Coupling agents for orthopedic biomaterials

• US 7,270,813 B2
• Filed: 10/08/2003
• Issued: 09/18/2007
• Est. Priority Date: 10/08/2002
• Status: Active Grant

• Current Assignee: Warsaw Orthopedic Incorporated (Medtronic Plc)
• Original Assignee: Osteotech Incorporated (Medtronic Plc)
• Inventors: Shimp, Lawrence A., Knaack, David
• Primary Examiner(s): Kennedy; Sharon E.
• Application Number:
  US10/681,651
• Publication Number:
  US 20050008620A1
• Time in Patent Office: 1,441 Days
• Field of Search: 424/93.7, 424/423, 424/426, 424/489, 424/490, 424/493, 424/497, 424/499, 424/520, 623/16.11, 623/20.17
• US Class Current: 424/93.7
• 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 27/3687 characterised by the use of chemical agents in the treatment, e.g. specific enzymes, detergents, capping agents, crosslinkers, anticalcification agents
• CPC Class Codes: A61L 27/3821 Bone-forming cells, e.g. osteoblasts, osteocytes, osteoprogenitor cells
• CPC Class Codes: A61L 27/3847 Bones
• CPC Class Codes: A61L 27/44 having a macromolecular matrix
• CPC Class Codes: A61L 27/46 with phosphorus-containing inorganic fillers

Abstract

The invention provides a method for the preparation of bone-polymer composites wherein the mineral portion of the bone is treated with a coupling agent before being incorporated into a biocompatible polymeric matrix. The resulting composites may be used as such or be further processed to form an osteoimplant.

Claims

1. A composite, comprising:

a plurality of bone particles and a biocompatible polymer, wherein at least a portion of the bone particles are covalently linked to the polymer through a silane coupling agent, wherein the bone particles represent about 60% to about 75% of the total weight of the composite.

5. The composite of claim 1, 2, or 4, wherein the bone particles are obtained from one or more of autologous bone, allogenic bone, xenogenic bone, or mixtures thereof.

6. The composite of claim 1, 2, or 4, wherein the bone particles are obtained from one or more of cortical bone, cancellous bone, cortico-cancellous bone, or mixtures thereof.

7. The composite of claim 1, 2, or 4, wherein the bone particles are obtained from one or more of nondemineralized bone, deorganified bone, anorganic bone, or mixtures thereof.

9. The composite of claim 1, 2, or 4, wherein the coupling agent is a silane selected from the group consisting of silanes bearing one hydrolyzable or leaving group, silanes bearing two hydrolyzable or leaving groups, and silanes bearing three hydrolyzable or leaving groups.

10. The composite of claim 1, 2, or 4, wherein the polymer is a biocompatible polymer selected from the group consisting of polymers of natural origin, polymers of artificial origin, and any combination of natural and artificial polymers.

11. The composite of claim 1, 2, or 4, wherein the polymer is a selected from the group consisting of biodegradable polymers, non-biodegradable polymers, co-polymers of biodegradable polymers, co-polymers of non-biodegradable polymers, and co-polymers of biodegradable and non-biodegradable polymers.

12. The composite of claim 1 or 4, wherein the polymer is a natural polymer selected from the group consisting of polysaccharides.

14. The composite of claim 1 or 4, wherein the polymer is an artificial polymer selected from the group consisting of poly(anhydrides), poly(hydroxy acids), polyesters, poly(orthoesters), polycarbonates, poly(propylene fumerates), poly(caprolactones), polyamides, polyamino acids, polyacetals, polylactides, polyglycolides, poly(dioxanones), polysulfones, polyhydroxybutyrates, polyhydroxyvalyrates, poly(vinyl pyrrolidone), biodegradable polycyanoacrylates, biodegradable polyurethanes, polysaccharides, tyrosine-based polymers, poly(methyl vinyl ether), poly(maleic anhydride), poly(glyconates), polyphosphazines, poly(esteramides), polyketals, poly(orthocarbonates), poly(maleic acid), poly(alkylene oxalates), poly(alkylene succinates), poly(pyrrole), poly(aniline), poly(thiophene), polystyrene, non-biodegradable polyurethanes, polyureas, poly(ethylene vinyl acetate), polypropylene, polymethacrylate, polyethylene, poly(ethylene oxide), and co-polymers, adducts, and mixtures thereof.

15. The composite of claim 1, 2, or 4, wherein a surface of at least a portion of the bone particles has been chemically modified.

16. The composite of claim 15, wherein the surface of at least a portion of the bone particles is treated with dilute phosphoric acid.

17. The composite of claim 1, 2, or 4, wherein the composition of the bone particle has been modified.

18. The composition of claim 17, wherein at least a portion of the bone particles are dried, lyophilized, defatted, treated with a detergent, treated with a solvent, treated with a surfactant, or treated to remove or inactivate pathogens.

19. The composite of claim 1 or 2, further comprising a cross-linking agent.

20. The composite of claim 19, wherein the cross-linking agent is selected from the group consisting of aldehydes, polyepoxy compounds, polyvalent metallic oxides, organic tannins, N-hydroxysuccinimides, N-hydroxysulfosuccinimides, phenolic oxides, hydrazides, carbodiimides, isocyanates, isothiocyanates, sugars and enzymes.

21. The composite of claim 1, 2, or 4, further comprising one or more of a wetting agent, biocompatible binder, filler, fiber, plasticizer, biostatic/biocidal agent, surface active agent, biomolecule, small molecule, or bioactive agent.

22. The composite of claim 21, wherein the bioactive agent is selected from the group consisting of antibiotics, chemotherapeutics, bone cell inducers, and bone cell stimulators.

23. The composite of claim 1, 2, or 4, further comprising osteoblasts.

24. The composite of claim 21, wherein the bioactive agent is selected from the group consisting of bone morphogenic proteins (BMPs), transforming growth factor-beta (TGF-β

), insulin-like growth factor, platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), parathyroid hormone (PTH), growth factor binding proteins, and angiogenic factor.

2. A composite comprising:

a plurality of bone particles; and

a biocompatible polymer;

wherein at least a portion of the bone particles are covalently linked to the polymer through a silane coupling agent; and

wherein the polymer is selected from the group consisting of polysaccharides.

3. The composite of claim 2, wherein the polymer is selected from the group consisting of starch, dextran, cellulose, gelatin, collagen, and derivatives thereof.

8. The composite of claim 2 or 4, wherein the bone particles represent about 60% to about 75% of the total weigh of the composite.

13. The composite of claim 8, wherein the polymer is selected from the group consisting starch, dextran, cellulose, gelatin, collagen, and derivatives thereof.

4. The composite comprising:

a plurality of bone particles;

a biocompatible polymer; and

a cross-linking agent;

wherein at least a portion of the bone particles are covalently linked to the polymer through a silane coupling agent; and

wherein the cross-linking agent is selected from the group consisting of aldehydes, polyepoxy compounds, polyvalent metallic oxides, organic tannins, N-hydroxysuccinimides, N-hydroxysulfosuccinimides, phenolic oxides, hydrazides, carbodiimides, isocyanates, isothiocyanates, sugars, and enzymes.