Load-bearing osteoimplant, method for its manufacture and method of repairing bone using same

Claim 3

The method of claim 1 wherein the biocompatible component is selected from the group consisting of wetting agent, biocompatible binder, filler, fiber, plasticizer, biostatic/biocidal agent, surface active agent, and bioactive substance.

Claim 4

The method of claim 2 wherein the wetting agent is selected from the group consisting of water, organic protic solvent, physiological saline, concentrated saline, sugar solution, ionic solution, liquid polyhydroxy compound and mixtures thereof.

Claim 5

The method of claim 3 wherein the polyhydroxy compound is selected from the group consisting of glycerol and glycerol esters.

Claim 6

The method of claim 2 wherein the binder is a biological adhesive.

Claim 7

The method of claim 5 wherein the biological adhesive is selected from the group consisting of fibrin glue, fibrinogen, thrombin, mussel adhesive protein, silk, elastin, collagen, casein, gelatin, albumin, keratin, chitin and chitosan.

Claim 8

The method of claim 2 wherein the binder is a bioabsorbable polymer.

Claim 9

The method of claim 7 wherein the bioabsorbable polymer is selected from the group consisting of starches, polylactic acid, polyglycolic acid, polylactic-co-glycolic acid, polydioxanone, polycaprolactone, polycarbonates, polyorthoesters, polyamino acids, polyanhydrides, polyhydroxybutyrate, polyhyroxyvalyrate, poly (propylene glycol-co-fumaric acid), tyrosine-based polycarbonates, pharmaceutical tablet binders, polyvinylpyrollidone, cellulose, ethyl cellulose, micro-crystalline cellulose, and blends thereof.

Claim 10

The method of claim 2 wherein the binder is a nonbioabsorbable polymer.

Claim 11

The method of claim 9 wherein the nonbioabsorbable polymer is selected from the group consisting of polyacrylate, polymethyl methacrylate, polytetrafluoroethylene, polyurethane, and polyamide.

Claim 12

The method of claim 2 wherein the filler is selected from the group consisting calcium phosphates, tricalcium phosphate, hydroxyapatite calcium salts, bone powder, demineralized bone powder, anorganic bone, dental tooth enamel, aragonite, calcite, nacre, graphite, pyrolytic carbon, Bioglass®, bioceramic, and mixtures thereof.

Claim 13

The method of claim 2 wherein the surface active agent is selected from the group consisting of nonionic, cationic, anionic, amphoteric surfactants, and mixtures thereof.

Claim 14

The method of claim 2 wherein the bioactive substance is selected from the group consisting of collagen, insoluble collagen derivatives, and soluble solids and/or liquids dissolved therein; antiviricides, antimicrobials and/or antibiotics selected from the group consisting of erythromycin, bacitracin, neomycin, penicillin, polymycin B, tetracyclines, biomycin, chloromycetin, streptomycins, cefazolin, ampicillin, azactam, tobramycin, clindamycin and gentamicin; biocidal/biostatic sugars selected from the group consisting of dextran, glucose, amino acids, peptides; vitamins; inorganic elements; co-factors for protein synthesis; hormones; endocrine tissue or tissue fragments; synthesizers; enzymes selected from the group consisting of collagenase, peptidases, oxidases; polymer cell scaffolds with parenchymal cells; angiogenic drugs and polymeric carriers containing such drugs; collagen lattices; antigenic agents; cytoskeletal agents; cartilage fragments; living cells selected from the group consisting of chondrocytes, bone marrow cells, mesenchymal stem cells, natural extracts, genetically engineered living cells or otherwise modified living cells, DNA delivered by plasmid or viral vectors, and tissue transplants; demineralized bone powder; autogenous tissues selected from the group consisting of blood, serum, soft tissue, bone marrow; bioadhesives, bone morphogenic proteins (BMPs); osteoinductive factor (IFO); fibronectin (FN); endothelial cell growth factor (ECGF); cementum attachment extracts (CAE); ketanserin; human growth hormone (HGH); animal growth hormones; epidermal growth factor (EGF); interleukin-1 (IL-1); human alpha thrombin; transforming growth factor (TGF-beta); insulin-like growth factor (IGF-1); platelet derived growth factors (PDGF); fibroblast growth factors (FGF, bFGF, etc.); periodontal ligament chemotactic factor (PDLGF); somatotropin; bone digestors; antitumor agents; immuno-suppressants; permeation enhancers; enamine derivatives; alpha-keto aldehydes; and nucleic acids.

