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Last Updated: November 30, 2021

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Claims for Patent: 6,767,928

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Summary for Patent: 6,767,928
Title: Mineralization and biological modification of biomaterial surfaces
Abstract:Disclosed are advantageous methods for patterning and/or mineralizing biomaterial surfaces. The techniques described are particularly useful for generating three-dimensional or contoured bioimplant materials with patterned surfaces or patterned, mineralized surfaces. Also provided are various methods of using the mineralized and/or patterned biomaterials in tissue engineering, such as bone tissue engineering, providing more control over ongoing biological processes, such as mineralization, growth factor release, cellular attachment and tissue growth.
Inventor(s): Murphy; William L. (Ann Arbor, MI), Peters; Martin C. (Ann Arbor, MI), Mooney; David J. (Ann Arbor, MI), Kohn; David H. (Ann Arbor, MI)
Assignee: The Regents of the University of Michigan (Ann Arbor, MI)
Application Number:09/527,636
Patent Claims:1. A method for generating an extended, osteoconductive mineral coating on a surface of a biomaterial, comprising functionalizing at least a first surface of a biomaterial to create a plurality of polar oxygen groups on the biomaterial surface and contacting the functionalized biomaterial surface with an amount of a mineral-containing solution effective to form a mineralized biomaterial that comprises an extended, osteoconductive mineral coating at the functionalized biomaterial surface; wherein said biomaterial comprises at least a first porous, biodegradable polymer portion that has an interconnected pore structure and that is degradable over a controllable time scale and wherein said biomaterial comprises at least a first portion that is prepared by a process comprising gas foaming and particulate leaching.

2. The method of claim 1, wherein said extended, osteoconductive mineral coating comprises a patterned mineral layer comprising a plurality of discrete mineral islands.

3. The method of claim 1, wherein said extended, osteoconductive mineral coating comprises a substantially homogeneous mineral coating.

4. The method of claim 1, wherein said functionalized biomaterial surface is generated by exposing at least a first surface of said biomaterial to a functionalizing pre-treatment prior to contact with said mineral-containing solution.

5. The method of claim 4, wherein said functionalizing pre-treatment comprises exposure to an effective amount of electromagnetic radiation or electron beam (e-beam) irradiation.

6. The method of claim 4, wherein said functionalizing pre-treatment comprises exposure to an effective amount of a NaOH solution.

7. The method of claim 1, wherein said functionalized biomaterial surface is generated during said contact with said mineral-containing solution.

8. The method of claim 1, wherein said at least a first surface of said biomaterial is enriched in carboxylic acid groups.

9. The method of claim 1, wherein said biomaterial comprises at least a first portion that is a 3-dimensional biomaterial scaffold.

10. The method of claim 1, wherein said biomaterial comprises at least a first portion that is a polylactic acid (PLA) polymer, polyglycolic acid (PGA) polymer or polylactic-co-glycolic acid (PLG) copolymer biomaterial.

11. The method of claim 10, wherein said biomaterial comprises at least a first portion that is a PLG copolymer biomaterial.

12. The method of claim 11, wherein said biomaterial comprises at least a first portion that is a PLG copolymer biomaterial having a ratio of about 85 percent lactide to about 15 percent glycolide.

13. The method of claim 1, wherein at least a first bioactive substance is operatively associated with said biomaterial during the gas foaming and particulate leaching process.

14. The method of claim 1, wherein said biomaterial is prepared by a gas foaming and particulate leaching process comprising the steps of: (a) preparing an admixture at least comprising a leachable particulate material and particles capable of forming a porous, degradable polymer biomaterial; (b) subjecting said admixture to a gas foaming process to create a porous, degradable polymer biomaterial that comprises said leachable particulate material; and (c) subjecting said porous, degradable polymer biomaterial to a leaching process that removes said leachable particulate material from said porous, degradable polymer biomaterial, thereby creating additional porosity.

15. The method of claim 14, wherein said leaching process comprises contacting said porous, degradable polymer biomaterial with a mineral-containing leaching material.

16. The method of claim 1, wherein said functionalized biomaterial surface is an inner pore surface within said porous, degradable polymer biomaterial and wherein an extended, osteoconductive mineral coating is generated on said inner pore surface.

