Implantable biomaterial and a method of producing same

• US 20060193885A1
• Filed: 12/21/2005
• Published: 08/31/2006
• Est. Priority Date: 12/24/2004
• Status: Active Grant

• Current Assignee: Anteris AUS Operations Pty Limited
• Original Assignee: Celxcel Pty Ltd. (Anteris Technologies Ltd.)
• Inventors: Leonard Neethling, William Morris, Hodge, Andrew J.
• Granted Patent: US 9,205,172 B2
• Time in Patent Office: Days
• US Class Current: 424/422
• CPC Class Codes: A61L 2400/02 Treatment of implants to prevent calcification or mineralisation in vivo
• 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 27/58 Materials at least partially resorbable by the body

Abstract

The present invention relates to an implantable biomaterial and methods of producing same. In particular, the present invention relates to a method for producing an implantable biomaterial comprising (a) exposing a biomaterial to an alcohol-containing solution for at least 24 hours.

Claims

1. A method for producing an implantable biomaterial comprising:

(a) exposing a biomaterial to an alcohol-containing solution for at least 24 hours.

2. The method of claim 1, wherein said biomaterial is a collagen containing biomaterial.

3. The method of claim 1, further comprising the steps:

(b) exposing said material in step (a) to a cross-linking agent; and

(c) exposing said material in step (b) to an acidic solution;

wherein step (b) and (c) are sequential to step (a).

6. The method of claim 3, further comprising a rinsing step between steps (a) and (b) and/or between steps (b) and (c).

7. The method of claim 3, further comprising a rinsing step after step (c).

8. The method of claim 7, wherein the step of rinsing the biomaterial is conducted using a phosphate-free solution of de-ionised water adjusted below pH7 with buffer-free acid.

9. The method of claim 1, wherein the biomaterial comprises collagen.

10. The method of claim 1, wherein the biomaterial is isolated from an animal.

11. The method of claim 10, wherein the animal is selected from the group consisting of an ovine, a bovine, a caprine, an equine, a porcine, a marsupial and a human.

12. The method of claim 1, wherein the biomaterial is a cultured tissue, a prosthesis containing extra-cellular matrix obtained from an animal or a reconstituted tissue.

13. The method of claim 1, wherein the biomaterial is a cellular tissue selected from the group consisting cardiovascular tissue, pelvic floor tissue, heart tissue, heart valve, aortic roots, aortic wall, aortic leaflets, pericardial tissue, connective tissue, the matrix of soft or solid organs, dura mater, dermal tissue, a vascular tissue, dura mater, cartilage, pericardium, ligament, tendon, blood vessels, umbilical tissue, bone tissue, fasciae, and submucosal tissue or skin.

14. The method of claim 1, wherein the alcohol-containing solution used in step (a) comprises one or more water-soluble alcohol(s).

15. The method of claim 14, wherein the water-soluble alcohol is a C₁-C₆ lower alcohol.

16. The method of claim 15, wherein the C₁-C₆ lower alcohol is selected from the group consisting of methanol, ethanol, cyclohexanol, isopropanol, propanol, butanol, pentanol, isobutanol, sec-butanol and t-butanol or combination thereof.

17. The method of claim 16, wherein the alcohol-containing solution comprises less than 100% alcohol in a non-buffered aqueous solvent.

18. The method of claim 3, wherein step (a) is carried out for at least 24 hours.

19. The method of claim 1, wherein step (a) is carried out for at least 36 hours.

20. The method of claim 1, wherein step (a) is carried out for at least 48 hours.

21. The method of claim 3, wherein the cross-linking agent is selected from the group consisting of carbodiimide, polyepoxy ethers, divinyl sulfone (DVS), genipin, polyaldehyde and diphenylphosphoryl azide (DPPA) or combinations thereof.

22. The method of claim 21, wherein the polyaldehyde is glutaraldehyde.

23. The method of claim 3, further comprising a sterilisation step after step (c).

24. The method of claim 1, wherein each step is carried out at a temperate between 2°

C. and 40°

C.

