Porous extracellular matrix scaffold and method

• US 20040166169A1
• Filed: 01/15/2004
• Published: 08/26/2004
• Est. Priority Date: 07/15/2002
• Status: Abandoned Application

• Current Assignee: Depuy Products Incorporated (Johnson & Johnson)
• Original Assignee: Depuy Products Incorporated (Johnson & Johnson)
• Inventors: Plouhar, Pamela Lynn, Malaviya, Prasanna, Pelo, Mark Joseph, Schwartz, Herbert Eugene
• Application Number:
  US10/483,930
• Publication Number:
  US 20040166169A1
• Time in Patent Office: Days
• US Class Current: 424/551
• CPC Class Codes: A61K 35/22 Urine; Urinary tract, e.g. kidney or bladder; Intraglomerular mesangial cells; Renal mesenchymal cells; Adrenal gland
• CPC Class Codes: A61K 35/38 Stomach; Intestine; Goblet cells; Oral mucosa; Saliva
• CPC Class Codes: A61K 35/407 Liver; Hepatocytes
• CPC Class Codes: A61K 35/42 Respiratory system, e.g. lungs, bronchi or lung cells
• CPC Class Codes: A61K 35/48 Reproductive organs
• CPC Class Codes: A61L 27/3608 Bone, e.g. demineralised bone matrix [DBM], bone powder
• CPC Class Codes: A61L 27/3629 Intestinal tissue, e.g. small intestinal submucosa
• CPC Class Codes: A61L 27/3633 Extracellular matrix [ECM]
• CPC Class Codes: A61L 27/3641 characterised by the site of application in the body materials for artificial blood vessels A61L27/507; materials for use in artificial skin A61L27/60
• CPC Class Codes: A61L 27/3645 Connective tissue
• CPC Class Codes: A61L 27/365 Bones
• CPC Class Codes: A61L 27/3683 subjected to a specific treatment prior to implantation, e.g. decellularising, demineralising, grinding, cellular disruption/non-collagenous protein removal, anti-calcification, crosslinking, supercritical fluid extraction, enzyme treatment
• CPC Class Codes: A61L 27/56 Porous materials, e.g. foams or sponges

Abstract

A method of making an implantable scaffold for repairing damaged or diseased tissue includes the step of suspending pieces of an extracellular matrix material in a liquid. The extracellular matrix material and the liquid are formed into a mass. The liquid is subsequently driven off so as to form interstices in the mass. Porous implantable scaffolds fabricated by such a method are also disclosed.

Claims

1. A method of making an implantable scaffold for repairing or regenerating body tissue, the method comprising the steps of:

suspending pieces of a naturally occurring extracellular matrix material in a liquid; and

freeze drying the pieces of naturally occurring extracellular matrix material and the liquid.

2. The method of claim 1, further comprising the step of freezing the extracellular matrix material and the liquid to form ice crystals from the liquid, the freezing step being performed prior to the freeze drying step.

3. The method of claim 2, wherein the freeze drying step further comprises subliming the ice crystals directly to vapor in the presence of a vacuum.

4. The method of claim 1, wherein the freeze drying step comprises subliming the liquid so as to form a porous body.

5. The method of claim 1, further comprising the step of comminuting the extracellular matrix material into the pieces.

6. The method of claim 1, wherein the extracellular matrix material comprises material selected from the group consisting of:

small intestine submucosa, bladder submucosa, stomach submucosa, alimentary submucosa, respiratory submucosa, genital submucosa, and liver basement membrane

7. The method of claim 1, further comprising the step of flash-freezing the extracellular matrix material and the liquid prior to the freeze drying step.

8. The method of claim 1, further comprising the step of compacting the pieces of naturally occurring extracellular matrix material prior to the freeze drying step.

9. The method of claim 1, further comprising the step of centrifuging the pieces of naturally occurring extracellular matrix material prior to the freeze drying step.

10. The method of claim 1, further comprising the step of freezing the naturally occurring extracellular matrix material and the liquid at a controlled rate of temperature drop.

11. The method of claim 10, wherein the freezing step comprises varying the rate of temperature drop so as to vary the pore size of the scaffold.

12. The method of claim 1, further comprising the step of adding at least one of the following:

a bioactive agent;

a biologically derived agent;

cells;

a biological lubricant;

a biocompatible inorganic material; and

a biocompatible polymer.

