Osteoinductive bone material

• US 8,221,781 B2
• Filed: 04/12/2004
• Issued: 07/17/2012
• Est. Priority Date: 04/11/2003
• Status: Active Grant

• Current Assignee: Etex Corporation (Zimmer Biomet Holdings, Inc.)
• Original Assignee: Etex Corporation (Zimmer Biomet Holdings, Inc.)
• Inventors: Rosenberg, Aron D., Gilles de Pelichy, Laurent D., Egan, Daniel, Tofighi, Aliassghar N., Lee, Dosuk D.
• Primary Examiner(s): AZPURU, CARLOS A
• Application Number:
  US10/822,540
• Publication Number:
  US 20050084542A1
• Time in Patent Office: 3,018 Days
• Field of Search: None
• US Class Current: 424/426
• CPC Class Codes: A61F 2/28 Bones joints A61F2/30
• CPC Class Codes: A61F 2002/2817 Bone stimulation by chemical reactions or by osteogenic or biological products for enhancing ossification, e.g. by bone morphogenetic or morphogenic proteins [BMP] or by transforming growth factors [TGF]
• 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: A61L 2430/02 for reconstruction of bones; weight-bearing implants
• CPC Class Codes: A61L 27/227 Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
• CPC Class Codes: A61L 27/26 Mixtures of macromolecular compounds
• CPC Class Codes: A61L 27/34 Macromolecular materials
• 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 27/46 with phosphorus-containing inorganic fillers
• CPC Class Codes: A61L 27/48 with macromolecular fillers
• CPC Class Codes: C08L 89/00 Compositions of proteins; Compositions of derivatives thereof foodstuff preparations A23J3/00

Abstract

Osteogenic bone implant compositions that approximate the chemical composition of natural bone are provided. The organic component of these implant compositions is osteoinductive despite the presence of the inorganic component and, further, is present in an amount sufficient to maximize the regenerative capabilities of the implant without compromising its formability and mechanical strength. The composition may be an osteoinductive powder, including demineralized bone matrix (DBM) particles, a calcium phosphate powder, and, optionally, a biocompatible cohesiveness agent. The powder may be combined with a physiologically-acceptable fluid to produce a formable, osteoinductive paste that self-hardens to form a poorly crystalline apatitic (PCA) calcium phosphate having significant compressive strength. The bone implant materials retain their cohesiveness when introduced at an implant site and are remodeled into bone in vivo. Methods for using these implant materials to repair damaged bone and a method of assaying the content of DBM particles, by weight, in a bone implant material are also provided.

Claims

1. An osteoinductive powder comprising:

(a) demineralized bone matrix (DBM) in an amount in the range of 40 to 70 wt %, wherein said DBM comprises particles having a particle size in the range of about 53 μ

m to about 850 μ

m, and

(b) a calcium phosphate powder in an amount in the range of about 25 to about 60 wt %,

wherein said osteoinductive powder forms a formable, self-hardening, poorly crystalline apatitic (PCA) calcium phosphate paste when admixed with a physiologically acceptable liquid, and wherein said paste is capable of hardening to form a PCA calcium phosphate having a compressive strength of greater than at least about 1 MPa.

2. The osteoinductive powder of claim 1, wherein said DBM comprises about 60 wt % of said osteoinductive powder.

3. The osteoinductive powder of claim 2, wherein said DBM comprises about 50 wt % of said osteoinductive powder.

4. The osteoinductive powder of claim 1, wherein said DBM comprises particles having a particle size in the range of about 125 to about 850 μ

m.

5. The osteoinductive powder of claim 1, wherein said DBM comprises particles having a particle size in the range of about 53 to about 125 μ

m.

6. The osteoinductive powder of claim 1, wherein said calcium phosphate powder comprises amorphous calcium phosphate and a second calcium phosphate.

7. The osteoinductive powder of claim 6, wherein said second calcium phosphate is an acidic or a neutral calcium phosphate.