17. The method of claim 1, wherein said mineral-containing solution is a calcium-rich solution.

18. The method of claim 1, wherein said mineral-containing solution comprises at least a first and second mineral and wherein said extended, osteoconductive mineral coating comprises a mixture of said first and second minerals.

19. The method of claim 1, wherein said mineral-containing solution comprises a plurality of distinct minerals and wherein said extended, osteoconductive mineral coating comprises a heterogeneous polymineralized coating.

20. The method of claim 1, wherein said mineral-containing solution is a body fluid.

21. The method of claim 1, wherein said mineral-containing solution is a synthetic medium that mimics a body fluid.

22. The method of claim 1, wherein said functionalized biomaterial surface is contacted with said mineral-containing solution by exposure to a mineral-containing solution in vitro.

23. The method of claim 1, wherein said functionalized biomaterial surface is contacted with said mineral-containing solution by exposure to a mineral-containing body fluid in vivo.

24. The method of claim 1, wherein said biomaterial is operatively associated with a biologically effective amount of at least a first bioactive substance or biological cell.

25. The method of claim 24, wherein said biomaterial is operatively associated with a biologically effective amount of at least two bioactive substances or at least two biological cells.

26. The method of claim 25, wherein said biomaterial is operatively associated with a biologically effective amount of a plurality of bioactive substances or a plurality of biological cells.

27. The method of claim 24, wherein said biomaterial is operatively associated with a biologically effective amount of at least a first bioactive substance.

28. The method of claim 27, wherein said biomaterial is operatively associated with a biologically effective amount of at least first bioactive drug.

29. The method of claim 27, wherein said biomaterial is operatively associated with a biologically effective amount of at least first bioactive DNA molecule, RNA molecule, antisense nucleic acid, ribozyme, plasmid, expression vector, viral vector or recombinant virus.

30. The method of claim 27, wherein said biomaterial is operatively associated with a biologically effective amount of at least a first marker protein, transcription or elongation factor, cell cycle control protein, kinase, phosphatase, DNA repair protein, oncogene, tumor suppressor, angiogenic protein, anti-angiogenic protein, cell surface receptor, accessory signaling molecule, transport protein, enzyme, anti-bacterial agent, anti-viral agent, antigen, immunogen, apoptosis-inducing agent, anti-apoptosis agent or cytotoxin.

31. The method of claim 27, wherein said biomaterial is operatively associated with a biologically effective amount of at least a first hormone, neurotransmitter, growth factor, hormone, neurotransmitter or growth factor receptor, interferon, interleukin, chemokine, cytokine, colony stimulating factor, chemotactic factor, extracellular matrix component or an adhesion molecule, ligand or peptide.

32. The method of claim 31, wherein said biomaterial is operatively associated with a biologically effective amount of growth hormone, parathyroid hormone (PTH), bone morphogenetic protein (BMP), transforming growth factor-.alpha. (TGF-.alpha.), TGF-.beta.1, TGF-.beta.2, fibroblast growth factor (FGF), granulocyte/macrophage colony stimulating factor (GMCSF), epidermal growth factor (EGF), platelet derived growth factor (PDGF), insulin-like growth factor (IGF), scatter factor/hepatocyte growth factor (HGF), fibrin, collagen, fibronectin, vitronectin, hyaluronic acid, an RGD-containing peptide or polypeptide, an angiopoietin or vascular endothelial cell growth factor (VEGF).

33. The method of claim 32, wherein said biomaterial is operatively associated with a biologically effective amount of VEGF.

34. The method of claim 27, wherein said at least a first bioactive substance is incorporated into said biomaterial prior to the generation of said extended, osteoconductive mineral coating.

35. The method of claim 27, wherein said at least a first bioactive substance is incorporated into said biomaterial during the generation of said extended, osteoconductive mineral coating.

36. The method of claim 27, wherein said at least a first bioactive substance is incorporated into said biomaterial subsequent to the generation of said extended, osteoconductive mineral coating.

37. The method of claim 27, wherein the generation of said extended, osteoconductive mineral coating controls the release of said bioactive substance from said biomaterial.