13. A method of making an implantable scaffold for repairing or regenerating body tissue, the method comprising the steps of:

suspending pieces of a naturally occurring extracellular matrix material in a liquid;

forming the pieces of the naturally occurring extracellular matrix and the liquid into a mass; and

driving off the liquid so as to form interstices in the mass.

14. The method of claim 13, wherein the driving off step comprises subliming the liquid.

15. The method of claim 13, wherein the driving off step comprises vaporizing the liquid.

16. The method of claim 13, further comprising the steps of:

providing a naturally occurring extracellular matrix in a raw form, and

comminuting the naturally occurring extracellular matrix material to form the pieces of naturally occurring extracellular matrix, the pieces of naturally occurring extracellular matrix being smaller than the raw form of the naturally occurring extracellular matrix.

17. The method of claim 13, wherein the naturally occurring extracellular matrix material comprises material selected from the group consisting of:

small intestine submucosa, stomach submucosa, respiratory submucosa, alimentary submucosa, genital submucosa, bladder submucosa, and liver basement membrane.

18. The method of claim 13, wherein the forming step comprises compacting the pieces of naturally occurring extracellular matrix material.

19. The method of claim 13, further comprising the step of adding at least one of the following:

a bioactive agent;

a biologically derived agent;

cells;

a biological lubricant;

a biocompatible inorganic material; and

a biocompatible polymer.

20. An implantable scaffold for repairing or regenerating body tissue, comprising a porous body which is prepared by a process comprising the steps of:

suspending pieces of a naturally occurring extracellular matrix material in a liquid, and

freeze drying the naturally occurring extracellular matrix material and the liquid.

21. The implantable scaffold of claim 20, wherein the process for preparing the porous body further comprises the step of freezing the naturally occurring extracellular matrix material and the liquid to form ice crystals from the liquid, the freezing step being performed prior to the freeze drying step.

22. The implantable scaffold of claim 21, wherein the freeze drying step further comprises subliming the ice crystals directly to vapor in the presence of a vacuum.

23. The implantable scaffold of claim 20, wherein the freeze drying step comprises subliming the liquid.

24. The implantable scaffold of claim 20, wherein the process for preparing the porous body further comprises the step of comminuting the naturally occurring extracellular matrix material into the pieces.

25. The implantable scaffold of claim 20, wherein the naturally occurring extracellular matrix material comprises material selected from the group consisting of:

small intestine submucosa, stomach submucosa, bladder submucosa, alimentary submucosa, respiratory submucosa, genital submucosa, and liver basement membrane.

26. The implantable scaffold of claim 20, wherein the process for preparing the porous body further comprises the step of flash-freezing the naturally occurring extracellular matrix material and the liquid prior to the freeze drying step.

27. The implantable scaffold of claim 20, wherein the process for preparing the porous body further comprises the step of compacting the pieces of naturally occurring extracellular matrix material prior to the freeze drying step.

28. The implantable scaffold of claim 20, wherein the process for preparing the porous body further comprises the step of centrifuging the pieces of naturally occurring extracellular matrix material prior to the freeze drying step.

29. The implantable scaffold of claim 20, further comprising at least one of the following:

a bioactive agent;

a biologically derived agent;

cells;

a biological lubricant;

a biocompatible inorganic material; and

a biocompatible polymer.

30. An implantable scaffold for repairing or regenerating body tissue, comprising:

porous body which is prepared by a process comprising the steps of;

suspending pieces of a naturally occurring extracellular matrix material in a liquid,

forming the pieces of the extracellular matrix and the liquid into a mass, and

driving off the liquid so as to form interstices in the mass.

31. The implantable scaffold of claim 30, wherein the driving off step comprises subliming the liquid.

32. The implantable scaffold of claim 30, wherein the driving off step comprises vaporizing the liquid.

33. The implantable scaffold of claim 30, wherein the process for preparing the porous scaffold further comprises the step of comminuting the naturally occurring extracellular matrix material into the pieces.

34. The implantable scaffold of claim 30, wherein the naturally occurring extracellular matrix material comprises material selected from the group consisting of:

small intestine submucosa, stomach submucosa, bladder submucosa, alimentary submucosa, respiratory submucosa, genital submucosa, and liver basement membrane.

35. The implantable scaffold of claim 30, wherein the forming step comprises compacting the pieces of naturally occurring extracellular matrix material.