8. The osteoinductive powder of claim 7, wherein said acidic calcium phosphate is calcium metaphosphate, dicalcium phosphate dihydrate, heptacalcium phosphate, tricalcium phosphate, calcium pyrophosphate dihydrate, poorly crystalline hydroxyapatite, calcium pyrophosphate, or octacalcium phosphate.

9. The osteoinductive powder of claim 8, wherein said acidic calcium phosphate is dicalcium phosphate dihydrate (DCPD).

10. The osteoinductive powder of claim 6, wherein said amorphous calcium phosphate and said second calcium phosphate have an average crystalline domain size of less than about 100 nm.

11. The osteoinductive powder of claim 1, wherein said calcium phosphate powder is subjected to a high energy milling process prior to admixing with said DBM particles.

12. The osteoinductive powder of claim 1 further comprising at least one supplemental material selected from a cohesiveness agent, a biologically active agent, and an effervescent agent.

13. The osteoinductive powder of claim 12, wherein said cohesiveness agent comprises about 0.5 to about 20 wt % of said osteoinductive powder.

14. The osteoinductive powder of claim 12, wherein said cohesiveness agent comprises less than about 20 wt % of said osteoinductive powder.

15. The osteoinductive powder of claim 14, wherein said cohesiveness agent comprises less than about 10 wt % of said osteoinductive powder.

16. The osteoinductive powder of claim 15, wherein said cohesiveness agent comprises less than about 5 wt % of said osteoinductive powder.

17. The osteoinductive powder of claim 16, wherein said cohesiveness agent comprises less than about 1 wt % of said osteoinductive powder.

18. The osteoinductive powder of claim 12, wherein said cohesiveness agent is a polymer selected from polysaccharides, nucleic acids, carbohydrates, proteins, polypeptides, poly(α

-hydroxy acids), poly(lactones), poly(amino acids), poly(anhydrides), poly(orthoesters), poly(anhydride-co-imides), poly(orthocarbonates), poly(α

-hydroxy alkanoates), poly(dioxanones), poly(phosphoesters), poly(L-lactide) (PLLA), poly(D,L-lactide) (PDLLA), polyglycolide (PGA), poly(lactide-co-glycolide (PLGA), poly(L-lactide-co-D, L-lactide), poly(D,L-lactide-co-trimethylene carbonate), polyhydroxybutyrate (PHB), poly(ε

-caprolactone), poly(δ

-valerolactone), poly(γ

-butyrolactone), poly(caprolactone), polyacrylic acid, polycarboxylic acid, poly(allylamine hydrochloride), poly(diallyldimethylammonium chloride), poly(ethyleneimine), polypropylene fumarate, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene, polymethylmethacrylate, carbon fibers, poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol), poly(vinylpyrrolidone), poly(ethyloxazoline), poly(ethylene oxide)-co-poly(propylene oxide) block copolymers, poly(ethylene terephthalate)polyamide, and copolymers thereof.

19. The osteoinductive powder of claim 12, wherein said cohesiveness agent is selected from alginic acid, arabic gum, guar gum, xantham gum, gelatin, chitin, chitosan, chitosan acetate, chitosan lactate, chondroitin sulfate, N,O-carboxymethyl chitosan, a dextran, fibrin glue, glycerol, hyaluronic acid, sodium hyaluronate, a cellulose, a glucosamine, a proteoglycan, a starch, lactic acid, a pluronic, sodium glycerophosphate, collagen, glycogen, a keratin, silk, and mixtures thereof.

20. The osteoinductive powder of claim 19, wherein said cellulose is methylcellulose, carboxy methylcellulose, hydroxypropyl methylcellulose, or hydroxyethyl cellulose.

21. The osteoinductive powder of claim 19, wherein said dextran is α

-cyclodextrin, β

-cyclodextrin, γ

-cyclodextrin, or sodium dextran sulfate.

22. The osteoinductive powder of claim 19, wherein said starch is hydroxyethyl starch or starch soluble.

23. The osteoinductive powder of claim 12, wherein said biologically active agent is selected from an antibody, an antibiotic, a polynucleotide, a polypeptide, a protein, an anti-cancer agent, a growth factor, and a vaccine.

