Osteoimplant and method of making same

Claim 2

1 . An osteoimplant which comprises a coherent aggregate of elongate bone particles, the osteoimplant possessing predetermined dimensions and shape.

Claim 3

2 . The osteoimplant of claim 1 wherein mutually contacting elongate bone particles are entangled with and/or bonded to each other.

Claim 4

3 . The osteoimplant of claim 1 wherein the elongate bone particles represent at least about 50 weight percent of the aggregate.

Claim 5

4 . The osteoimplant of claim 1 wherein the elongate bone particles represent at least about 60 weight percent of the aggregate.

Claim 6

5 . The osteoimplant of claim 1 wherein the elongate bone particles represent at least about 90 weight percent of the aggregate.

Claim 7

6 . The osteoimplant of claim 1 wherein the aggregate further comprises non-elongate bone particles.

Claim 8

7 . The osteoimplant of claim 1 wherein the elongate bone particles are obtained from cortical, cancellous, corticocancellous allogenic, xenogenic or transgenic bone tissue.

Claim 9

8 . The osteoimplant of claim 1 wherein the elongate bone particles possess the capability to facilitate or accelerate new bone growth by at least one of osteogenesis, osteoconduction and osteoinduction.

Claim 10

9 . The osteoimplant of claim 1 wherein the median length of the elongate bone particles is from about 2 to about 200 mm, the median width of the elongate bone particles is from about 0.05 to about 50 mm and the ratio of median length to median width is from about 10:1 to about 2000:1.

Claim 11

10 . The osteoimplant of claim 1 wherein the median length of the elongate bone particles is from about 1 to about 100 mm, the median width of the elongate particles is from about 0.1 to about 20 mm and the ratio of median length to median width is from about 20:1 to about 600:1

Claim 12

11 . The osteoimplant of claim 1 wherein at least some of the elongate bone particles are substantially fully mineralized, substantially fully demineralized, partially demineralized or superficially demineralized.

Claim 13

12 . The osteoimplant of claim 6 wherein at least some of the non-elongate bone particles are substantially fully mineralized, substantially fully demineralized, partially demineralized or superficially demineralized.

Claim 14

13 . The osteoimplant of claim 1 wherein elongate bone particles are admixed with one or more of the group consisting of binders/fillers, plasticizers, biostatic/biocidal agents, bioactive substances, surface active agents prior to, during and/or after forming the aggregate into the osteoimplant.

Claim 15

14 . The osteoimplant of claim 13 wherein the binder/filler is selected from the group consisting of cyanoacrylates, epoxy-based compounds, dental resin sealants, dental resin cements, calcium phosphate and calcium sulfate self-setting cements, glass ionomer cements, polymethyl methacrylate, gelatin-resorcinol-formaldehyde glues, protein and collagen-based glues, acrylic resins, cellulosics, bioabsorbable polymers such as polyglycolide, polylactide, glycolide-lactide copolymers, polycaprolactone, polyanhydrides, polycarbonates, polyorthoesters, polyamino acids, polyarylates, polycyanoacrylates, polyhydroxybutyrate, polyhydroxyvalyrate, polyphosphazenes, polyvinylpyrrolidone, polyarylates, tyrosine-based polycarbonates and polyarylates, carbohydrate polymers, polyiminocarbonates, polypropylene fumarates, polyanhydride esters, polytetrafluroethylene, hexacryl, Hyaluronic acid, fibrin, fibrin-collagen, polyethylene glycol glues, mucopolysaccharides and mussel adhesive proteins, fatty acids and fatty acid derivatives.

Claim 16

15 . The osteoimplant of claim 13 wherein the binder/filler is selected from the group consisting of bone powder, demineralized bone powder, porous calcium phosphate ceramics, hydroxyapatite, tricalcium phosphate, Bioglass® and other calcium phosphate materials, calcium sulfate or calcium carbonate particles.

Claim 17

16 . The osteoimplant of claim 13 wherein the plasticizer is selected from the group liquid polyhydroxy compound.

Claim 18

17 . The osteoimplant of claim 16 wherein the liquid polyhydroxy compound is glycerol.

Claim 19

18 . The osteoimplant of claim 13 wherein the biostatic/biocidal agent is selected from the group consisting of antibiotics, povidone, sugars and mucopolysaccharides.

Claim 20

19 . The osteoimplant of claim 13 wherein the surface-active agent is selected from the group consisting of biocompatible nonionic, cationic, anionic and amphoteric surfactant.