38. The method of claim 24, wherein said biomaterial is operatively associated with a biologically effective amount of at least a first biological cell.

39. The method of claim 38, wherein said biomaterial is operatively associated with a biologically effective amount of at least a first bone progenitor cell, fibroblast or endothelial cell.

40. The method of claim 39, wherein said biomaterial is operatively associated with a biologically effective amount of at least a first bone progenitor cell selected from the group consisting of a stem cell, macrophage, fibroblast, vascular cell, osteoblast, chondroblast or osteoclast.

41. The method of claim 38, wherein said biomaterial is operatively associated with a biologically effective amount of at least a first recombinant cell that expresses at least a first exogenous nucleic acid segment that produces a transcriptional or translated product in said cell.

42. The method of claim 38, wherein said biomaterial is operatively associated with a biologically effective amount of at least a first mineral-adherent cell by exposing said mineralized biomaterial to mineral-adherent cells that bind to the extended, osteoconductive mineral coating at said biomaterial surface.

43. The method of claim 42, wherein said biomaterial is operatively associated with said mineral-adherent cells by exposing said mineralized biomaterial to a population of mineral-adherent cells in vitro.

44. The method of claim 42, wherein said biomaterial is operatively associated with said mineral-adherent cells by exposing said mineralized biomaterial to a population of mineral-adherent cells in vivo.

45. The method of claim 24, wherein said biomaterial is operatively associated with a combined biologically effective amount of at least a first bioactive substance and at least a first biological cell.

46. The method of claim 45, wherein said biomaterial is operatively associated with a combined biologically effective amount of at least a first osteotropic growth factor or osteotropic growth factor nucleic acid and a cell population comprising bone progenitor cells.

47. The method of claim 45, wherein said biomaterial is operatively associated with a combined biologically effective amount of VEGF or a VEGF nucleic acid and a cell population comprising endothelial cells.

48. The method of claim 1, wherein said method is executed at a temperature compatible to mammalian biological systems.

49. A single step method for forming a mineralized biomaterial that comprises an extended, osteoconductive mineral coating on a biomaterial surface, comprising incubating a mineralizable biomaterial with an amount of a mineral-containing aqueous solution effective to generate a functionalized biomaterial surface upon which an extended, osteoconductive mineral coating forms during the incubation; wherein said mineralizable biomaterial comprises at least a first porous, biodegradable polymer portion that has an interconnected pore structure and that is degradable over a controllable time scale and wherein said biomaterial comprises at least a first portion that is prepared by a process comprising gas foaming and particulate leaching.

50. The method of claim 49, wherein said mineralizable biomaterial comprises at least a first portion that is a polylactic acid (PLA) polymer, polyglycolic acid (PGA) polymer or polylactic-co-glycolic acid (PLG) copolymer biomaterial.

51. A mineralized biomaterial that comprises an extended, osteoconductive mineral coating on at least a first surface prepared by the process of claim 1.

52. The mineralized biomaterial of claim 51, wherein said extended, osteoconductive mineral coating comprises a plurality of discrete mineral islands.

53. The mineralized biomaterial of claim 51, wherein said extended, osteoconductive mineral coating comprises a substantially homogeneous mineral coating.

54. The mineralized biomaterial of claim 51, prepared by the process of claim 49.

55. The mineralized biomaterial of claim 51, wherein said mineralized biomaterial further comprises a biologically effective amount of at least a first bioactive substance or biological cell.

56. A biocompatible device comprising at least one surface portion comprising an extended, osteoconductive mineral coating formed by the process of claim 1.

57. The method of claim 1, wherein said biomaterial comprises at least a first portion that is a poly(vinyl alcohol), poly(ethylene glycol), pluronic, poly(vinylpyrollidone), hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, poly(ethylene terephthalate), poly(anhydride) or poly(propylene fumarate) polymer biomaterial.

58. The method of claim 1, wherein said biomaterial comprises at least a first portion that is a collagen, alginate, modified alginate, fibrin, matrigel, elastin, chitosan or gelatin polymer biomaterial.

