Dural/meningeal repair product using collagen matrix

• US 5,997,895 A
• Filed: 04/30/1998
• Issued: 12/07/1999
• Est. Priority Date: 09/16/1997
• Status: Expired due to Term

• Current Assignee: Integra Lifesciences Corporation (Integra LifeSciences Holdings Corporation)
• Original Assignee: Integra Lifesciences Corporation (Integra LifeSciences Holdings Corporation)
• Inventors: Archibald, Simon J., O'Fee, Robert P., Narotam, Pradeep K., McKinney, George W. III, van Dellen, James R., O'Grady, Judith
• Primary Examiner(s): Weber, Jon P.
• Application Number:
  US09/070,659
• Time in Patent Office: 586 Days
• Field of Search: 424/423, 602/50
• US Class Current: 424/423
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 38/39 Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
• CPC Class Codes: A61L 2430/00 Materials or treatment for tissue regeneration
• CPC Class Codes: A61L 27/24 Collagen
• CPC Class Codes: C08L 89/06 derived from leather or skin , e.g. gelatin

Abstract

Dural substitutes are provided, which include collagen treated and/or prepared to be physiologically compatible and substantially free of active viruses and prions. Suitable forms for the dural substitutes include a sponge, a film, a non-woven matrix, a felt or a combination of at least two of the foregoing forms. Also provided are a method for preparing dural substitutes and a method for promoting meningeal tissue growth.

Claims

1. A method for promoting meningeal tissue growth to replace a damaged meningeal tissue, said method comprising;

providing certified collagen prepared by a process certified to provide physiologically compatible collagen which is free of effective amounts of active viruses and prions;

forming a cross-linked matrix comprising said certified collagen and pores having a diameter of 10-500 micrometers that permit growing meningeal tissue to infiltrate said matrix, wherein said matrix is substantially free of non-collagenous proteins;

contacting said matrix and said damaged meningeal tissue;

maintaining said contact between said matrix and said damaged meningeal tissue to promote meningeal tissue growth through said matrix; and

substantially resorbing said matrix.

2. The method of claim 1, wherein said matrix is a planar object and conforms on contact to a surface contour of an organ underlying said damaged meningeal tissue.

3. The method of claim 1, wherein said pores have an average diameter of about 50 to about 150 microns.

4. The method of claim 1, wherein said pores proximate to a surface of said matrix are outermost pores ranging in diameter from about 30 μ

m to about 150 μ

m and a balance of said pores are innermost pores ranging in diameter from about 50 μ

m to about 300 μ

m.

5. The method of claim 4, wherein said outermost pores are about 70 μ

m in diameter and said innermost pores are about 150 μ

m in diameter.

6. The method of claim 1, wherein said matrix is a sponge.

7. The method of claim 1, wherein said matrix is a film.

8. The method of claim 1, wherein said matrix is a non-woven or a felt.

9. The method of claim 1, wherein said collagen is derived from a bovine source.

10. The method of claim 9, wherein said collagen is derived from bovine corium.

11. The method of claim 9, wherein said collagen is derived from bovine tendon.

12. The method of claim 1, wherein said certified process comprises alkalinizing said material to a pH of about 13 to about 14 to substantially remove contaminating glycoproteins and lipids.

13. The method of claim 1, wherein said collagen is obtained by a process comprising:

cleaning extraneous matter from a native source of Type I collagen;

washing said cleaned collagen containing material;

comminuting said washed collagen containing material;

digesting said comminuted collagen containing material with a proteolytic enzyme to substantially remove elastin and non-collagenous impurities which can cause antigenic activity and to swell said collagen;

inactivating said proteolytic enzyme;

washing said enzymatically digested collagen containing material to substantially remove excess enzyme and non-collagenous protein impurities;

alkalinizing said collagen containing material to a pH of about 13 to about 14, at a temperature of about 25°

C. to about 30°

C. for a period of about 35 to about 48 hours, to substantially remove contaminating glycoproteins and lipids;

neutralizing said alkalinized collagen containing material with an acid;

washing said neutralized collagen containing material;

acidifying said washed and neutralized collagen containing material to a pH of about 2 to about 3 to further swell said material, wherein said acidifying does not employ an acid that causes substantial cross-linking of collagen;

homogenizing said acidified collagen containing material;

filtering said homogenized collagen containing material to remove unswollen, non-collagenous material from collagen fibers; and

collecting said filtered collagen fibers for use in said matrix.