24. The osteoinductive powder of claim 23, wherein said protein is an osteogenic protein.

25. The osteoinductive powder of claim 24, wherein said osteogenic protein is selected from BMP-2, BMP-4, BMP-5, BMP-6, BMP-7, BMP-10, BMP-12, BMP-13, and BMP-14.

26. The osteoinductive powder of claim 23, wherein said anti-cancer agent is selected from alkylating agents, platinum agents, antimetabolites, topoisomerase inhibitors, antitumor antibiotics, antimitotic agents, aromatase inhibitors, thymidylate synthase inhibitors, DNA antagonists, farnesyltransferase inhibitors, pump inhibitors, histone acetyltransferase inhibitors, metalloproteinase inhibitors, ribonucleoside reductase inhibitors, tumor necrosis factor (TNF) alpha agonists, tumor necrosis factor (TNF) alpha antagonists, endothelin A receptor antagonists, retinoic acid receptor agonists, immuno-modulators, hormonal agents, antihormonal agents, photodynamic agents, and tyrosine kinase inhibitors.

27. The osteoinductive powder of claim 12, wherein said effervescent agent is sodium bicarbonate, carbon dioxide, air, nitrogen, helium, oxygen, or argon.

28. The osteoinductive powder of claim 27, wherein said effervescent agent comprises about 1 to about 40 wt % of said osteoinductive powder.

29. The osteoinductive powder of claim 1, wherein said paste hardens to form a PCA calcium phosphate having an overall Ca/P ratio of less than about 1.67.

30. The osteoinductive powder of claim 29, wherein said paste hardens to form a PCA calcium phosphate having an overall Ca/P ratio of less than about 1.5 when admixed with said physiologically acceptable liquid.

31. The osteoinductive powder of claim 1, wherein said paste hardens to form a PCA calcium phosphate having an overall Ca/P ratio in the range of about 1.0 to about 1.67 when admixed with said physiologically acceptable liquid.

72. The osteoinductive powder of claim 1, wherein said paste is capable of hardening to form a PCA calcium phosphate having a compressive strength of between about 1 MPa and 20 MPa.

73. The osteoinductive powder of claim 1, wherein said paste is capable of hardening to form a PCA calcium phosphate having a compressive strength of between about 2 MPa and 10 MPa.

83. The osteoinductive powder of claim 1, wherein said DBM comprises fibers.

84. The osteoinductive powder of claim 83, wherein said DBM fibers have a length between about 50 μ

m and 3 mm and an aspect ratio of greater than 4.

32. An osteoinductive powder comprising:

(a) demineralized bone matrix (DBM) in an amount in the range of 40 to 70 wt %, wherein said DBM comprises particles having a particle size in the range of about 53 μ

m to about 850 μ

m;

(b) a calcium phosphate powder in an amount in the range of about 25 to about 60 wt %; and

(c) a biocompatible cohesiveness agent in an amount in the range of about 0.5 to 20 wt %;

wherein said osteoinductive powder forms a formable, self-hardening, poorly crystalline apatitic (PCA) calcium phosphate paste when admixed with a physiologically acceptable liquid, and wherein said paste is capable of hardening to form a PCA calcium phosphate having a compressive strength of greater than at least about 1 MPa.

74. The osteoinductive powder of claim 32, wherein said paste is capable of hardening to form a PCA calcium phosphate having a compressive strength of between about 1 MPa and 20 MPa.

75. The osteoinductive powder of claim 32, wherein said paste is capable of hardening to form a PCA calcium phosphate having a compressive strength of between about 2 MPa and 10 MPa.

85. The osteoinductive powder of claim 32, wherein said DBM comprises fibers.

86. The osteoinductive powder of claim 85, wherein said DBM fibers have a length between about 50 μ

m and 3 mm and an aspect ratio of greater than 4.