Claim 21

20 . The osteoimplant of claim 13 wherein the bioactive substance is selected from the group consisting of trophic factors, analgesics, anti-cancer agents, vaccines, adjuvants, antibodies, neuroleptics, genes and genetic elements for transfection, cells or cellular components, collagen, insoluble collagen derivatives, and soluble solids and/or liquids dissolved therein, antiviricides, particularly those effective against HIV and hepatitis; antimicrobials and/or antibiotics such as erythromycin, bacitracin, neomycin, penicillin, polymicin B, tetracyclines, biomycin, chloromycetin, and streptomycins, cephalosporins, ampicillin, azactam, tobramycin, clindamycin and gentamicin; biocidal/biostatic sugars such as dextran, glucose; amino acids, peptides, vitamins, inorganic elements, co-factors for protein synthesis; hormones; endocrine tissue or tissue fragments, synthesizers; enzymes such as 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, modified living cells such as 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, genes or genetic elements, tissue transplants, demineralized bone powder, autogenous tissues, blood, serum, soft tissue, bone marrow, bioadhesives; non-collagenous proteins, osteopontin, osteonectin, bone sialo protein, laminin, fibrinogen, vitronectin, thrombospondin, proteoglycans, decorin, beta glycan, biglycan, aggrecan, versican, tenascin, matrix gla protein, hyaluronan, amino acids, amino acid residues, peptides, bone morphogenic proteins (BMPs); osteoinductive factor (OIF); 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) (IGF-2); platelet derived growth factors (PDGF); fibroblast growth factors (FGF, aFGF, bFGF, etc.); periodontal ligament chemotactic factor (PDLGF); somatotropin; bone digestors; antitumor agents; immuno-suppressants; fatty acids (including polar and non-polar fatty acids); permeation enhancers, fatty acid esters, laureate, myristate and stearate monoesters of polyethylene glycol, enamine derivatives, alpha-keto-aldehydes, and nucleic acids; inorganic elements, inorganic compounds, cofactors for protein synthesis, hormones, soluble and insoluble components of the immune system; soluble and insoluble receptors including truncated forms; soluble, insoluble and cell surface bound ligands including truncated forms; chemokines, bioactive compounds that are endocytosed; endocrine tissue or tissue fragments, growth factor binding proteins, insulin-like growth factor binding protein (IGFBP-2) (IGFBP-4) (IGFBP-5) (IGFBP-6); angiogenic agents, bone promoters, cytokines, interleukins, genetic material, genes encoding bone promoting actions, cells containing genes encoding bone promoting action; growth hormones such as somatotrophin; bone digestors; antiumor agents; cellular attractants and attachment agents; immunosuppressants; bone resorption inhibitors and stimulators; angiogenic and mitogenic factors; bioactive factors that inhibit and stimulate secondary messenger molecules; cell adhesion molecules, cell-matrix and cell-cell adhesion molecules; secondary messengers, monoclonal antibodies specific to cell surface determinants on mesenchymal stem cells, clotting factors; externally expanded autograft or xenograft cells, nucleic acids and any combination thereof.

Claim 22

21 . The osteoimplant of claim 1 wherein the elongate bone particles are in the lyophilized state.

Claim 23

22 . The osteoimplant of claim 1 wherein the aggregate of elongate bone particles has been subjected to a compressive force of up to about 100,000 psi.

Claim 24

23 . The osteoimplant of claim 22 wherein the compressed aggregate of elongate bone particles is in the lyophilized state.

Claim 25

24 . The osteoimplant of claim 1 wherein the elongate bone particles are cross-linked.

Claim 26

25 . The osteoimplant of claim 1 possessing regions one of which comprises demineralized elongate bone particles and another of which comprises nondemineralized elongate bone particles.

Claim 27

26 . The osteoimplant of claim 25 wherein the region of demineralized elongate bone particles defines at least a portion of the exterior surface of the osteoimplant and the region of mineralized elongate bone particles defines at least a portion of core of the osteoimplant.

Claim 28

27 . The osteoimplant of claim 1 which is swellable upon contact with body and/or irrigation fluids.

Claim 29

28 . The osteoimplant of claim 1 possessing an open pore structure and a bulk density of not greater than about 0.3 g/cm 3 .

Claim 30

29 . The osteoimplant of claim 28 wherein the elongate bone particles are demineralized.

Claim 31

30 . The osteoimplant of claim 1 in the shape of a sheet, plate, disk, cone, pin, screw, tube, tooth, tooth root, plug, bone or portion of bone, wedge or portion of wedge, cylinder or threaded cylinder.

Claim 32

31 . The osteoimplant of claim 1 possessing at least one recess therein.

Claim 33

32 . An implant for bone repair possessing at least one cavity containing the osteoimplant of claim 1 .

Claim 34

33 . The implant of claim 32 which is an intervertebral implant.

Claim 35

34 . The implant of claim 32 which is a fusion cage.

