl)adipate (DOA), dimethyl adipate (DMAD), monomethyl adipate (MMAD), dioctyl adipate (DOA, bibutyl maleate (DBM), diisobutylmaleate (DIBM), dibutyl sebacate (DBS), triethyl citrate (TEC), acetyl triethyl citrate (ATEC), tributyl citrate (TBC), acetyl tributyl citrate (ATBC), trioctyl citrate (TOC), acetyl trioctyl citrate (ATOC), trihexyl citrate (THC), acetyl trihexyl citrate (ATHC), butyryl trihexyl citrate (BTHC), trimehtylcitrate (TMC), N-methyl phthalate, bis(2-ethylhexyl)phthalate (DEHP), diisononyl phthalate (DINP), bis(n-butyl)phthalate (DBP), butyl benzyl phthalate (BBzP), diisodecyl phthalate (DOP), diethyl phthalate (DEP), diisobutyl phthalate (DIBP), di-n-hexyl phthalate, glycerol, polyethylene glycol (PEG), triethylene glycol, sorbitol, monacetin, diacetin, trimethyl trimellitate (TMTM), tri-(2-ethylhexyl)trimellitate (TEHTM-MG), tri-(n-octyl,n-decyl) trimellitate (ATM), tri-(heptyl,nonyl)trimellitate (LTM), n-octyl trimellitate (OTM), benzoates, epoxidized vegetable oils, sulfonamides, N-ethyl toluene sulfonamide (ETSA), N-(2-hydroxypropyl)benzene sulfonamide (HP BSA), N-(n-butyl)butyl sulfonamide (BBSA-NBBS), organophosphates, tricresyl phosphate (TCP), tributyl phosphate (TBP), triethylene glycol dihexanoate, tetraethylene glycol diheptanoate, and polymeric plasticizers.

67. The composite osteoimplant of claim 65, wherein the plasticizer is poly(ethylene glycol) (PEG).

68. The composite osteoimplant of claim 65 wherein the plasticizer is PEG, wherein the PEG has an average molecule weight ranging from approximately 4,000 to approximately 10,000 g/mol.

74. The composite osteoimplant of claim 2, further comprising a porogen.

75. The composite osteoimplant of claim 74, whereby the porogen dissolves and/or degrades after implantation of the composite osteoimplant leaving a pore.

76. The composite osteoimplant of claim 74, wherein the porogen is water soluble.

81. The composite osteoimplant of claim 74, wherein the porogen is a gas.

82. The composite osteoimplant of claim 74, wherein the porogen is carbon dioxide.

86. The composite osteoimplant of claim 74, wherein the porogen is a carbohydrate.

87. The composite osteoimplant of claim 74, wherein the porogen is a polysaccharide or oligosaccharide.

88. The composite osteoimplant of claim 74, wherein the porogen is pullulan, poly(dextrose), sorbitol, or dextran.

91. The composite osteoimplant of claim 74, wherein the porogen is a polymer.

92. The composite osteoimplant of claim 74, wherein the porogen is selected from the group consisting of poly(vinylpyrollidone), poly(glycolide), poly(lactide), and poly(lactide-co-glycolide).

102. The composite osteoimplant of claim 2, wherein the composite after implantation has pores or channels that can support the in-growth of cells.

103. The composite osteoimplant of claim 2, wherein the composite after implantation has pores or channels that can support the formation or remodeling of bone.

104. The composite osteoimplant of claim 2, wherein the composite comprises latent pores that become actual pores after the composite is implanted in vivo.

105. The composite osteoimplant of claim 2, wherein the bone-derived material is selected from the group consisting of non-demineralized bone particles, demineralized bone particles, partially deminineralized bone particles, deorganified bone particles, and combinations thereof.

106. The composite osteoimplant of claim 2, wherein the bone-derived material is derived from cortical bone, cancellous bone, cortico-cancellous bone, and combinations thereof.

107. The composite osteoimplant of claim 2, wherein the bone-derived material is derived from autogenous bone, allogenic bone, or xenogeneic bone.

108. The composite osteoimplant of claim 2, wherein the inorganic material or bone substitute material is selected from the group consisting of aragonite, dahlite, calcite, amorphous calcium carbonate, vaterite, weddellite, whewellite, struvite, urate, ferrihydrite, francolite, monohydrocalcite, magnetite, goethite, dentin, calcium carbonate, calcium sulfate, calcium phosphosilicate, sodium phosphate, calcium aluminate, calcium phosphate, hydroxyapatite, α

-tricalcium phosphate, dicalcium phosphate, β

-tricalcium phosphate, tetracalcium phosphate, amorphous calcium phosphate, octacalcium phosphate (OCP), BIOGLASS™

, fluoroapatite, chloroapatite, magnesium-substituted tricalcium phosphate, carbonate hydroxyapatite, and combinations and derivative thereof.

112. The composite osteoimplant of claim 2, wherein the composite comprises approximately 40-70% particles by weight.

117. The composite osteoimplant of claim 2, wherein the composite comprises approximately 60% particles by weight.

119. The composite osteoimplant of claim 2, further comprising a bioactive agent.

120. The composite osteoimplant of claim 2, wherein the bioactive agent is selected from the group consisting of antiviral agent, antimicrobial agent, antibiotic agent, amino acid, peptide, protein, glycoprotein, lipoprotein, antibody, steroidal compound, antibiotic, antimycotic, cytokine, vitamin, carbohydrate, lipid, extracellular matrix, extracellular matrix component, chemotherapeutic agent, cytotoxic agent, growth factor, anti-rejection agent, analgesic, anti-inflammatory agent, viral vector, protein synthesis co-factor, hormone, endocrine tissue, synthesizer, enzyme, polymer-cell scaffolding agent with parenchymal cells, angiogenic drug, collagen lattice, antigenic agent, cytoskeletal agent, mesenchymal stem cells, bone digester, antitumor agent, cellular attractant, fibronectin, growth hormone cellular attachment agent, immunosuppressant, nucleic acid, surface active agent, hydroxyapatite, and penetraction enhancer.

122. The composite osteoimplant of claim 119 wherein the bioactive agent is a protein or peptide.

123. The composite osteoimplant of claim 119, wherein the bioactive agent is at least one cell.

124. The composite osteoimplant of claim 123, wherein the cell is an osteoblast.

125. The composite osteoimplant of claim 123, wherein the cell is a stem cell.

126. The composite osteoimplant of claim 123, wherein the cell is a mesenchymal stem cell.

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