33. A formable, self-hardening, poorly crystalline apatitic (PCA) calcium phosphate paste suitable for use as a bone implant material comprising:

(a) a powder component comprising;

(i) demineralized bone matrix (DBM) in an amount in the range of 40 to 70 wt %, wherein said DBM comprises particles having a particle size in the range of about 53 μ

m to about 850 μ

m, and

(ii) a calcium phosphate powder in an amount in the range of about 25 to about 60 wt %; and

(b) a physiologically-acceptable fluid in an amount to produce a cohesive, formable paste, wherein said paste retains its cohesiveness when introduced at an implant site in vivo and hardens to form a PCA calcium phosphate having a compressive strength of greater than at least about 1 MPa.

34. The paste of claim 33, wherein said DBM comprises about 60 wt % of said powder component.

35. The paste of claim 34, wherein said DBM comprises about 50 wt % of said powder component.

36. The paste of claim 33, wherein said DBM comprises particles having a particle size in the range of about 125 to about 850 μ

m.

37. The paste of claim 33, wherein said DBM comprises particles having a particle size in the range of about 53 to about 125 μ

m.

38. The paste of claim 33, wherein said calcium phosphate powder comprises amorphous calcium phosphate and a second calcium phosphate.

39. The paste of claim 38, wherein said second calcium phosphate is an acidic or a neutral calcium phosphate.

40. The paste of claim 39, wherein said acidic calcium phosphate is calcium metaphosphate, dicalcium phosphate dihydrate, heptacalcium phosphate, tricalcium phosphate, calcium pyrophosphate dihydrate, poorly crystalline hydroxyapatite, calcium pyrophosphate, or octacalcium phosphate.

41. The paste of claim 40, wherein said acidic calcium phosphate is dicalcium phosphate dihydrate (DCPD).

42. The paste of claim 38, wherein said amorphous calcium phosphate and said second calcium phosphate have an average crystalline domain size of less than about 100 nm.

43. The paste of claim 33, wherein said calcium phosphate powder is subjected to a high energy milling process prior to admixing with said DBM particles.

44. The paste of claim 33 further comprising at least one supplemental material selected from a cohesiveness agent, a biologically active agent, and an effervescent agent.

45. The paste of claim 44, wherein said cohesiveness agent comprises about 0.5 to about 20 wt % of said powder component.

46. The paste of claim 44, wherein said cohesiveness agent comprises less than about 20 wt % of said powder component.

47. The paste of claim 46, wherein said cohesiveness agent comprises less than about 10 wt % of said powder component.

48. The paste of claim 47, wherein said cohesiveness agent comprises less than about 5 wt % of said powder component.

49. The paste of claim 48, wherein said cohesiveness agent comprises less than about 1 wt % of said powder component.

50. The paste of claim 44, wherein said cohesiveness agent is a polymer selected from polysaccharides, nucleic acids, carbohydrates, proteins, polypeptides, poly(α

-hydroxy acids), poly(lactones), poly(amino acids), poly(anhydrides), poly(orthoesters), poly(anhydride-co-imides), poly(orthocarbonates), poly(α

-hydroxy alkanoates), poly(dioxanones), poly(phosphoesters), poly(L-lactide) (PLLA), poly(D,L-lactide) (PDLLA), polyglycolide (PGA), poly(lactide-co-glycolide (PLGA), poly(L-lactide-co-D, L-lactide), poly(D,L-lactide-co-trimethylene carbonate), polyhydroxybutyrate (PHB), poly(ε

-caprolactone), poly(δ

-valerolactone), poly(γ

-butyrolactone), poly(caprolactone), polyacrylic acid, polycarboxylic acid, poly(allylamine hydrochloride), poly(diallyldimethylammonium chloride), poly(ethyleneimine), polypropylene fumarate, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene, polymethylmethacrylate, carbon fibers, poly(ethylene glycol), poly(ethylene oxide), poly(vinyl alcohol), poly(vinylpyrrolidone), poly(ethyloxazoline), poly(ethylene oxide)-co-poly(propylene oxide) block copolymers, poly(ethylene terephthalate)polyamide, and copolymers thereof.