36. The implantable scaffold of claim 30, further comprising at least one of the following:

a bioactive agent;

a biologically derived agent;

cells;

a biological lubricant;

a biocompatible inorganic material; and

a biocompatible polymer.

37. An implantable scaffold for repairing or regenerating body tissue, the scaffold comprising:

a porous body of naturally occurring extracellular matrix pieces interconnected to define an interior surface having a three-dimensional topography of irregular shape.

38. The implantable scaffold of claim 37, wherein:

the interconnected naturally occurring extracellular matrix pieces define interstices in the body, and

the interstices are sized by mixing the matrix pieces with water to form a moistened mass and freezing the water in a controlled manner to control the size of the frozen water crystals, thereby controlling the size of the interstices.

39. The implantable scaffold of claim 37, wherein at least part of the interconnected naturally occurring extracellular matrix pieces defines pores having a nominal pore size of 100-700 microns.

40. The implantable scaffold of claim 39, wherein at least part of the interconnected naturally occurring extracellular matrix pieces defines pores having a nominal pore size of 300-700 microns.

41. The implantable scaffold of claim 37, wherein at least part of the interconnected naturally occurring extracellular matrix pieces defines pores having a nominal pore size of less than 100 microns.

42. The implantable scaffold of claim 37, further comprising at least one of the following:

a bioactive agent;

a biologically derived agent;

cells;

a biological lubricant;

a biocompatible inorganic material; and

a biocompatible polymer.

43. An implantable device for repairing or regenerating body tissue, the device comprising a three-dimensional-open cell foam comprising a plurality of interconnected pores defining three-dimensional interconnected passageways having irregular shapes, at least part of the foam comprising naturally occurring bioremodelable collagenous tissue matrix.

44. The implantable device of claim 43, wherein the foam comprises interconnected pieces of naturally occurring bioremodelable collagenous tissue matrix.

45. The implantable device of claim 43, wherein the foam has an interior surface, said interior surface comprising naturally occurring bioremodelable collagenous tissue matrix having an irregularly shaped three-dimensional topography.

46. The implantable device of claim 43, further comprising at least one of the following:

a bioactive agent;

a biologically derived agent;

cells;

a biological lubricant;

a biocompatible inorganic material; and

a biocompatible polymer.

47. The implantable device of claim 43, wherein the naturally occurring bioremodelable collagenous tissue matrix comprises at least a portion of at least one of the following:

small intestine submucosa, stomach submucosa, bladder submucosa, alimentary submucosa, respiratory submucosa, genital submucosa and liver basement membrane.

48. The implantable device of claim 43, wherein the nominal pore size of at least part of the device is between 100-700 microns.

49. The implantable device of claim 43, wherein the nominal pore size of at least part of the device is between 300-700 microns.

50. The implantable device of claim 43, wherein the nominal pore size of at least part of the device is less than 100 microns.

51. The implantable device of claim 43, wherein the foam has a density of about 0.005-0.5 g/cc.

52. An implantable device for repairing or regenerating body tissue, the device comprising a porous reticulated body of naturally occurring bioremodelable collagenous tissue matrix.

53. The implantable device of claim 52, wherein the naturally occurring bioremodelable collagenous tissue matrix comprises at least a portion of at least one of the following:

small intestine submucosa, stomach submucosa, bladder submucosa, alimentary submucosa, respiratory submucosa, genital submucosa and liver basement membrane.

54. The implantable device of claim 52, further comprising at least one of the following:

a bioactive agent;

a biologically derived agent;

cells;

a biological lubricant;

a biocompatible inorganic material; and

a biocompatible polymer.

55. The implantable device of claim 52, wherein at least part of the reticulated body defines pores having a nominal pore size of 100-700 microns.

56. The implantable device of claim 52, wherein at least part of the reticulated body defines pores having a nominal pore size of 300-700 microns.

57. The implantable device of claim 52, wherein at least part of the reticulated body defines pores having a nominal pore size of less than 100 microns.

58. The implantable device of claim 52, wherein at least part of the reticulated body defines a plurality of interconnected pores defining three-dimensional interconnected passageways having irregular shapes.

59. A method of making an implantable device for repairing or regenerating body tissue, the method comprising the steps of:

providing a naturally occurring extracellular matrix material in a raw form;

comminuting the raw naturally occurring extracellular matrix in the presence of a liquid to form a slurry of naturally occurring extracellular matrix; and

lyophilizing the slurry of naturally occurring extracellular matrix to form an open cell foam of naturally occurring extracellular matrix.