14. The method of claim 13, wherein said proteolytic enzyme is ficin or pepsin.

15. The method of claim 13, wherein said digesting step comprises adding about one part of proteolytic enzyme per 150 parts of said collagen containing material, adjusting a pH of said collagen containing material to about 6.0 to about 6.3, and digesting said collagen containing material for about 1 to about 2 hours at a temperature of about 36.5°

C. to about 37.5°

C.

16. The method of claim 15, wherein said proteolytic enzyme is ficin.

17. The method of claim 13, wherein said enzyme is inactivated by adding an oxidizing agent to said enzymatically digested collagen containing material.

18. The method of claim 17, wherein said oxidizing agent is sodium chlorite.

19. The method of claim 13, wherein said method further comprises further washing with dilute aqueous hydrogen peroxide said washed and enzyme inactivated collagen containing material.

20. The method of claim 13, wherein said alkalinizing employs an aqueous solution of about 5% sodium hydroxide and about 20% sodium sulfate.

21. The method of claim 13, wherein said acidifying step employs acetic acid, hydrochloric acid or lactic acid to adjust said pH.

22. The method of claim 13, wherein said acidifying step employs aqueous lactic acid to adjust said pH, and said method further comprises:

forming an aqueous dispersion of said filtered collagen fibers;

precipitating collagen fibers from said aqueous dispersion by addition of ammonium hydroxide; and

casting a dispersion of said precipitated collagen fibers to form said matrix.

23. The method of claim 1, wherein said collagen is non-antigenic.

24. The method of claim 1, wherein said matrix connects undamaged portions of meningeal tissue adjacent to said damaged meningeal tissue.

25. The method of claim 1, wherein said damaged meningeal tissue is a human spinal dura.

26. The method of claim 1, wherein said damaged meningeal tissue is a human cerebral dura.

27. The method of claim 1, wherein said damaged meningeal tissue contacted with said matrix defines a margin of presumptively benign tissue surrounding a surgically excised section of cancerous tissue.

28. The method of claim 1, wherein said matrix is sutured to said damaged meningeal tissue.

29. The method of claim 1, wherein said matrix is not sutured to meningeal tissue.

30. The method of claim 1, wherein said matrix is not mechanically or chemically bonded to meningeal tissue by artificial means.

31. The method of claim 1, wherein said matrix further comprises an effective amount of a meningeal tissue growth factor.

32. The method of claim 31, wherein said meningeal tissue growth factor is selected from the group consisting of RGD containing peptides, decorin, laminin, merosin, chondroitin sulfate, dermatin sulfate, heparan sulfate, keratin sulfate, basic fibroblast growth factor, fibronectin, entactin and tenascin.

33. The method of claim 31, wherein said pores have an average diameter of about 50 to about 150 microns.

34. The meningeal tissue growth matrix of claim 31, wherein said pores proximate to a surface of said matrix are outermost pores ranging in diameter from about 30 μ

m to about 150 μ

m and a balance of said pores are innermost pores ranging in diameter from about 50 μ

m to about 300 μ

m.

35. The method of claim 34, wherein said outermost pores are about 70 μ

m in diameter and said innermost pores are about 150 μ

m in diameter.

36. The method of claim 31, wherein said certified process comprises:

cleaning extraneous matter from a native source of Type I collagen;

washing said cleaned collagen containing material;

comminuting said washed collagen containing material;

digesting said comminuted collagen containing material with a proteolytic enzyme to substantially remove elastin and non-collagenous impurities which can cause antigenic activity and to swell said collagen;

inactivating said proteolytic enzyme;

washing said enzymatically digested collagen containing material to substantially remove excess enzyme and non-collagenous protein impurities;

alkalinizing said collagen containing material to a pH of about 13 to about 14, at a temperature of about 25°

C. to about 30°

C. for a period of about 35 to about 48 hours, to substantially remove contaminating glycoproteins and lipids;

neutralizing said alkalinized collagen containing material with an acid;

washing said neutralized collagen containing material;

acidifying said washed and neutralized collagen containing material to a pH of about 2 to about 3 to further swell said material, wherein said acidifying does not employ an acid that causes substantial cross-linking of collagen;

homogenizing said acidified collagen containing material;

filtering said homogenized collagen containing material to remove unswollen, non-collagenous material from collagen fibers; and

collecting said filtered collagen fibers for use in said matrix.