25. The method of claim 24, wherein the temperature is between 4°

C. and 30°

C.

26. The method of claim 24, wherein the temperature is between 5°

C. and 25°

C.

27. The method of claim 3, wherein the acidic solution contains an acid capable of inactivating and/or modifying the fixed and/or unfixed cross-linking agent moieties present in the biomaterial after step (b).

28. The method of claim 3, wherein the acidic solution contains an acid capable of cross-linking activated carboxyl and amine groups on collagen to form amide bonds.

29. The method of claim 3, wherein the acidic solution used in step (c) contains an aminocarboxylic acid.

30. The method of claim 29, wherein the aminocarboxylic acid is selected from the group consisting of L-histidine, L-arginine, L-lysine, L-glutamate and L-aspartate.

31. The method of claim 1, wherein the alcohol-containing solution, cross-linking agent and acidic solution are all buffer-free.

32. The method of claim 3, wherein step (c) is replaced by step (d) or supplemented with step (d) said step (d) comprising exposing said material in step (b) to a buffer-free solution containing one or more multi-valent cation.

33. The method of claim 32, wherein the multi-valent cation is selected from the group consisting of magnesium, ferric and aluminium salts.

34. A calcification resistant biomaterial produced by the method of claim 1.

38. An implantable biological device comprising the calcification resistant biomaterial of claim 34.

39. The device of claim 38, wherein said biomaterial is coated onto a surface of said device.

40. The device of claim 38, further comprising at least a second coating.

41. The device of claim 40, wherein the at least second coating comprises an anti-microbial agent, an anti-viral agent, an anti-fungal agent, a growth factor, an anti-dehydration agent or an anti-septic agent.

42. The device of claim 41, wherein the anti-microbial agent is selected from the group consisting of isoniazid, ethambutol, pyrazinamide, streptomycin, clofazimine, rifabutin, fluoroquinolones, ofloxacin, sparfloxacin, rifampicin, azithromycin, clarithromycin, dapsone, tetracycline, erythromycin, ciprofloxacin, doxycycline, ampicillin, amphotericin B, ketoconazole, fluconazole, pyrimethamine, sulfadiazine, clindamycin, lincomycin, pentamidine, atovaquone, paromomycin, diclazaril, acyclovir, trifluorouridine, foscarnet, penicillin, gentamicin, ganciclovir, iatroconazole, miconazole, Zn-pyrithione, heavy metals including, but not limited to, gold, platinum, silver, zinc and copper, and their combined forms including, salts, such as chloride, bromide, iodide and periodate, and complexes with carriers, and other forms.

43. The device of claim 41, wherein the growth factor agent is selected from the group consisting of hydroxyapatite, basic fibroblast growth factor (bFGF), acidic fibroblast growth factor (aFGF), nerve growth factor (NGF), epidermal growth factor (EGF), insulin-like growth factors 1 and 2, (IGF-1 and IGF-2), platelet derived growth factor (PDGF), tumor angiogenesis factor (TAF), vascular endothelial growth factor (VEGF), corticotropin releasing factor (CRF), transforming growth factors α

and β

(TGF-α and

TGF-β

interleukin-8 (IL-8);

granulocyte-macrophage colony stimulating factor (GM-CSF);

interleukins, and interferons.

44. The device of claim 40, wherein the at least second coating further comprises bioabsorbable material selected from the group consisting of polylactic acid, polyglycolic acid, polylactic acid—

polyglycolic acid copolymers, polydioxanone, polycaprolactone, polypeptides, polycarbonates, polyhydroxybutyrate, poly(alkylene oxalate), copolymers of vinyl acetates with unsaturated carboxylic acids, water soluble or dispersible cellulose derivatives, ethylene oxide polymers, polyacrylamide, collagen, gelatin, poly(orthoester), polyamides of amino acids, polyvinyl alcohol, polyvinyl pyrrolidone, polyetheretherketone, tricalcium phosphate, and mixtures thereof.

