Composition and method for the repair and regeneration of cartilage and other tissues

• US 20020082220A1
• Filed: 06/29/2001
• Published: 06/27/2002
• Est. Priority Date: 06/29/2000
• Status: Abandoned Application

• Current Assignee: Piramal Healthcare Limited (Piramal Enterprises Limited)
• Original Assignee: Piramal Healthcare Limited (Piramal Enterprises Limited)
• Inventors: Buschmann, Michael D., Hoemann, Caroline D., McKee, Marc D.
• Application Number:
  US09/896,912
• Publication Number:
  US 20020082220A1
• Time in Patent Office: Days
• US Class Current: 514/21
• 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 31/727 Heparin; Heparan
• CPC Class Codes: A61K 31/728 Hyaluronic acid
• CPC Class Codes: A61K 31/737 Sulfated polysaccharides, e.g. chondroitin sulfate, dermatan sulfate A61K31/727 takes precedence
• CPC Class Codes: A61K 35/15 Cells of the myeloid line, e.g. granulocytes, basophils, eosinophils, neutrophils, leucocytes, monocytes, macrophages or mast cells; Myeloid precursor cells; Antigen-presenting cells, e.g. dendritic cells presenting a specific antigen A61K39/00; therapeutic combinations of antibodies, or fragments thereof, and blood-derived cells A61K39/00
• CPC Class Codes: A61K 35/16 Blood plasma; Blood serum umbilical cord blood A61K35/51
• CPC Class Codes: A61K 35/18 Erythrocytes haemoglobin A61K38/42
• CPC Class Codes: A61K 35/19 Platelets; Megacaryocytes
• CPC Class Codes: A61K 38/363 Fibrinogen
• CPC Class Codes: A61K 38/4833 Thrombin (3.4.21.5)
• CPC Class Codes: A61K 38/4846 Factor VII (3.4.21.21); Factor IX (3.4.21.22); Factor Xa (3.4.21.6); Factor XI (3.4.21.27); Factor XII (3.4.21.38)
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: A61L 27/18 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• CPC Class Codes: A61L 27/20 Polysaccharides
• CPC Class Codes: A61L 27/22 Polypeptides or derivatives thereof , e.g. degradation products
• CPC Class Codes: A61L 27/3616 Blood, e.g. platelet-rich plasma
• 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 27/3687 : characterised by the use of chemical agents in the treatment, e.g. specific enzymes, detergents, capping agents, crosslinkers, anticalcification agents
• CPC Class Codes: A61L 27/3691 : characterised by physical conditions of the treatment, e.g. applying a compressive force to the composition, pressure cycles, ultrasonic/sonication or microwave treatment, lyophilisation
• CPC Class Codes: A61L 27/3804 : characterised by specific cells or progenitors thereof, e.g. fibroblasts, connective tissue cells, kidney cells
• CPC Class Codes: A61L 27/3839 : 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 27/50 : Materials characterised by their function or physical properties , e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• CPC Class Codes: A61P 19/04 : for non-specific disorders of the connective tissue

Abstract

The present invention relates to a new method for repairing human or animal tissues such as cartilage, meniscus, ligament, tendon, bone, skin, cornea, periodontal tissues, abscesses, resected tumors, and ulcers. The method comprises the step of introducing into the tissue a temperature-dependent polymer gel composition such that the composition adhere to the tissue and promote support for cell proliferation for repairing the tissue. Other than a polymer, the composition preferably comprises a blood component such as whole blood, processed blood, venous blood, arterial blood, blood from bone, blood from bone-marrow, bone marrow, umbilical cord blood, placenta blood, erythrocytes, leukocytes, monocytes, platelets, fibrinogen, thrombin and platelet rich plasma. The present invention also relates to a new composition to be used with the method of the present invention.

Claims

1. A method for repairing a tissue of a patient, said method comprising the step of introducing into said tissue a temperature-dependent polymer gel composition such that said composition adhere to the tissue and promote support for cell proliferation for repairing the tissue.

2. The method of claim 1, wherein the composition comprises at least one blood component.

3. A method for repairing a tissue of a patient, said method comprising the step of introducing a polymer composition in said tissue, said polymer composition being mixable with at least one blood component, said polymer composition when mixed with said blood component results in a mixture, said mixture turning into a non-liquid state in time or upon heating, said mixture being retained at the site of introduction and adhering thereto for repairing the tissue.

4. The method of claim 3, wherein the polymer is a modified or natural polysaccharide.

5. The method of claim 4, wherein the polysaccharide is selected from the group consisting of chitosan, chitin, hyaluronan, glycosaminoglycan, chondroitin sulfate, keratan sulfate, dermatan sulfate, heparin, and heparin sulfate.