37. The method of claim 36, wherein said acidifying step employs aqueous lactic acid to adjust said pH, and said process further comprises:

forming an aqueous dispersion of said filtered collagen fibers;

precipitating collagen fibers from said aqueous dispersion by addition of ammonium hydroxide; and

casting a dispersion of said precipitated collagen fibers to form said matrix.

38. The method of claim 36, wherein said matrix is a sponge, a film, a non-woven or a felt.

39. The method of claim 36, wherein said collagen is derived from a bovine source.

40. The method of claim 39, wherein said collagen is derived from bovine corium or tendon.

41. The method of claim 36, wherein said collagen is human collagen expressed by a transgenic animal which is not a human.

42. The method of claim 31, wherein said meningeal tissue growth factor is a ligand for integrin.

43. The method of claim 1, wherein said matrix forming comprises:

forming said certified collagen into at least two different members selected from the group consisting of a film, a sponge, a non-woven and a felt; and

bonding said at least two different members together to provide said matrix.

44. The method of claim 43, wherein said at least two different members are a film and a sponge.

45. The method claim 43, wherein said at least two different members are a sponge and two sheets of film, and said sponge is laminated between said two sheets of film.

46. The method of claim 43, wherein said matrix further comprises an effective amount of a meningeal tissue growth factor.

47. The method of claim 46, wherein said meningeal tissue growth factor is selected from the group consisting of RGD containing peptides, decorin, laminin, merosin, chondroitin sulfate, dermatin sulfate, heparan sulfate, keratin sulfate, basic fibroblast growth factor (bFGF), fibronectin entactin and tenascin.

48. The method of claim 46, wherein said meningeal tissue growth factor is a ligand for integrin.

49. The method of claim 43, wherein at least one porous-member of said at least two different members has pores of a sufficient size and quantity to permit growing meningeal tissue to infiltrate therein, and at least one suturable member of said at least two different members is sufficiently durable to hold a suture.

50. The method of claim 49, wherein said pores have an average diameter of about 50 to about 150 microns.

51. The method of claim 49, wherein said pores proximate to a surface of said porous member are outermost pores ranging in diameter from about 30 μ

m to about 150 μ

m and a balance of said pores are innermost pores ranging in diameter from about 50 μ

m to about 300 μ

m.

52. The method of claim 51, wherein said outermost pores are about 70 μ

m in diameter and said innermost pores are about 150 μ

m in diameter.

53. The method of claim 43, wherein said matrix is planar.

54. The method of claim 43, wherein said certified process comprises:

cleaning extraneous matter from a native source of Type I collagen;

washing said cleaned collagen containing material;

comminuting said washed collagen containing material;

digesting said comminuted collagen containing material with a proteolytic enzyme to substantially remove elastin and non-collagenous impurities which can cause antigenic activity and to swell said collagen;

inactivating said proteolytic enzyme;

washing said enzymatically digested collagen containing material to substantially remove excess enzyme and non-collagenous protein impurities;

alkalinizing said collagen containing material to a pH of about 13 to about 14, at a temperature of about 25°

C. to about 30°

C. for a period of about 35 to about 48 hours, to substantially remove contaminating glycoproteins and lipids;

neutralizing said alkalinized collagen containing material with an acid;

washing said neutralized collagen containing material;

acidifying said washed and neutralized collagen containing material to a pH of about 2 to about 3 to further swell said material, wherein said acidifying does not employ an acid that causes substantial cross-linking of collagen;

homogenizing said acidified collagen containing material;

filtering said homogenized collagen containing material to remove unswollen, non-collagenous material from collagen fibers; and

collecting said filtered collagen fibers for use in said matrix.

55. The method of claim 54, wherein said acidifying step employs aqueous lactic acid to adjust said pH, and said process further comprises:

forming an aqueous dispersion of said filtered collagen fibers;

precipitating collagen fibers from said aqueous dispersion by addition of ammonium hydroxide; and

casting a dispersion of said precipitated collagen fibers to form said matrix.

56. The method of claim 43, wherein said collagen is derived from a bovine source.

57. The method of claim 56, wherein said collagen is derived from bovine corium or tendons.

58. The method of claim 43, wherein said collagen is human collagen expressed by a transgenic animal which is not a human.

