Porous osteoimplant

• US 9,034,356 B2
• Filed: 01/19/2007
• Issued: 05/19/2015
• Est. Priority Date: 01/19/2006
• Status: Active Grant

• Current Assignee: Warsaw Orthopedic Incorporated (Medtronic Plc)
• Original Assignee: Warsaw Orthopedic Incorporated (Medtronic Plc)
• Inventors: Shimp, Lawrence A., Winterbottom, John, Kaes, David R., Belaney, Ryan M., Bhattacharyya, Subhabrata
• Primary Examiner(s): Yu, Misook
• Assistant Examiner(s): AKHOON, KAUSER M
• Application Number:
  US11/625,086
• Publication Number:
  US 20080069852A1
• Time in Patent Office: 3,042 Days
• Field of Search: 424/423, 424/426
• US Class Current: 424/423
• CPC Class Codes: A61F 2/28 Bones joints A61F2/30
• 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 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 27/56 Porous materials, e.g. foams or sponges
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders

Abstract

The invention is directed toward porous composites for application to a bone defect site to promote new bone growth. The inventive porous composites comprise a biocompatible polymer and a plurality of particles of bone-derived material, inorganic material, bone substitute material or composite material. In certain embodiments, the porous composites are prepared using a method that includes a supercritical fluid (e.g., supercritical carbon dioxide) treatment. The invention also discloses methods of using these composites as bone void fillers.

Claims

1. A method of making a porous composite comprising steps of:

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

providing a biocompatible polymer and a plasticizer comprising poly(ethylene glycol) (PEG);

mixing the plurality of particles, the biocompatible polymer, and the plasticizer to obtain a mixture; and

submitting the mixture to a supercritical fluid treatment that comprises steps of;

contacting the mixture with a supercritical fluid having a maximum pressure of about 7500 to about 8000 psi, and

returning the supercritical fluid to a non-supercritical state by rapid or explosive decompression to atmospheric pressure in about 60 seconds to about 90 seconds, so that the porous composite is obtained, the porous composite having a wet compressive strength between about 3 MPa to about 5 MPa and having the PEG in an amount comprising 1-40% by weight of the porous composite.

2. The method of claim 1, wherein the porous composite has a porosity of at least about 30%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90% or more than 90%.

3. The method of claim 1, wherein the porous composite, after implantation, has pores or channels that can support the in-growth of cells.

4. The method of claim 1, wherein the bone-derived material is obtained from a member of the group consisting of autologous bone, allogenic bone, xenogenic bone, and mixtures thereof.

5. The method of claim 1, wherein the bone-derived material is obtained from a member of the group consisting of non-demineralized bone particles, demineralized bone particles, deorganified bone particles, partially demineralized bone particles, anorganic bone particles, and combinations thereof.

6. The method 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), fluoroapatite, chloroapatite, magnesium-substituted tricalcium phosphate, carbonate hydroxyapatite, and combinations and derivative thereof.

7. The method of claim 1, wherein the porous composite further comprises one or more of:

inorganic material and a bone-derived material and one or more of bovine serum albumin, collagen, an extracellular matrix component, a synthetic polymer, and a naturally-derived polymer.

8. The method of claim 1, wherein the porous composite comprises approximately 40-70% of the plurality of particles by weight.

9. The method of claim 1, wherein the biocompatible 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, polyhydroxy-butyrate/valerate copolymers, poly(vinyl pyrrolidone), polycyanoacrylates, poly-urethanes, and polysaccharides.

10. The method of claim 1, wherein the biocompatible polymer comprises poly(caprolactone).

11. The method of claim 1, wherein the biocompatible polymer comprises poly(lactide), poly(glycolide), poly(lactide-co-glycolide), and/or combination thereof.

12. The method of claim 1, wherein the biocompatible polymer is resorbed within approximately 1 month to approximately 3 years.

13. The method of claim 1, wherein the porous composite further comprises a lubricant agent.

14. The method of claim 1, wherein the plasticizer further comprises 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, 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.

15. The method of claim 1, wherein the porous composite further comprises a porogen.

16. The method of claim 15, whereby the porogen dissolves and/or degrades after implantation of the porous composite leaving a pore.

17. The method of claim 1, wherein the porous composite further comprises a bioactive agent.

18. The method of claim 17, 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, penetration enhancer, anti-inflammatory agents, growth factors, angiogenic factors, antibiotics, analgesics, chemotactic factors, bone morphogenic protein, and cytokines.

19. The method of claim 1, wherein the porous composite further comprises a pharmaceutically acceptable excipient.

20. The method of claim 1, wherein the porous composite has a shape selected from the group consisting of morsels, cylinder, block, wedge, and sheet.

21. The method of claim 1, wherein the plurality of particles and the biocompatible polymer are dried.

22. The method of claim 1, wherein the porous composite comprises at least approximately 50% of the plurality of particles by weight.

23. The method of claim 1, wherein the plurality of particles have a size range of 200-500 microns.

24. The method of claim 1, wherein the biocompatible polymer is ground and sieved to give a particle size range on the same scale as the plurality of particles.

25. The method of claim 1, wherein the porous composite has macroporosity, mesoporosity, and/or microporosity.

26. The method of claim 1, wherein the porous composite has macroporosity, mesoporosity, and microporosity.

27. The method of claim 1 or 25, wherein the porous composite has macroporosity characterized by pore diameters greater than about 100 microns.

28. The method of claim 1, wherein the plasticizer has an average molecular weight of from 4000 to 8000 g/mol.

29. The method of claim 1, wherein the PEG is PEG 6000.