Osteoimplant and method of making same

• US 20030009235A1
• Filed: 05/02/2002
• Published: 01/09/2003
• Est. Priority Date: 07/19/2000
• Status: Active Grant

• Current Assignee: Warsaw Orthopedic Incorporated (Medtronic Plc)
• Original Assignee: Warsaw Orthopedic Incorporated (Medtronic Plc)
• Inventors: Edwards, Jean T., Shimp, Lawrence A., Boden, Scott D., Traianedes, Kathy, Manrique, Albert, Scarborough, Nelson L., Russell, James L.
• Granted Patent: US 9,387,094 B2
• Time in Patent Office: Days
• US Class Current: 623/23.63
• CPC Class Codes: A61B 17/866 Material or manufacture
• CPC Class Codes: A61F 2/28 Bones joints A61F2/30
• CPC Class Codes: A61F 2/3094 Designing or manufacturing processes
• CPC Class Codes: A61F 2/442 Intervertebral or spinal discs, e.g. resilient non-disc-shaped intervertebral inflatable pockets A61F2/441; non-disc-shaped intervertebral fusion implants A61F2/4455
• CPC Class Codes: A61F 2/446 having a circular or elliptical cross-section substantially parallel to the axis of the spine, e.g. cylinders or frustocones
• CPC Class Codes: A61F 2/4644 Preparation of bone graft, bone plugs or bone dowels, e.g. grinding or milling bone material bone material A61F2/28; disintegrating or milling devices B02C
• CPC Class Codes: A61F 2002/2817 Bone stimulation by chemical reactions or by osteogenic or biological products for enhancing ossification, e.g. by bone morphogenetic or morphogenic proteins [BMP] or by transforming growth factors [TGF]
• 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 2002/2839 Bone plugs or bone graft dowels
• CPC Class Codes: A61F 2002/30059 differing in bone mineralization, e.g. made from both mineralized and demineralized adjacent parts
• CPC Class Codes: A61F 2002/30075 swellable, e.g. when wetted
• CPC Class Codes: A61F 2002/30113 circular
• CPC Class Codes: A61F 2002/30131 horseshoe- or crescent- or C-shaped or U-shaped
• CPC Class Codes: A61F 2002/30153 rectangular
• CPC Class Codes: A61F 2002/30154 square
• CPC Class Codes: A61F 2002/30156 triangular
• CPC Class Codes: A61F 2002/30158 trapezoidal
• CPC Class Codes: A61F 2002/302 toroidal, e.g. rings
• CPC Class Codes: A61F 2002/30205 conical
• CPC Class Codes: A61F 2002/30224 cylindrical
• CPC Class Codes: A61F 2002/30225 : Flat cylinders, i.e. discs
• CPC Class Codes: A61F 2002/30237 : partial tubes
• CPC Class Codes: A61F 2002/30261 : parallelepipedal
• CPC Class Codes: A61F 2002/3028 : polyhedral different from parallelepipedal and pyramidal
• CPC Class Codes: A61F 2002/30733 : Inserts placed into an endoprosthetic cavity, e.g. for modifying a material property
• CPC Class Codes: A61F 2002/30879 : Ribs
• CPC Class Codes: A61F 2002/30891 : Plurality of protrusions
• CPC Class Codes: A61F 2002/30892 : parallel
• CPC Class Codes: A61F 2002/30957 : using a positive or a negative model, e.g. moulds
• CPC Class Codes: A61F 2002/30971 : Laminates, i.e. layered products
• CPC Class Codes: A61F 2002/4649 : Bone graft or bone dowel harvest sites
• CPC Class Codes: A61F 2210/0061 : swellable
• CPC Class Codes: A61F 2230/0006 : circular
• CPC Class Codes: A61F 2230/0013 : Horseshoe-shaped, e.g. crescent-shaped, C-shaped, U-shaped
• CPC Class Codes: A61F 2230/0019 : rectangular
• CPC Class Codes: A61F 2230/0021 : square
• CPC Class Codes: A61F 2230/0023 : triangular
• CPC Class Codes: A61F 2230/0026 : trapezoidal
• CPC Class Codes: A61F 2230/0063 : Three-dimensional shapes
• CPC Class Codes: A61F 2230/0065 : toroidal, e.g. ring-shaped, doughnut-shaped
• CPC Class Codes: A61F 2230/0067 : conical
• CPC Class Codes: A61F 2230/0069 : cylindrical
• CPC Class Codes: A61F 2230/0082 : parallelepipedal
• CPC Class Codes: A61F 2310/00365 : Proteins; Polypeptides; Degradation products thereof
• CPC Class Codes: A61L 2430/02 : for reconstruction of bones; weight-bearing implants
• CPC Class Codes: A61L 27/3608 : Bone, e.g. demineralised bone matrix [DBM], bone powder
• CPC Class Codes: A61L 27/365 : Bones
• CPC Class Codes: A61L 27/3683 : subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
• CPC Class Codes: A61L 27/3691 : characterised by physical conditions of the treatment, e.g. applying a compressive force to the composition, pressure cycles, ultrasonic/sonication or microwave treatment, lyophilisation
• CPC Class Codes: A61L 27/38 : containing added animal cells organs or tissue containing native cells A61L27/36
• CPC Class Codes: A61L 31/005 : Ingredients of undetermined constitution or reaction products thereof
• CPC Class Codes: B29C 41/22 : Making multilayered or multicoloured articles
• CPC Class Codes: B29C 41/46 : Heating or cooling
• CPC Class Codes: B29K 2105/16 : Fillers
• CPC Class Codes: B29K 2511/06 : Bone, horn or ivory
• CPC Class Codes: B29L 2031/7532 : Artificial members, protheses

Abstract

An osteoimplant is provided which comprises a coherent aggregate of elongate bone particles, the osteoimplant possessing predetermined dimensions and shape. The osteoimplant is highly absorbent and sponge-like in nature. Also provided herein are a method of fabricating the osteoimplant and a method of repairing and/or treating bone defects utilizing the osteoimplant.

Claims

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

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

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

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

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

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

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

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.

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.

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

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.

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.

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.

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.

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.

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

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

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

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.

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.

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

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.

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

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

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.

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.

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

28. The osteoimplant of claim 1 possessing an open pore structure and a bulk density of not greater than about 0.3 g/cm³.

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

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.

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

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

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

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

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

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.

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.

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.

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

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

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.

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).

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).

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

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

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

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).

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

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.

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.