59. A method for generating an extended, osteoconductive mineral coating on a surface of a porous, biodegradable polymer biomaterial, comprising contacting a surface of said porous, biodegradable polymer biomaterial with an amount of a mineral-containing solution effective to form an extended, osteoconductive mineral coating on said surface; wherein said porous, biodegradable polymer biomaterial has an interconnected pore structure and is degradable over a controllable time scale and wherein said biomaterial comprises at least a first portion that is prepared by a process comprising gas foaming and particulate leaching.

60. A method for generating an extended, osteoconductive mineral coating on a surface of a biomaterial, comprising exposing at least a first surface of said biomaterial to a functionalizing pre-treatment to create a functionalized biomaterial surface, and contacting said functionalized biomaterial surface with an amount of a mineral-containing solution effective to form an extended, osteoconductive mineral coating on said functionalized biomaterial surface; wherein said biomaterial comprises at least a first portion that is prepared by a process comprising gas foaming and particulate leaching.

61. The method of claim 60, wherein said biomaterial comprises at least a first portion that is a porous, degradable polymer biomaterial that has an interconnected pore structure and that is degradable over a controllable time scale.

62. The method of claim 60, wherein said functionalizing pre-treatment comprises exposure to an effective amount of electromagnetic radiation or electron beam (e-beam) irradiation.

63. The method of claim 60, wherein said functionalizing pre-treatment comprises exposure to an effective amount of a NaOH solution.

64. A method for generating an extended mineral coating on a surface of a porous, biodegradable polymer biomaterial, comprising contacting a surface of said porous, biodegradable polymer biomaterial with an amount of a mineral-containing solution effective to form an extended mineral coating on said surface; wherein said porous, biodegradable polymer biomaterial has an interconnected pore structure, is degradable over a controllable time scale and is prepared by a process comprising gas foaming and particulate leaching.

65. The method of claim 64, wherein said porous, biodegradable polymer biomaterial is prepared by a gas foaming and particulate leaching process comprising the steps of: (a) preparing an admixture at least comprising a leachable particulate material and particles capable of forming a porous, biodegradable polymer biomaterial; (b) subjecting said admixture to a gas foaming process to create a porous, biodegradable polymer biomaterial that comprises said leachable particulate material; and (c) subjecting said porous, biodegradable polymer biomaterial to a leaching process that removes said leachable particulate material from said porous, biodegradable polymer biomaterial, thereby creating additional porosity.

66. A method for generating an extended, osteoconductive mineral coating on an inner pore surface of a porous, biodegradable polymer biomaterial, comprising exposing said porous, biodegradable polymer biomaterial to an amount of a mineral-containing solution effective to form an extended, osteoconductive mineral coating on an inner pore surface of said porous, biodegradable polymer biomaterial; wherein said porous, biodegradable polymer biomaterial comprises at least a first portion that is prepared by a process comprising gas foaming and particulate leaching.

67. The method of claim 66, wherein said porous, biodegradable polymer biomaterial has an interconnected pore structure and is degradable over a controllable time scale.

68. A method for generating an extended mineral coating on a surface of a 3-dimensional biomaterial scaffold, comprising contacting a surface of said 3-dimensional biomaterial scaffold with an amount of a mineral-containing solution effective to form an extended mineral coating on said surface; wherein said 3-dimensional biomaterial scaffold comprises at least a first porous, biodegradable polymer portion that has an interconnected pore structure, that is degradable over a controllable time scale and that is prepared by a process comprising gas foaming and particulate leaching.

69. A method for generating an extended mineral coating on a surface of a biomaterial, comprising contacting a surface of said biomaterial with an amount of a mineral-containing solution effective to form an extended mineral coating on said surface; wherein said biomaterial comprises at least a first porous, biodegradable polymer portion that has an interconnected pore structure, that is degradable over a controllable time scale and that is prepared by a process comprising gas foaming and particulate leaching and wherein said biomaterial is operatively associated with a biologically effective amount of at least a first bioactive substance or biological cell.

70. The method of claim 1, wherein said functionalized biomaterial surface is contacted with said mineral-containing solution for a time effective to form discrete mineral islands that expand to form a substantially homogeneous, osteoconductive mineral coating.

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