59. The method of claim 43, wherein said matrix forming further comprises:

providing at least two different volumes of a liquid medium containing said certified collagen; and

evaporating said liquid medium from each of said different volumes to provide said at least two different members of the group consisting of a film, a sponge, a non-woven and a felt.

60. The method of claim 1, wherein said matrix forming further comprises:

providing a volume of a liquid medium containing said certified collagen; and

evaporating said liquid medium to provide said matrix.

61. The method of claim 1, wherein said matrix is provided with a plurality of layers, including a high porosity layer and a low porosity layer, said high porosity layer being more porous than said low porosity layer.

62. The method of claim 61, wherein said high porosity layer is a collagen sponge and said low porosity layer is a substantially water-impermeable, suturable film bonded to said collagen sponge.

63. The method of claim 1, wherein said matrix is substantially resorbed within about three months after implantation.

64. The method of claim 1, wherein said matrix has a density of about 0.0001 mg/mm³ to about 0.12 mg/mm³.

65. The method of claim 1, wherein said matrix has a density of about 0.009 mg/mm³.

66. The method of claim 1, wherein said matrix is not continuously sutured about its perimeter to meningeal tissue.

67. A method for promoting meningeal tissue growth to replace a damaged meningeal tissue, said method comprising:

providing certified collagen prepared by a process certified to provide physiologically compatible collagen which is free of effective amounts of active viruses and prions;

forming a cross-linked matrix consisting essentially of said certified collagen and optionally, at least one meningeal tissue growth factor, wherein said matrix has pores having a diameter of 10-500 micrometers that permit growing meningeal tissue to infiltrate said matrix;

contacting said matrix and said damaged meningeal tissue;

maintaining said contact between said matrix and said damaged meningeal tissue to promote meningeal tissue growth through said matrix; and

substantially resorbing said matrix.

68. The method of claim 67, wherein said matrix consists essentially of said certified collagen and said at least one meningeal tissue growth factor.

69. A matrix for promoting meningeal tissue growth to replace a damaged meningeal tissue, said matrix prepared by a process comprising:

providing certified collagen fibers which are physiologically compatible and certified to be free of effective amounts of active viruses and prions;

dispersing said certified collagen fibers in a liquid medium to provide a collagen dispersion; and

evaporating said liquid medium from said collagen dispersion to provide said matrix;

wherein said matrix comprises said certified collagen fibers and pores having a diameter of 50-150 micrometers adapted to permit growing meningeal tissue to infiltrate said pores, said matrix is substantially free of non-collagenous proteins, and said matrix is adapted to be resorbed within about three months after implantation.

70. The matrix of claim 69, wherein said matrix is a planar object adapted to conform on contact to a surface contour of an organ underlying said damaged meningeal tissue being replaced.

71. The matrix of claim 69, wherein said pores have an average diameter of about 50 to about 150 μ

m.

72. The matrix of claim 69, wherein said pores proximate to a surface of said matrix are outermost pores ranging in diameter from about 50 μ

m to less than about 150 μ

m and a balance of said pores are innermost pores having a larger diameter than said outermost pores.

73. The matrix of claim 69, wherein said pores proximate to a surface of said matrix are outermost pores having an average diameter of about 70 μ

m and a balance of said pores are innermost pores having an average diameter of about 150 μ

m.

74. The matrix of claim 69, wherein said matrix is a sponge.

75. The matrix of claim 69, wherein said matrix is a film.

76. The matrix of claim 69, wherein said matrix is a non-woven or a felt.

77. The matrix of claim 69, wherein said matrix is adapted to provide a liquid-tight seal against cerebrospinal fluid leakage without mechanical or chemical bonding to meningeal tissue.

78. A matrix for promoting meningeal tissue growth to replace a damaged meningeal tissue, said matrix prepared by a process comprising:

providing certified collagen fibers which are physiologically compatible and certified to be free of effective amounts of active viruses and prions;

providing at least two different volumes of a liquid medium containing said certified collagen; and

evaporating said liquid medium from each of said different volumes to provide at least two different members of the group consisting of a film, a sponge, a non-woven and a felt, and

wherein said matrix comprises said at least two different members, said certified collagen fibers, and pores having a diameter of 50-150 μ

m adapted to permit growing meningeal tissue to infiltrate said pores, and wherein said matrix is substantially free of non-collagenous proteins, and said matrix is adapted to be resorbed within about three months after implantation.