45. The device of claim 38, wherein said device is selected from the group consisting of an artificial heart, an internal or external cardiac assist device, a heart valve prosthesis, an annuloplasty ring, a dermal graft, a vascular graft, a vascular stent, a structural stent, a vascular shunt, a cardiovascular shunt, a dura mater graft, a cartilage graft, a cartilage implant, a pericardium graft, a ligament prosthesis, a tendon prosthesis, a urinary bladder prosthesis, a pledget, a suture, a permanently in-dwelling percutaneous device, a surgical patch, a cardiovascular stent, a coated stent, and a coated catheter.

46. The device of claim 38, wherein the device is a heart valve prosthesis.

47. The device of claim 38, wherein the device further comprises a tissue fragment.

48. The device of claim 47, wherein the tissue fragment is harvested from an animal.

49. The device of claim 48, wherein the animal is selected from the group consisting of a human, a cow, a pig, a dog, a deer, and a kangaroo.

50. The device of claim 38, wherein the device further comprises a synthetic analog of a tissue.

51. The device of claim 48, wherein the tissue fragment includes a plurality of cells and, upon implantation at a surgical site, at least a portion of the plurality of cells is able to migrate out of the tissue fragment, proliferate and integrate with surrounding tissue at a site of implantation.

57. A kit for repairing a tissue injury, comprising:

(a) a sterile container having one or more of the devices of claim 38 or the implant of claim 52;

and

(b) instructions for use on an injured subject.

58. The kit of claim 57, further comprising:

(c) a harvesting tool for collecting at least one viable tissue sample from an injured subject.

59. The kit of claim 58, further comprising at least one reagent for sustaining the viability of the at least one tissue sample.

60. The kit of claim 58, wherein the harvesting tool further comprises a processing tool for dividing the tissue sample, under sterile conditions, into at least one tissue fragment.

61. A method of treating living tissue, comprising:

(a) providing the calcification resistant biomaterial of claim 34;

and

(b) implanting the biomaterial in a subject in need of treatment.

62. The method of claim 61, wherein the calcification resistant biomaterial is incorporated into or onto a medical device.

63. The method of claim 61, further comprising the step of affixing the calcification resistant biomaterial in the desired position within the subject being treated.

64. The method of claim 61, wherein the method of treating tissue is a tissue treatment technique selected from the group consisting of tissue repair, tissue bulking, cosmetic treatment, therapeutic treatment, tissue augmentation, and tissue sealing.

4. A method for producing an implantable biomaterial comprising:

(a) exposing a biomaterial to an alcohol-containing solution;

(b) exposing said material in step (a) to a cross-linking agent; and

(c) exposing said material in step (b) to an acidic solution;

wherein step (b) and (c) are sequential to step (a).

5. The method of claim 4, wherein the implantable biomaterial is a calcification-resistant biomaterial.

35. A calcification resistant biomaterial comprising cross-linked collagen, wherein said biomaterial has a calcium content of less than about 50 μ

g per mg of biomaterial and wherein said biomaterial is capable of being implanted for at least 200 days without the biomaterial increasing its calcium content above 50 μ

g/mg of biomaterial.

36. The calcification resistant biomaterial of claim 35, wherein said biomaterial before implantation has a calcium content of less than about 20 μ

g per mg of biomaterial.

37. The calcification resistant biomaterial of claim 35, wherein said biomaterial before implantation has a calcium content of less than about 10 μ

g per mg of biomaterial.

52. A biocompatible implant, comprising a biocompatible scaffold comprising a calcification-resistant biomaterial comprising cross-linked collagen, wherein said biomaterial has a calcium content of less than about 50 μ

g per mg of biomaterial and wherein said biomaterial is capable of being implanted for at least 200 days without the biomaterial increasing its calcium content above 50 μ

g/mg of biomaterial.

53. The biocompatible implant of claim 52, wherein said biomaterial before implantation has a calcium content of less than about 20 μ

g per mg of biomaterial.

54. The biocompatible implant of claim 52, wherein said biomaterial before implantation has a calcium content of less than about 10 μ

g per mg of biomaterial.

55. A biocompatible implant, comprising a biocompatible scaffold comprising calcification resistant biomaterial comprising cross-linked collagen, wherein said collagen comprises secondary amines.