Claim 15

The method of claim 12 wherein the bioactive substance is a growth factor selected from the group consisting of transforming growth factor (TGF-beta), insulin-like growth factor (IGF-1), somatotropin, basic fibroblast growth factor (BFGF) and mixtures thereof.

Claim 16

The method of claim 2 wherein the bioactive substance is bone morphogenetic protein (BMP).

Claim 17

The method of claim 2 wherein the biostatic/biocidal agent is selected from the group consisting of antibiotics, povidone, sugars and mixtures thereof.

Claim 18

The method of claim 1 wherein the composition comprises from about 5 to about 100 weight percent bone particles and from about 0 to about 95 weight percent of at least one biocompatible component.

Claim 19

The method of claim 1 wherein at least about 60 weight percent of the bone particles are elongate.

Claim 20

The method of claim 1 wherein the bone particles are selected from the group consisting of nondemineralized bone particles, demineralized bone particles, and mixtures thereof.

Claim 21

The method of claim 19 wherein the demineralized bone particles are selected from the group consisting of superficially demineralized, partially demineralized and fully demineralized bone particles.

Claim 22

The method of claim 19 wherein the demineralized bone particles are fully demineralized bone particles.

Claim 23

The method of claim 1 wherein the bone particles are obtained from cortical, cancellous or cortico-cancellous bone of autogenous, allogenic or xenogeneic origin.

Claim 24

The method of claim 1 wherein the bone particles are obtained from porcine or bovine bone.

Claim 25

The method of claim 1 wherein the bone particles comprise a mixture of nondemineralized bone particles and demineralized bone particles.

Claim 26

The method of claim 24 wherein at least about 60 weight percent of the nondemineralized bone particles are elongate and at least about 60 weight percent of the demineralized bone particles are elongate.

Claim 27

The method of claim 24 wherein the weight ratio of nondemineralized to demineralized bone particles ranges from about 20:1 to about 1:20.

Claim 28

The method of claim 24 wherein the mixture comprises from about 5 to about 100 weight percent of the composition.

Claim 29

The method of claim 24 wherein the biocompatible component comprises a wetting agent.

Claim 30

The method of claim 24 wherein the biocompatible component comprises a binder.

Claim 31

The method of claim 1 which further comprises applying heat to the composition before, during or after the application of compressive force to the composition.

Claim 32

The method of claim 1 which further comprises cross-linking bone particles within the composition before, during or after the application of compressive force to the composition.

Claim 33

The method of claim 1 which further comprises freeze-drying the composition before, during or after the application of compressive force to the composition.

Claim 34

The method of claim 1 which further comprises applying heat to the composition before, during or after the application of compressive force to the composition followed by freeze-drying the heated, compressed composition.

Claim 35

The load-bearing osteoimplant produced by the method of claim 1 .

Claim 36

A load-bearing osteoimplant comprising a shaped, compressed composition of bone particles, wherein the osteoimplant possesses a bulk density of greater than about 0.7 g/cm 3 and a wet compressive strength of at least about 3 MPa.

Claim 37

A load-bearing osteoimplant comprising a shaped, compressed composition of bone particles, wherein the osteoimplant possesses a bulk density of greater than about 0.7 g/cm 3 and a wet compressive strength of at least about 3 MPa.