60. The method of claim 59 wherein the open cell foam of naturally occurring extracellular matrix includes molecules other than collagen, said molecules other than collagen being present in the raw form of the naturally occurring extracellular matrix.

61. The method of claim 59, further comprising adding at least one of the following:

a bioactive agent;

a biologically derived agent;

cells;

a biological lubricant;

a biocompatible inorganic material; and

a biocompatible polymer.

62. A method of making an implantable scaffold for repairing or regenerating body tissue, the method comprising the steps of:

providing a naturally occurring bioremodelable collagenous tissue matrix in a raw form;

comminuting the raw naturally occurring bioremodelable collagenous tissue matrix to form cohesive pieces of naturally occurring bioremodelable collagenous tissue matrix; and

lyophilizing the cohesive pieces of naturally occurring bioremodelable collagenous tissue matrix to form a reticulated foam of naturally occurring bioremodelable collagenous tissue matrix.

63. The method of claim 62, wherein the reticulated foam of naturally occurring bioremodelable collagenous tissue matrix includes molecules other than collagen, said molecules other than collagen being present in the raw form of the naturally occurring extracellular matrix.

64. The method of claim 62, further comprising adding at least one of the following:

a bioactive agent;

a biologically derived agent;

cells;

a biological lubricant;

a biocompatible inorganic material; and

a biocompatible polymer.

65. A method of making an implantable scaffold for repairing or regenerating body tissue, the method comprising the steps of:

providing a extracellular matrix material derived from tissue selected from the group consisting of;

small intestine submucosa, stomach submucosa, bladder submucosa, respiratory submucosa, alimentary submucosa, genital submucosa, and liver basement membrane;

physically comminuting the extracellular matrix to form cohesive pieces of extracellular matrix; and

lyophilizing the cohesive pieces of extracellular matrix to form an open cell foam of extracellular matrix.

66. The method of claim 65, wherein the extracellular matrix comprises naturally occurring extracellular matrix, and the step of physically comminuting the extracellular matrix comprises physically comminuting the naturally occurring extracellular matrix.

67. The method of claim 65, further comprising purifying the extracellular matrix prior to physically comminuting the extracellular matrix.

68. The method of claim 65, further comprising treating the extracellular matrix to substantially remove glycoproteins, glycosaminoglycans, proteoglycans, lipids, non-collagenous proteins and nucleic acids.

69. The method of claim 65, further comprising treating the extracellular matrix to remove substantially all materials other than collagen prior to physically comminuting the extracellular matrix.

70. The method of claim 65, wherein the step of physically comminuting the extracellular matrix comprises physically comminuting the extracellular matrix in the presence of a liquid.

71. A product made by the process of claim 65.

72. The product of claim 71 further comprising at least one of the following:

a bioactive agent;

a biologically derived agent;

cells;

a biological lubricant;

a biocompatible inorganic material; and

a biocompatible polymer.

78. A product made according to the method of claim 66.

79. The product of claim 78 further comprising at least one of the following:

a bioactive agent;

a biologically derived agent;

cells;

a biological lubricant;

a biocompatible inorganic material; and

a biocompatible polymer.

73. A method of making an implantable device for repairing or regenerating body tissue, the method comprising the steps of:

providing a extracellular matrix material selected from the group consisting of;

small intestine submucosa, stomach submucosa, bladder submucosa, respiratory submucosa, alimentary submucosa, genital submucosa, and liver basement membrane; and

physically comminuting the extracellular matrix in the presence of a liquid to form a slurry of extracellular matrix.

74. The method of claim 73, further comprising lyophilizing the slurry of extracellular matrix to form a reticulated foam of extracellular matrix.

75. The method of claim 73, wherein the extracellular matrix material comprises naturally occurring extracellular matrix material and wherein the step of physically comminuting the extracellular matrix in the presence of a liquid comprises physically comminuting naturally occurring extracellular matrix in the presence of a liquid.

76. The method of claim 73, further comprising purifying the extracellular matrix prior to physically comminuting the extracellular matrix.

77. The method of claim 73, further comprising treating the extracellular matrix to substantially remove glycoproteins, glycosaminoglycans, proteoglycans, lipids, non-collagenous proteins and nucleic acids such as DNA and RNA.