56. The biocompatible implant of claim 55, wherein the scaffold further comprises a synthetic polymer, a natural polymer, an injectable gel, a ceramic material, autogeneic tissue, allogeneic tissue, xenogeneic tissue and combinations thereof.

65. A wound dressing comprising a calcification resistant biomaterial comprising cross-linked collagen, wherein said collagen comprises secondary amines.

66. The wound dressing of claim 65, wherein said calcification resistant biomaterial has been exposed to alcohol before cross-linked.

67. The wound dressing of claim 66, wherein said alcohol is a C₁-C₆ lower alcohol.

68. The wound dressing of claim 67, wherein the C₁-C₆ lower alcohol is selected from the group consisting of methanol, ethanol, cyclohexanol, isopropanol, propanol, butanol, pentanol, isobutanol, sec-butanol and t-butanol.

69. The wound dressing of claim 65, wherein the cross-linking agent is selected from the group consisting of carbodiimide, polyepoxy ethers, divinyl sulfone (DVS), genipin, polyaldehyde and diphenylphosphoryl azide (DPPA)

70. The wound dressing of claim 69, wherein the polyaldehyde is glutaraldehyde.

71. The wound dressing of claim 65, wherein the biomaterial is selected from the group consisting of ovine collagen, bovine collagen, caprine collagen, equine collagen, porcine collagen, marsupial collagen and human collagen.

72. The wound dressing of claim 71, further comprising a sulphated polysaccharide selected from the group consisting of heparin, chondroitin sulphate, dextran sulfate, dermatan sulfate, heparan sulfate, keratan sulfate, hexuronyl hexosaminoglycan sulfate, inositol hexasulfate, and sucrose octasulfate.

73. The wound dressing of claim 65, further comprising an anti-microbial agent, an anti-viral agent, an anti-fungal agent, a growth factor, an anti-dehydration agent or an anti-septic agent.

74. The wound dressing of claim 73, wherein the anti-microbial agent is selected from the group consisting of isoniazid, ethambutol, pyrazinamide, streptomycin, clofazimine, rifabutin, fluoroquinolones, ofloxacin, sparfloxacin, rifampicin, azithromycin, clarithromycin, dapsone, tetracycline, erythromycin, ciprofloxacin, doxycycline, ampicillin, amphotericin B, ketoconazole, fluconazole, pyrimethamine, sulfadiazine, clindamycin, lincomycin, pentamidine, atovaquone, paromomycin, diclazaril, acyclovir, trifluorouridine, foscarnet, penicillin, gentamicin, ganciclovir, iatroconazole, miconazole, Zn-pyrithione, heavy metals including, but not limited to, gold, platinum, silver, zinc and copper, and their combined forms including, salts, such as chloride, bromide, iodide and periodate, and complexes with carriers, and other forms.

75. The wound dressing of claim 73, wherein the growth factor agent is selected from the group consisting of basic fibroblast growth factor (bFGF), acidic fibroblast growth factor (aFGF), nerve growth factor (NGF), epidermal growth factor (EGF), insulin-like growth factors 1 and 2, (IGF-1 and IGF-2), platelet derived growth factor (PDGF), tumor angiogenesis factor (TAF), vascular endothelial growth factor (VEGF), corticotropin releasing factor (CRF), transforming growth factors α

and β

(TGF-α and

TGF-β

interleukin-8 (IL-8);

granulocyte-macrophage colony stimulating factor (GM-CSF);

interleukins, and interferons.

76. A calcification resistant biomaterial comprising cross-linked collagen, wherein said cross-linked collagen comprise secondary amines.

77. The calcification resistant biomaterial of claim 76, wherein the biomaterial comprises at least 50% collagen.

78. The calcification resistant biomaterial of claim 76, wherein the biomaterial comprises at least 70% collagen.

79. The calcification resistant biomaterial of claim 76, wherein the biomaterial comprises at least 90% collagen.

80. The calcification resistant biomaterial of claim 79, wherein the biomaterial consists essentially of collagen.