Method and apparatus for engineered regenerative biostructures such as hydroxyapatite substrates for bone healing applications

• US 7,122,057 B2
• Filed: 04/12/2002
• Issued: 10/17/2006
• Est. Priority Date: 04/12/2001
• Status: Expired due to Fees

• Current Assignee: Theken Spine LLC (Orthofix Medical Inc.)
• Original Assignee: Therics Inc.
• Inventors: Liu, Qing, Beam, Heather Ann, Surprenant, Henry Leon, Chesmel, Kathleen D., Materna, Peter Albert, Monkhouse, Donald, Patterson, Jennifer, Wang, Chen-Chao, Gaylo, Christopher M., Yoo, Jaedeok, Pryor, Timothy J., Litwak, Alfred Anthony, West, Thomas George, Saini, Sunil, Bradbury, Thomas J.
• Primary Examiner(s): Robert, Eduardo C.
• Assistant Examiner(s): Cornstock, David
• Application Number:
  US10/122,129
• Publication Number:
  US 20030065400A1
• Time in Patent Office: 1,649 Days
• Field of Search: 623/16.11, 623/23.51, 623/23.61, 419/2, 419/5, 264/43, 264/44, 424/423
• US Class Current: 623/23.51
• CPC Class Codes: A61F 2/28 Bones joints A61F2/30
• CPC Class Codes: A61F 2002/30032 differing in absorbability or resorbability, i.e. in absorption or resorption time
• CPC Class Codes: A61F 2002/30059 differing in bone mineralization, e.g. made from both mineralized and demineralized adjacent parts
• CPC Class Codes: A61F 2002/30062 (bio)absorbable, biodegradable, bioerodable, (bio)resorbable, resorptive
• CPC Class Codes: A61F 2002/30225 Flat cylinders, i.e. discs
• CPC Class Codes: A61F 2002/30261 parallelepipedal
• CPC Class Codes: A61F 2002/30593 hollow
• CPC Class Codes: A61F 2002/30971 Laminates, i.e. layered products
• CPC Class Codes: A61F 2210/0004 bioabsorbable
• CPC Class Codes: A61F 2230/0069 cylindrical
• CPC Class Codes: A61F 2230/0082 parallelepipedal
• CPC Class Codes: A61F 2250/0031 made from both resorbable and non-resorbable prosthetic parts, e.g. adjacent parts
• CPC Class Codes: A61F 2310/00293 containing a phosphorus-containing compound, e.g. apatite
• CPC Class Codes: A61L 2430/02 for reconstruction of bones; weight-bearing implants
• CPC Class Codes: A61L 27/12 Phosphorus-containing materials, e.g. apatite
• CPC Class Codes: A61L 27/46 with phosphorus-containing inorganic fillers
• CPC Class Codes: A61L 27/50 Materials characterised by their function or physical properties , e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• CPC Class Codes: A61L 27/56 Porous materials, e.g. foams or sponges
• CPC Class Codes: B33Y 30/00 Apparatus for additive manufacturing; Details thereof or accessories therefor
• CPC Class Codes: B33Y 80/00 Products made by additive manufacturing
• CPC Class Codes: C04B 2111/00181 : Mixtures specially adapted for three-dimensional printing (3DP), stereo-lithography or prototyping
• CPC Class Codes: C04B 2111/00836 : for medical or dental applications
• CPC Class Codes: C04B 2235/3212 : Calcium phosphates, e.g. hydroxyapatite
• CPC Class Codes: C04B 2235/447 : Phosphates or phosphites calcium phosphates C04B2235/3212, e.g. orthophosphate, hypophosphite
• CPC Class Codes: C04B 2235/5436 : micrometer sized, i.e. from 1 to 100 micron
• CPC Class Codes: C04B 2235/6026 : Computer aided shaping, e.g. rapid prototyping
• CPC Class Codes: C04B 2235/616 : Liquid infiltration of green bodies or pre-forms
• CPC Class Codes: C04B 2235/6567 : Treatment time
• CPC Class Codes: C04B 2235/80 : Phases present in the sintered or melt-cast ceramic products other than the main phase
• CPC Class Codes: C04B 2235/96 : Properties of ceramic products, e.g. mechanical properties such as strength, toughness, wear resistance
• CPC Class Codes: C04B 28/34 : containing cold phosphate binders
• CPC Class Codes: C04B 35/00 : Shaped ceramic products characterised by their composition porous ceramic products C04B38/00; ceramic articles characterised by particular shape, see the relevant classes, e.g. linings for casting ladles, tundishes, cups or the like B22D41/02; ceramic substrates for microelectronic semi-conductors H01L23/15; Ceramics compositions containing free metal bonded to carbides, diamond, oxides, borides, nitrides, silicides, e.g. cermets, or other metal compounds, e.g. oxynitrides or sulfides other than as macroscopic reinforcing agents C22C; shaping of ceramics B28B; Processing powders of inorganic compounds preparatory to the manufacturing of ceramic products chemical preparation of powders of inorganic compounds C01; infiltration of sintered ceramic preforms with molten metal C04B41/51
• CPC Class Codes: C04B 35/447 : based on phosphates , e.g. hydroxyapatite
• CPC Class Codes: C04B 35/634 : Polymers C04B35/636 takes precedence
• CPC Class Codes: C04B 35/638 : Removal thereof
• CPC Class Codes: C04B 38/0054 : the pores being microsized or nanosized
• CPC Class Codes: C04B 38/0074 : expressed as porosity percentage
• CPC Class Codes: C04B 38/06 : by burning-out added substances by burning natural expanding materials or by sublimating or melting out added substances