Claim 36

35 . A method of making an osteoimplant which comprises: a. providing a quantity of elongate bone particles; b. mixing the elongate bone particles with an aqueous wetting agent to provide a fluid composition containing from about 5 to about 40 volume percent swollen, hydrated elongate bone particles; c. introducing the fluid composition into a mold; and, d. removing aqueous wetting agent thereby providing a coherent aggregate of elongate bone particles possessing the dimensions and shape of the osteoimplant.

Claim 37

35 . A method of making an osteoimplant which comprises: a. providing a quantity of elongate bone particles; b. mixing the elongate bone particles with an aqueous wetting agent to provide a fluid composition containing from about 5 to about 40 volume percent swollen, hydrated elongate bone particles; c. introducing the fluid composition into a mold; and, d. removing aqueous wetting agent thereby providing a coherent aggregate of elongate bone particles possessing the dimensions and shape of the osteoimplant.

Claim 38

36 . The method of claim 35 wherein prior to step (d), the elongate bone particles are heated.

Claim 39

37 . The method of claim 35 wherein at least some of the elongate bone particles are substantially fully mineralized, substantially fully demineralized, partially demineralized or superficially demincralized.

Claim 40

38 . The method of claim 35 wherein at least some of the elongate bone particles are superficially demineralized, such elongate bone particles being bonded to each other through cross-links formed in their mutually-contacting surface-exposed collagen.

Claim 41

39 . A method of making a plug for insertion in a cavity of an implant or bone defect site which comprises: a) providing a coherent aggregate of elongate bone particles; b) lyophilizing the coherent aggregate of elongate bone particles; and, c) forming the coherent aggregate of elongate bone particles into the plug before or after carrying out step (b).

Claim 42

39 . A method of making a plug for insertion in a cavity of an implant or bone defect site which comprises: a) providing a coherent aggregate of elongate bone particles; b) lyophilizing the coherent aggregate of elongate bone particles; and, c) forming the coherent aggregate of elongate bone particles into the plug before or after carrying out step (b).

Claim 43

40 . A method of making a plug for insertion in a cavity of an implant or bone defect site which comprises: a) providing a coherent aggregate of elongate bone particles; b) subjecting the coherent aggregate of elongate bone particles to a compressive force; and, c) forming the compressed coherent aggregate of elongate bone particles into the plug before or after carrying out step (b).

Claim 44

40 . A method of making a plug for insertion in a cavity of an implant or bone defect site which comprises: a) providing a coherent aggregate of elongate bone particles; b) subjecting the coherent aggregate of elongate bone particles to a compressive force; and, c) forming the compressed coherent aggregate of elongate bone particles into the plug before or after carrying out step (b).

Claim 45

41 . The method of claim 40 wherein the coherent aggregate of elongate bone particles is lyophilized.

Claim 46

42 . The method of claim 40 wherein the compressive force is up to about 100,000 psi.

Claim 47

43 . The method of claim 41 wherein the compressive force is up to about 100,000 psi.

Claim 48

44 . A method of making a plug for insertion in a cavity of an implant or bone defect site which comprises: a) providing a coherent aggregate of elongate bone particles at least some of which possess surface-exposed collagen; b) crosslinking elongate bone particles in the coherent aggregate through their mutually-contacting surface-exposed collagen; and, c) shaping the crosslinked coherent aggregate of elongate bone particles into the plug before or after carrying out step (b).

Claim 49

44 . A method of making a plug for insertion in a cavity of an implant or bone defect site which comprises: a) providing a coherent aggregate of elongate bone particles at least some of which possess surface-exposed collagen; b) crosslinking elongate bone particles in the coherent aggregate through their mutually-contacting surface-exposed collagen; and, c) shaping the crosslinked coherent aggregate of elongate bone particles into the plug before or after carrying out step (b).

Claim 50

45 . A method of treating a bone defect in which the bone defect site possesses at least one cavity which comprises inserting a plug in the cavity, the plug comprising a coherent aggregate of elongate bone particles sized and shaped to substantially fill said cavity.

Claim 51

45 . A method of treating a bone defect in which the bone defect site possesses at least one cavity which comprises inserting a plug in the cavity, the plug comprising a coherent aggregate of elongate bone particles sized and shaped to substantially fill said cavity.

Claim 52

46 . A method of fusing adjacent vertebrae which comprises: a) providing a space between adjacent vertebrae to be fused; and, b) implanting in said space the implant of claim 31 .

Claim 53

47 . The method of claim 46 wherein the implant is an intervertebral implant or fusion cage.

Claim 54

48 . A method of repairing and/or treating bone comprising implanting at a bone repair site the osteoimplant of claim 1 .

Claim 55

49 . The method of claim 48 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, lumar vertebra, scarum, 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 56

50 . The method of claim 49 comprising the implantation of the osteoimplant of claim 1 dimensioned and shaped as an intervertebral implant.