80. A method of making an implantable scaffold for repairing or regenerating body tissue, the method comprising the steps of:

providing an extracellular matrix material selected from the group consisting of;

small intestine submucosa, stomach submucosa, bladder submucosa, respiratory submucosa, alimentary submucosa, genital submucosa, and liver basement membrane;

suspending pieces of the extracellular matrix material in a liquid; and

freeze drying the pieces of extracellular matrix material and the liquid.

81. The method of claim 80, further comprising adding at least one of the following:

a bioactive agent;

a biologically derived agent;

cells;

a biological lubricant;

a biocompatible inorganic material; and

a biocompatible polymer.

82. A method of making an implantable scaffold for repairing or regenerating body tissue, the method comprising the steps of:

providing an extracellular matrix material selected from the group consisting of;

small intestine submucosa, stomach submucosa, bladder submucosa, respiratory submucosa, alimentary submucosa, genital submucosa and liver basement membrane;

suspending pieces of the extracellular matrix material in a liquid;

forming the pieces of the naturally occurring extracellular matrix and the liquid into a mass; and

driving off the liquid so as to form interstices in the mass.

83. The method of claim 82, further comprising adding at least one of the following:

a bioactive agent;

a biologically derived agent;

cells;

a biological lubricant;

a biocompatible inorganic material; and

a biocompatible polymer.

84. A slurry comprising cohesive pieces of naturally occurring extracellular matrix in a liquid.

85. A slurry of extracellular matrix material comprising cohesive pieces of extracellular matrix in a liquid, the extracellular matrix material being selected from the group consisting of:

small intestine submucosa, stomach submucosa, bladder submucosa, respiratory submucosa, alimentary submucosa, genital submucosa, and liver basement membrane.

86. A method of treating defective cartilage in a joint of a patient comprising:

implanting a biocompatible device in the patient at the joint;

the device comprising a foam comprising naturally occurring extracellular matrix having a plurality of interconnected pores, at least part of the extracellular matrix having interconnected pores having a nominal pore size of between about 30 and 100 microns.

87. A method of treating defective cartilage in a joint of a patient comprising:

providing an extracellular matrix material selected from the group consisting of;

small intestine submucosa, stomach submucosa, bladder submucosa, respiratory submucosa, alimentary submucosa, genital submucosa, and liver basement membrane;

forming the extracellular matrix material into a foam having a plurality of interconnected pores, at least part of the extracellular matrix having interconnected pores having a nominal pore size of between 30 and 100 microns; and

implanting the foam at the joint of the patient.

88. A method of treating diseased or damaged bone comprising:

implanting a device in the diseased or damaged bone;

the device comprising a foam comprising naturally occurring extracellular matrix having a plurality of interconnected pores, at least part of the extracellular matrix having interconnected pores having a nominal pore size greater than about 200 microns.

89. A method of treating diseased or damaged bone comprising:

providing an extracellular matrix material selected from the group consisting of;

small intestine submucosa, stomach submucosa, bladder submucosa, respiratory submucosa, alimentary submucosa, genital submucosa, and liver basement membrane;

forming the extracellular matrix material into a foam having a plurality of interconnected pores, the interconnected pores having an irregular shape and extending in three dimensions, at least part of the extracellular matrix having interconnected pores having a nominal pore size greater than 200 microns; and

implanting the foam in the bone having the disease or damage.

90. An implantable device for repairing or regenerating body tissue, the device comprising a porous naturally occurring extracellular matrix, the porous matrix having a density of less than 0.1 g/cc.

91. The implantable device of claim 90 wherein the porous matrix has a density of less than 0.04 g/cc.

92. The implantable device of claim 91 wherein the porous matrix has a density of less than 0.01 g/cc.

93. The implantable device of claim 90 wherein the porous naturally occurring extracellular matrix comprises SIS.

94. The implantable device of claim 90 wherein the porous matrix comprises a reticulated foam.

95. The implantable device of claim 90 wherein the porous matrix comprises an open cell foam.

96. The implantable device of claim 90 wherein the porous matrix comprises a plurality of pores defining three-dimensional interconnected passageways having irregular shapes.

97. A method of processing an extracellular matrix material comprising the step of comminuting the extracellular matrix material in the presence of a liquid.

98. The method of claim 97, wherein:

the extracellular matrix material comprises small intestine submucosa, and

the comminuting step comprises comminuting the small intestine submucosa in the presence of the liquid.

99. The method of claim 97, wherein:

the liquid comprises water, and

the comminuting step comprises comminuting the extracellular matrix material in the presence of water.