Abstract

An engineered regenerative biostructure (erb) for implantation into a human body as a bone substitute, which includes an internal microstructure, mesostructure and/or macrostructure to provide improved bone in-growth, and methods for making the erb. Under one aspect of the invention, the biostructure has resorbable and nonresorbable regions. Under another aspect of the invention, the biostructure is constructed of hydroxyapatite, tricalcium phosphate and/or demineralized bone. Under yet another aspect of the invention, the porous biostructure is partially or fully infused with a resorbable, nonresorbable or dissolvable material.

Claims

1. An osteoinductive or osteoconductive biostructure comprising a matrix of interconnected ceramic particles joined directly to each other and having at least one of a porous portion, wherein said porous portion comprises controlled particle packing providing controlled inter-particle pores, and further wherein said matrix of interconnected particles comprises multiple discrete regions having different compositions wherein the multiple discrete regions comprise a first region having a composition comprising hydroxyapatite and a second region having a composition comprising tricalcium phosphate, and wherein both the first region and the second region are porous, and further wherein said first and second porous regions have pore sizes that are approximately equal.

2. The biostructure of claim 1, wherein the biostructure further comprises macrochannels therethrough.

3. The biostructure of claim 1 produced by a process comprising heating a precursor biostructure, wherein the precursor biostructure comprises multiple discrete regions having different compositions, and wherein at least one of the multiple discrete regions comprises a different composition which converts to another substance by a chemical reaction initiated by said heating.

4. The biostructure produced by the process of claim 3, wherein said precursor biostructure further comprises a calcium-rich reactant that facilitates the chemical reaction.

5. The biostructure produced by the process of claim 4, wherein the calcium-rich reactant is selected from calcium carbonate, calcium oxide, calcium hydroxide, and combinations thereof.

6. The biostructure produced by the process of claim 3, wherein said precursor biostructure further comprises a phosphorus-rich reactant that facilitates the chemical reaction.

7. The biostructure produced by the process of claim 6, wherein the phosphorus-rich reactant is selected from dicalcium phosphate, monocalcium phosphate, phosphoric acid, ammonium phosphate, and combinations thereof.

21. The biostructure of claim 1, 8 or 16, wherein said biostructure further comprises a resorbable polymer.

22. The biostructure of claim 21, wherein said resorbable polymer is polylactic acid or polylactic co-glycolic acid.

23. The biostructure of claim 1, 8 or 16, wherein said biostructure further comprises a nonresorbable polymer.

24. The biostructure of claim 23, wherein said nonresorbable polymer is polymethylmethacrylate.

25. The biostructure of claim 1, 8 or 16, wherein said biostructure further comprises bioactive substances.

26. The biostructure of claim 25, wherein said bioactive substances comprise cells, cell fragments, cellular material, proteins, growth factors, hormones, active pharmaceutical ingredients, peptides, or mixtures thereof.