51. The paste of claim 44, wherein said cohesiveness agent is selected from alginic acid, arabic gum, guar gum, xantham gum, gelatin, chitin, chitosan, chitosan acetate, chitosan lactate, chondroitin sulfate, N,O-carboxymethyl chitosan, a dextran, fibrin glue, glycerol, hyaluronic acid, sodium hyaluronate, a cellulose, a glucosamine, a proteoglycan, a starch, lactic acid, a pluronic, sodium glycerophosphate, collagen, glycogen, a keratin, silk, and mixtures thereof.

52. The paste of claim 51, wherein said cellulose is methylcellulose, carboxy methylcellulose, hydroxypropyl methylcellulose, or hydroxyethyl cellulose.

53. The paste of claim 51, wherein said dextran is α

-cyclodextrin, β

-cyclodextrin, γ

-cyclodextrin, or sodium dextran sulfate.

54. The paste of claim 51, wherein said starch is hydroxyethyl starch or starch soluble.

55. The paste of claim 46, wherein said biologically active agent is selected from an antibody, an antibiotic, a polynucleotide, a polypeptide, a protein, an anti-cancer agent, a growth factor, and a vaccine.

56. The paste of claim 55 wherein said protein is an osteogenic protein.

57. The paste of claim 56, wherein said osteogenic protein is selected from BMP-2, BMP-4, BMP-5, BMP-6, BMP-7, BMP-10, BMP-12, BMP-13, and BMP-14.

58. The paste of claim 55, wherein said anti-cancer agent is selected from alkylating agents, platinum agents, antimetabolites, topoisomerase inhibitors, antitumor antibiotics, antimitotic agents, aromatase inhibitors, thymidylate synthase inhibitors, DNA antagonists, farnesyltransferase inhibitors, pump inhibitors, histone acetyltransferase inhibitors, metalloproteinase inhibitors, ribonucleoside reductase inhibitors, tumor necrosis factor (TNF) alpha agonists, tumor necrosis factor (TNF) alpha antagonists, endothelin A receptor antagonists, retinoic acid receptor agonists, immuno-modulators, hormonal agents, antihormonal agents, photodynamic agents, and tyrosine kinase inhibitors.

59. The paste of claim 44, wherein said effervescent agent is sodium bicarbonate, carbon dioxide, air, nitrogen, helium, oxygen, or argon.

60. The paste of claim 59, wherein said effervescent agent comprises about 1 to about 40 wt % of said powder component.

61. The paste of claim 33, wherein said paste self-hardens to a PCA calcium phosphate having an overall Ca/P ratio of less than about 1.67.

62. The paste of claim 61, wherein said paste self-hardens to a PCA calcium phosphate having an overall Ca/P ratio of less than about 1.5.

63. The paste of claim 33, wherein said paste self-hardens to a PCA calcium phosphate having an overall Ca/P ratio in the range of about 1.0 to about 1.67.

64. The paste of claim 33, wherein said paste hardens to form a PCA calcium phosphate having a compressive strength in the range of about 1 MPa to about 20 MPa.

65. The paste of claim 64, wherein said paste hardens to form a PCA calcium phosphate having a compressive strength in the range of about 2 MPa to about 10 MPa.

66. The paste of claim 33, wherein said paste hardens to form a PCA calcium phosphate having a compressive strength of about 2 MPa.

71. A method of bone repair comprising introducing the bone implant material of claim 33 into a patient in need thereof at a site requiring bone repair, wherein, upon hardening, said bone implant material has a compressive strength between about 1 MPa and about 20 MPa.

76. The paste of claim 33, wherein said paste hardens to form a PCA calcium phosphate having a compressive strength of between about 1 MPa and 20 MPa.

77. The paste of claim 33, wherein said paste hardens to form a PCA calcium phosphate having a compressive strength of between about 2 MPa and 10 MPa.

82. The method of claim 71, wherein, upon hardening, said bone implant material has a compressive strength of between about 2 MPa and 10 MPa.

87. The paste of claim 33, wherein said DBM comprises fibers.

88. The paste of claim 87, wherein said DBM fibers have a length between about 50 μ

m and 3 mm and an aspect ratio of greater than 4.