Claim 38

The osteoimplant of claim 35 wherein the bone particles are selected from the group consisting of nondemineralized bone particles, demineralized bone particles, and mixtures thereof.

Claim 39

The osteoimplant of claim 36 wherein the demineralized bone particles are selected from the group consisting of superficially demineralized, partially demineralized and fully demineralized bone particles.

Claim 40

The osteoimplant of claim 36 wherein the demineralized bone particles are fully demineralized.

Claim 41

The osteoimplant of claim 35 wherein the bone particles are obtained from cortical, cancellous or cortico-cancellous bone of autogenous, allogenic or xenogeneic origin.

Claim 42

The osteoimplant of claim 35 wherein the bone particles are obtained from porcine or bovine bone.

Claim 43

The osteoimplant of claim 35 wherein the bone particles comprise a mixture of nondemineralized bone particles and demineralized bone particles.

Claim 44

The osteoimplant of claim 35 wherein the bone particles comprise a mixture of partially demineralized bone particles and fully demineralized bone particles.

Claim 45

The osteoimplant of claim 42 wherein the bone particles further comprise nondemineralized bone particles.

Claim 46

The osteoimplant of claim 35 wherein at least about 60 weight percent of the bone particles are elongate.

Claim 47

The osteoimplant of claim 35 wherein at least about 90 weight percent of the bone particles are elongate.

Claim 48

The osteoimplant of claim 35 further comprising at least one biocompatible component.

Claim 49

The osteoimplant of claim 46 wherein the biocompatible component is selected from the group consisting of wetting agent, biocompatible binder, filler, fiber, surface active agent, bioactive substance and biostatic/biocidal agent.

Claim 50

The osteoimplant of claim 47 wherein the wetting agent is selected from the group consisting of water, organic protic solvent, physiological saline liquid polyhydroxy compound and mixture of water and liquid polyhydroxy compound.

Claim 51

The osteoimplant of claim 48 wherein the polyhydroxy compound is selected from the group consisting of glycerol and glycerol esters.

Claim 52

The osteoimplant of claim 47 wherein the biocompatible binder is a biological adhesive.

Claim 53

The osteoimplant of claim 50 wherein the biological adhesive is fibrin glue, fibrinogen thrombin, mussel adhesive protein, silk, elastin, collagen, casein, gelatin, albumin, keratin, chitin or chitosan.

Claim 54

The osteoimplant of claim 47 wherein the biocompatible binder is a bioabsorbable polymer.

Claim 55

The osteoimplant of claim 52 wherein the bioabsorbable polymer is selected from the group consisting of starches, polylactic acid, polyglycolic acid, polylactic-co-glycolic acid, polydioxanone, polycaprolactone, polycarbonates, polyorthoesters, polyamino acids, polyanhydrides, polyhydroxybutyrate, polyhyroxyvalyrate, poly (propylene glycol-co-fumaric acid), tyrosine-based polycarbonates, tablet binders, polyvinylpyrollidone, cellulose, ethyl cellulose, micro-crystalline cellulose, and blends thereof.

Claim 56

The osteoimplant of claim 47 wherein the biocompatible binder is a nonbioabsorbable polymer.

Claim 57

The osteoimplant of claim 54 wherein the nonbioabsorbable polymer is selected from the group consisting of polyacrylate, polymethyl methacrylate polytetrafluoroethylene, polyurethane, and polyamide.

Claim 58

The osteoimplant of claim 47 wherein the filler is selected from the group consisting calcium phosphates, calcium salts, bone powder, graphite, pyrolytic carbon, bioglass, bioceramic, and mixtures thereof.

Claim 59

The osteoimplant of claim 47 wherein the surface active agent is selected from the group consisting of nonionic, cationic, anionic, amphoteric surfactants, and mixtures thereof.

