Injectable and moldable bone substitute materials

• US 9,107,751 B2
• Filed: 01/19/2007
• Issued: 08/18/2015
• 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, Kaes, David R., Tunc, Deger C., Boyce, Todd M., Knaack, David, Russell, James, Bhattacharyya, Subhabrata
• Primary Examiner(s): DAVIS, RUTH A
• Application Number:
  US11/625,119
• Publication Number:
  US 20070191963A1
• Time in Patent Office: 3,133 Days
• Field of Search: 424/400, 424/422
• US Class Current: 1/1
• 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. A composite osteoimplant comprising:

a plurality of particles comprising an inorganic material, a bone substitute material, a bone-derived material, or any combination thereof; and

a polymer with which the plurality of particles has been combined;

wherein the composite is moldable at a temperature greater than about 40°

C. and settable on implantation into bone at a temperature of about 37°

C.

2. The composite osteoimplant of claim 1, wherein the polymer has penetrated the pores, spaces, or voids of the particles.

3. The composite osteoimplant of claim 1, wherein the composite can be shaped manually, can be shaped using a surgical instrument, or can be shaped using a machine.

4. The composite osteoimplant of claim 1, wherein the suitable conditions for setting the composite include cooling the composite.

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

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

7. The composite osteoimplant of claim 1, 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™

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

8. The composite osteoimplant of claim 1, wherein the particles are elongated particles.

9. The composite osteoimplant of claim 1, 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.

10. The composite osteoimplant of claim 1, further comprising a plasticizer.

11. The composite osteoimplant of claim 10, 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.

12. The composite osteoimplant of claim 1, further comprising a porogen.

13. The composite osteoimplant of claim 12, whereby the porogen dissolves and/or degrades after implantation of the composite osteoimplant leaving a pore.

14. The composite osteoimplant of claim 1 wherein composite after implantation has pores or channels that can support the in-growth of cells.

15. The composite osteoimplant of claim 1, wherein the bone-derived material is selected from the group consisting of non-demineralized bone particles, demineralized bone particles, partially demineralized bone particles, deorganified bone particles, and combinations thereof.

16. The composite osteoimplant of claim 1, wherein the bone-derived material is derived from autogenous bone, allogenic bone, or xenogeneic bone.

17. The composite osteoimplant of claim 1, wherein the composite comprises approximately 40-70% particles by weight.

18. The composite osteoimplant of claim 1, further comprising a bioactive agent.

19. The composite osteoimplant of claim 18, 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.

20. The composite osteoimplant of claim 1, wherein the composite sets in situ.

21. A method of administering a composite osteoimplant of claim 1 to a subject, the method comprising steps of:

administering the moldable composite osteoimplant of claim 1 to a subject in need thereof;

and causing the moldable composite osteoimplant to set.

22. A method of preparing a composite osteoimplant of claim 1, the method comprising steps of:

combining a plurality of particles comprising an inorganic material, a bone substitute material, a bone-derived material, or any combination thereof; and

a polymer; and

adding a solvent to the resulting composite so that the composite becomes moldable.

33. The composite osteoimplant of claim 1, wherein the polymer comprises monomers, pre-polymers, oligomers, polymers, cross-linked polymers, partially polymerized polymers, and/or combinations thereof.

23. A composite osteoimplant comprising:

a plurality of bone-derived particles; and

a polymer with which the particles have been combined;

wherein the composite has a first phase and a second phase;

wherein the first phase is more moldable relative to the second phase; and

wherein the composite is moldable at a temperature greater than about 40°

C. and settable on implantation into bone at a temperature of about 37°

C.

24. The composite osteoimplant of claim 23, wherein the particles are elongated particles.

25. The composite osteoimplant of claim 23, 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.

26. The composite osteoimplant of claim 23, further comprising a plasticizer.

27. The composite osteoimplant of claim 23, further comprising a porogen.

28. The composite osteoimplant of claim 23, wherein the composite after implantation has pores or channels that can support the in-growth of cells.

29. The composite osteoimplant of claim 23, wherein the bone-derived material is selected from the group consisting of non-demineralized bone particles, demineralized bone particles, partially demineralized bone particles, deorganified bone particles, and combinations thereof.

30. The composite osteoimplant of claim 23, wherein the bone-derived material is derived from autogenous bone, allogenic bone, or xenogeneic bone.

31. The composite osteoimplant of claim 23, wherein the composite comprises approximately 40-70% particles by weight.

32. The composite osteoimplant of claim 23, further comprising a bioactive agent.