67. A formable, self-hardening, poorly crystalline apatitic (PCA) calcium phosphate paste suitable for use as a bone implant material comprising:

(a) a powder component, including;

(i) demineralized bone matrix (DBM) in an amount in the range of 40 to 70 wt %, wherein said DBM comprises particles having a particle size in the range of about 53 μ

m to about 850 μ

m,

(ii) a calcium phosphate powder in an amount in the range of about 25 to about 60 wt %, and

(iii) a biocompatible cohesiveness agent in an amount in the range of about 0.5 to 20 wt %; and

(b) a physiologically acceptable fluid in an amount to produce a cohesive, formable paste, wherein said paste retains its cohesiveness when introduced at an implant site in vivo and hardens to form a PCA calcium phosphate having a compressive strength of greater than at least about 1 MPa.

78. The paste of claim 67, wherein said paste hardens to form a PCA calcium phosphate having a compressive strength of between about 1 MPa and 20 MPa.

79. The paste of claim 67, wherein said paste hardens to form a PCA calcium phosphate having a compressive strength of between about 2 MPa and 10 MPa.

89. The paste of claim 67, wherein said DBM comprises fibers.

90. The paste of claim 89, wherein said DBM fibers have a length between about 50 μ

m and 3 mm and an aspect ratio of greater than 4.

68. A formable, self-hardening, poorly crystalline apatitic (PCA) calcium phosphate paste suitable for use as a bone implant material comprising:

(a) a powder component, comprising;

(i) demineralized bone matrix (DBM) in an amount in the range of 40 wt % to 70 wt % of said powder component, wherein said DBM comprises particles having a particle size in the range of about 53 μ

m to about 850 μ

m, and

(ii) a calcium phosphate powder in an amount in the range of about 25 wt % to about 60 wt % of said powder component, wherein said calcium phosphate powder comprises an amorphous calcium phosphate and a second calcium phosphate having an average crystalline domain size of less than about 100 nm, and

(b) a physiologically acceptable fluid in an amount to produce a coherent, formable paste, wherein said paste retains its cohesiveness when introduced at an implant site in vivo and hardens to form a poorly crystalline apatitic (PCA) calcium phosphate having a compressive strength between about 1 MPa and about 20 MPa.

69. The paste of claim 68 further comprising

a biocompatible cohesiveness agent in an amount in the range of about 0.5 wt % to about 20 wt % of said powder component.

80. The paste of claim 68, wherein said paste hardens to form a PCA calcium phosphate having a compressive strength of between about 2 MPa and 10 MPa.

91. The paste of claim 68, wherein said DBM comprises fibers.

92. The paste of claim 91, wherein said DBM fibers have a length between about 50 μ

m and 3 mm and an aspect ratio of greater than 4.

70. A bone implant material comprising a poorly crystalline apatitic (PCA) calcium phosphate, wherein said PCA calcium phosphate is formed by combining:

(a) a powder component comprising;

(i) demineralized bone matrix (DBM) in an amount in the range of 40 wt % to 70 wt % of said powder component, wherein said DBM comprises particles having a particle size in the range of about 53 μ

m to about 850 μ

m,

(ii) a calcium phosphate powder comprising an amorphous calcium phosphate and a second calcium phosphate source, wherein said second calcium phosphate source is an acidic calcium phosphate, and

(iii) a biocompatible cohesiveness agent; and

(b) a physiologically-acceptable fluid,

wherein said powder component and said liquid combine to produce a paste that hardens to form a PCA calcium phosphate having a compressive strength between about 1 MPa and about 20 MPa.

81. The bone implant material of claim 70, wherein said paste hardens to form a PCA calcium phosphate having a compressive strength of between about 2 MPa and 10 MPa.

93. The bone implant material of claim 70, wherein said DBM comprises fibers.

94. The bone implant material of claim 93, wherein said DBM fibers have a length between about 50 μ

m and 3 mm and an aspect ratio of greater than 4.