Claim 60

The osteoimplant of claim 47 wherein the bioactive substance is selected from the group consisting of collagen, insoluble collagen derivatives, and soluble solids and/or liquids dissolved therein; antiviricides, antimicrobials and/or antibiotics selected from the group consisting of erythromycin, bacitracin, neomycin, penicillin, polymycin B, tetracyclines, biomycin, ehloromycetin, streptomycins, cefaxolin, ampicillin, azactam, tobramycin, clindamycin and gentamicin; biocidal/biostatic sugars selected from the group consisting of dextran, glucose, amino acids, peptides; vitamins; inorganic elements; co-factors for protein synthesis; hormones; endocrine tissue or tissue fragments; synthesizers; enzymes selected from the group consisting of collagenase, peptidases, oxidases; polymer cell scaffolds with parenchymal cells; angiogenic drugs and polymeric carriers containing such drugs; collagen lattices; antigenic agents; cytoskeletal agents; cartilage fragments; living cells selected from the group consisting of chondrocytes, bone marrow cells, mesenchymal stem cells, natural extracts, genetically engineered living cells or otherwise modified living cells, DNA delivered by plasmid or viral vectors, and tissue transplants; demineralized bone powder; autogenous tissues selected from the group consisting of blood, serum, soft tissue, bone marrow, bioadhesives, bone morphogenic proteins (BMPs); osteoinductive factor (IFO); fibronectin (FN); endothelial cell growth factor (ECGF); cementum attachment extracts (CAE); ketanserin; human growth hormone (HGH); animal growth hormones; epidermal growth factor (ECF); interleukin-1 (IL-1); human alpha thrombin; transforming growth factor (TGF-beta); insulin-like growth factor (IGF-1); platelet derived growth factors (PDGF); fibroblast growth factors (FGF, bFGF, etc.); periodontal ligament chemotactic factor (PDLGF); somatotropin; bone digestors; antitumor agents; immuno-suppressants; permeation enhancers; enamine derivatives; alpha-keto aldehydes; and nucleic acids.

Claim 61

The osteoimplant of claim 47 wherein the bioactive substance is a growth factor selected from the group consisting of transforming growth factor (TGF-beta), insulin-like growth factor (IGF-1), somatotropin, basic fibroblast growth factor (BFGF) and mixtures thereof.

Claim 62

The osteoimplant of claim 47 wherein the bioactive substance is bone morphogenetic protein (BMP).

Claim 63

The osteoimplant of claim 47 wherein the biostatic/biocidal agent is selected from the group consisting of antibiotics, povidone, sugars and mixtures thereof.

Claim 64

The osteoimplant of claim 47 wherein the bone particles represent from about 5 to about 100 and the biocompatible component represents from about 0 to about 95 weight percent of the osteoimplant.

Claim 65

The osteoimplant of claim 41 wherein the weight ratio of nondemineralized bone particles to demineralized bone particles ranges from about 20:1 to about 1:20.

Claim 66

The osteoimplant of claim 42 wherein the weight ratio of partially demineralized bone particles to fully demineralized bone particles ranges from about 20:1 to about 1:20.

Claim 67

An osteoimplant comprising a shaped, compressed composition of elongate bone particles selected from the group consisting of nondemineralized bone particles, demineralized bone particles, and combinations thereof, wherein the osteoimplant possesses a bulk density of greater than about 1.0 g/cm 3 and a wet compressive strength of at least about 15 MPa.

Claim 68

An osteoimplant comprising a shaped, compressed composition of elongate bone particles selected from the group consisting of nondemineralized bone particles, demineralized bone particles, and combinations thereof, wherein the osteoimplant possesses a bulk density of greater than about 1.0 g/cm 3 and a wet compressive strength of at least about 15 MPa.

Claim 69

The osteoimplant of claim 65 further comprising at least one biocompatible component.

Claim 70

The osteoimplant of claim 66 wherein the biocompatible component is selected from the group consisting of wetting agent, binder, filler, fiber, surface active agent, bioactive substance and biostatic/biocidal agent.