27. The biostructure of claims 1, 8, or 16, wherein the pores of said biostructure are at least partially occupied by a strengthening agent.

28. The biostructure of claim 27, wherein the pores are completely filled with said strengthening agent.

29. The biostructure of claim 27, wherein porous portions not occupied by said strengthening agent contain a bioactive substance.

30. The biostructure of claim 27, wherein said strengthening agent is selected from fibrin, fibrinogen, polymers, polylactic co-glycolic acid and combinations thereof.

31. The biostructure of claims 1, 8, 16, wherein the pores of said biostructure are filled with an interpenetrating material.

32. The biostructure of claim 31, wherein the interpenetrating material is a polymer.

33. The biostructure of claim 32, wherein said polymer is resorbable.

34. The biostructure of claim 32, wherein said polymer is non-resorbable.

35. The biostructure of claim 32, wherein said polymer is a comb polymer.

36. The biostructure of claim 31, wherein said interpenetrating material further comprises a bioactive substance.

37. The biostructure of claim 36, wherein the bioactive substance is selected from antibiotics, active pharmaceutical ingredients, anesthetics, anti-inflammatozy substances, growth promoting substances, hormones, peptides, bone morphogenic proteins, cells, cell fragments, cellular material, proteins, and growth factors.

46. The biostructure of claim 1, 8, 12, 16, or 38, wherein said biostructure comprises a porosity between 30% and 70%.

47. The biostructure of claim 1, 8, 12, 16, or 38, wherein said particles are substantially spherical.

48. The biostructure of claim 1, 8, 12, 16, or 38, wherein said particles are substantially non-spherical.

49. The biostructure of claim 1, 8, 12, 16, or 38, wherein said particles are bound through the application of a binder liquid that is deposited on the particles in a staggered configuration.

50. The biostructure of claim 1, 8, 12, 16, or 38, wherein said particles are bound through the application of a binder liquid that is deposited on the particles in a stacked configuration.

51. The biostructure of claim 1, 8, 12, 16, or 38, wherein said biostructure is a bone substitute.

52. The biostructure of claim 51, wherein the biostructure is a bone substitute for at least a portion of a bone selected from the group consisting of the ethmoid, frontal, nasal, occipital, parietal, temporal, mandible, maxilla, zygomatic, cervical vertebra, thoracic vertebra, lumbar vertebra, sacrum, rib, sternum, clavicle, scapula, humerus, radius, nina, carpal bones, metacarpal bones, phalanges, ilium, ischium, pubis, femur, tibia, fibula, patella, calcaneus tarsal and metatarsal bones, and condyle.

54. The biostructure of claim 1, 12, 16, 38 or 53, wherein said biostructure comprises undercuts, recesses or interior voids.

55. The biostructure of claim 54, wherein said undercuts or recesses comprise dead-end channels, grooves, dimples or tread-like features.

56. The biostructure of claim 1, 8, 12, 16, 38, or 53, wherein said biostructure is uniquely shaped or dimensioned for implantation into an individual patient.

8. An osteoinductive or osteoconductive biostructure comprising a matrix of interconnected ceramic particles joined directly to each other and having at least one of a porous portion, wherein said porous portion comprises controlled particle packing providing controlled inter-particle pores, and at least two intersecting macrochannels, and having an exterior surface wherein the exterior surface contains at least one groove.

10. The biostructure of claim 8, wherein said biostructure comprises particles selected from calcium phosphates, hydroxyapatite, tricalcium phosphate, calcium salts, dental tooth enamel, aragonite, calcite, nacre, bioceramic and mixtures thereof.

11. The biostructure of claim 8, further comprising distinct regions of a first composition of hydroxyapatite and a second composition of tricalcium phosphate.

9. The biostructure of clalm 8, wherein said inter-particle pores have a pore size distribution having a peak in the range of 60 microns to 100 microns.