Claim 73

The method of claim 68 wherein the bone particles are selected from the group consisting of nondemineralized bone particles, demineralized bone particles, and mixtures thereof.

Claim 74

The method of claim 68 wherein the bone particles are obtained from cortical, cancellous or cortico-cancellous bone of autogenous, allogenic or xenogeneic origin.

Claim 75

The method of claim 68 wherein at least about 60 weight percent of the bone particles are elongate.

Claim 76

The method of claim 68 wherein the osteoimplant further comprises at least on e biocompatible component.

Claim 77

The method of claim 72 wherein the biocompatible component is selected from the group consisting of wetting agent, biocompatible binder, filler, fiber, surface active agent, bioactive substance and biostatic/biocidal agent.

Claim 78

The method of claim 68 wherein the bone particles represent from about 5 to about 100 weight percent of the osteoimplant.

Claim 79

The method of claim 72 wherein the biocompatible component represents from about 0 to about 95 weight percent of the osteoimplant.

Claim 80

The method of claim 30 wherein heat is applied to the composition by contacting the composition with a heated biocompatible liquid.

Claim 81

The method of claim 1 wherein the compressive force is from about 2,500 to about 60,000 psi.

Claim 82

The method of claim 1 wherein bulk density is greater than about 1.0 g/cm 3 .

Claim 83

The method of claim 1 wherein wet compressive strength is at least about 15 MPa.

Claim 84

The load-bearing osteoimplant produced by the method of claim 77 .

Claim 85

The osteoimplant of claim 35 wherein bulk density is greater than about 1.0 g/cm 3 .

Claim 86

The osteoimplant of claim 35 wherein wet compressive strength is at least about 15 MPa.

Claim 87

The osteoimplant of claim 35 wherein the shaped compressed composition of bone particles is produced by applying a compressive force of greater than about 1000 psi to the composition.

Claim 88

The osteoimplant of claim 35 wherein the shaped, compressed composition of bone particles is produced by applying a compressive force of from about 2,500 to about 60,000 psi to the composition.

Claim 89

The osteoimplant of claim 65 wherein the shaped, compressed composition of elongate bone particles is produced by applying a compressive force of greater than about 1,000 psi to the composition.

Claim 90

The osteoimplant of claim 65 wherein the shaped, compressed composition of elongate bone particles is produced by applying a compressive force of from about 2,500 to about 60,000 psi to the composition.

Claim 91

The method of claim 68 wherein the shaped, compressed composition of bone particles is produced by applying a compressive force of greater than about 1000 psi to the composition.

Claim 92

The method of claim 68 wherein the shaped, compressed composition of bone particles is produced by applying a compressive force of from about 2,500 to about 60,000 psi to the composition.

Claim 93

The method of claim 68 wherein bulk density is greater than about 1.0 g/cm 3 .

Claim 94

The method of claim 68 wherein wet compressive strength is at least about 15 MPa.

Claim 95

The osteoimplant of claim 35 possessing a shape selected from the group consisting of a sheet, plate, disk, cone, pin, screw, tube, cup, tooth, tooth Toot, strut, wedge, cylinder, threaded cylinder and rod.

Claim 96

The method of claim 68 wherein the repaired bone is selected from the group consisting of the ethmoid, frontal, nasal, occipital, parietal, temporal, mandible, maxilla, zygomatic, cervical vertebra, thoracic vertebra, lumbar vertebra, sacrum, rib, sternum, clavicle, scapula, humerus, radius, ulna, carpal bones, metacarpal bones, phalanges, ilium, ischium, pubis, femur, tibia, fibula, patella, calcaneus tarsal and metatarsal bones.

Claim 97

The osteoimplant of claim 35 possessing macroporous holes.

Claim 98

The osteoimplant of claim 93 wherein the macroporous holes contain therein an osteogenic material.