12. An osteoinductive or osteoconductive biostructure comprising a matrix of interconnected ceramic particles joined directly to each other and having at least one of a porous portion, wherein said porous portion comprises controlled particle packing providing controlled inter-particle pores, and macrochannels, wherein the biostructure further comprises, in space not otherwise occupied, a co-located polymer and bioactive substance.

13. The biostructure of claim 12, wherein said inter-particle pores have a pore size distribution having a peak in the range of 60 microns to 100 microns.

14. The biostructure of claim 12, wherein said biostructure comprises particles selected from calcium phosphates, hydroxyapatite, tricalcium phosphate, calcium salts, dental tooth enamel, aragonite, calcite, nacre, bioceramic and mixtures thereof.

15. The biostructure of claim 12, further comprising distinct regions of a first composition of hydroxyapatite and a second composition of tricalcium phosphate.

42. The biostructure of claim 2, 8, 12, 16, or 39, wherein said macrochannels have uniform cross-sections, one or more non-uniform cross-sections, non-straight paths, branching, or dead-ends.

16. An osteoinductive or osteoconductive biostructure comprising a matrix of interconnected particles having at least one of a porous portion, wherein said porous portion comprises controlled particle packing providing controlled inter-particle pores, and having macrochannels such that at least three non-coplanar macrochannels intersect at a common location.

17. The biostructure of claim 16, wherein said controlled inter-particle pores have a pore size distribution having a peak in the range of 60 microns to 100 microns.

18. The biostructure of claim 16, wherein said matrix of interconnected particles comprises ceramic particles directly joined to each other.

19. The biostructure of claim 16, wherein said macrochannels have a cross-sectional dimension from 300 to 700 microns.

20. The biostructure of claim 16, wherein said macrochannels have a cross-sectional dimension from 1000 to 1600 microns.

38. An osteoinductive or osteoconductive biostructure comprising a matrix of interconnected ceramic particles joined directly to each other and having at least one of a porous portion, wherein said porous portion comprises controlled particle packing providing controlled inter-particle pores, wherein the pores of said porous portion are partially occupied with a strengthening agent, and wherein open spaces not occupied by said strengthening agent contain a bioactive substance.

39. The biostructure of claim 38, wherein said biostructure further comprises macrochannels.

40. The biostructure of claim 39, wherein said macrochannels have a cross-sectional dimension from 300 to 700 microns.

41. The biostructure of claim 39, wherein said macrochannels have a cross-sectional dimension from 1000 to 1600 microns.

43. The biostructure of claim 38, wherein said biostructure comprises particles selected from calcium phosphates, hydroxyapatite, tricalcium phosphate, calcium salts, dental tooth enamel, aragonite, calcite, nacre, bioceramic and mixtures thereof.

44. The biostructure of claim 38, wherein the strengthening agent is a polymer.

45. The biostructure of claim 38, further comprising distinct regions of a first composition of hydroxyapatite and a second composition of tricalcium phosphate.

53. A precursor biostnzcture comprising a matrix of ceramic particales joined to each other by a substance which decomposes into gaseous decomposition products at a first suitable temperature and having at least one of a porous portion, wherein said porous portion comprises controlled particle packing providing controlled inter-particle pores, and further wherein said matrix of interconnected particles comprises multiple discrete regions having different compositions, and wherein at least one of said multiple discrete regions having different compositions converts to another substance by a chemical reaction at a second suitable temperature.

57. The precursor biostructure of claim 53, wherein said precursor biostructure comprises a calcium-rich reactant that facilitates the chemical reaction.

58. The precursor biostructure of claim 57, wherein the calcium-rich reactant is selected from calcium carbonate, calcium oxide, calcium hydroxide, and combinations thereof.

59. The precursor biostructure of claim 53, wherein said precursor biostructure comprises a phosphorus-rich reactant that facilitates the chemical reaction.

60. The precursor biostructure of claim 59, wherein the phosphorus-rich reactant is selected from dicalcium phosphate, monocalcium phosphate, phosphoric acid, ammonium phosphate, and combinations thereof.