6. The method of claim 3, wherein the polymer composition comprises a natural, recombinant or synthetic protein or a polyamino acids.

7. The method of claim 6, wherein the polyamino acids is a polylysine.

8. The method of claim 6, wherein the natural protein is soluble collagen or gelatin.

9. The method of claim 3, wherein the polymer composition comprises polylactic acid, polyglycolic acid, a synthetic homo and block copolymers containing carboxylic, amino, sulfonic, phosphonic, phosphenic functionalities with or without additional functionalities.

10. The method of claim 9, wherein the additional functionalities are selected from the group consisting of hydroxyl, thiol, alkoxy, aryloxy, acyloxy, and aroyloxy.

11. The method of claim 3, wherein the polymer composition is initially dissolved or suspended in a buffer containing inorganic salts.

12. The method of claim 11, wherein the inorganic salts are selected from the group consisting of including sodium, chloride, potassium, calcium, magnesium, phosphate, sulfate, and carboxylate.

13. The method of claim 3, wherein the polymer composition is dissolved or suspended in a buffer containing an organic salt selected from the group consisting of glycerol-phosphate, fructose phosphate, glucose phosphate, L-Serine phosphate, adenosine phosphate, glucosamine, galactosamine, HEPES, PIPES, and MES.

14. The method of claim 3, wherein the polymer composition has a pH between 6.5 and 7.8.

15. The method of claim 3, wherein the polymer solution has an osmolarity adjusted to a physiological value between 250 mOsm/L and 600 mOsm/L.

16. The method of claim 3, wherein the blood component is selected from the group consisting of whole blood, processed blood, venous blood, arterial blood, blood from bone, blood from bone-marrow, bone marrow, umbilical cord blood, and placenta blood.

17. The method of claim 3, wherein the blood component is selected from the group consisting of erythrocytes, leukocytes, monocytes, platelets, fibrinogen, and thrombin.

18. The method of claim 3, wherein the blood component comprises platelet rich plasma free of erythrocytes.

19. The method of claim 3, wherein the blood component is anticoagulated.

20. The method of claim 19, wherein the blood component contains an anticoagulant selected from the group consisting of citrate, heparin or EDTA.

21. The method of claim 3, wherein the blood component comprises a pro-coagulant to improve coagulation/solidification at the site of introduction.

22. The method of claim 21, wherein the pro-coagulant is selected from the group consisting of thrombin, calcium, collagen, ellagic acid, epinephrine, adenosine diphosphate, tissue factor, a phospholipid, and a coagulation factor.

23. The method of claim 22, wherein the coagulation factor is factor VII.

24. The method of claim 3, wherein the blood component is autologous or non-autologous.

25. The method of claim 3, wherein the polymer composition is used in a ratio varying from 1:

100 to 100;

1 with respect to the blood component.

26. The method of claim 3, wherein the polymer composition and the blood component are mechanically mixed using sound waves, stirring, vortexing, or multiple passes in syringes.

27. The method according to any one of claims 3 to 26, wherein the tissue is selected from the group consisting of cartilage, meniscus, ligament, tendon, bone, skin, cornea, periodontal tissues, maxillofacial tissues, temporomandibular tissues, abscesses, resected tumors, and ulcers.

30. The polymer composition of claim 29, wherein the polymer is a modified or natural polysaccharide.

31. The polymer composition of claim 30, wherein the polysaccharide is selected from the group consisting of chitosan, chitin, hyaluronan, glycosaminoglycan, chondroitin sulfate, keratan sulfate, dermatan sulfate, heparin, and heparin sulfate.

32. The polymer composition of claim 29, wherein said polymer composition comprises a natural, recombinant or synthetic protein or a polyamino acids.

33. The polymer composition of claim 32, wherein the polyamino acids is a polylysine.

34. The polymer composition of claim 32, wherein the natural protein is soluble collagen or gelatin.

35. The polymer composition of claim 29, wherein said polymer composition comprises polylactic acid, polyglycolic acid, a synthetic homo and block copolymers containing carboxylic, amino, sulfonic, phosphonic, phosphenic functionalities with or without additional functionalities.

36. The polymer composition of claim 35, wherein the additional functionalities are selected from the group consisting of hydroxyl, thiol, alkoxy, aryloxy, acyloxy, and aroyloxy.

37. The polymer composition of claim 29, wherein the polymer composition is dissolved or suspended in a buffer containing inorganic salts.

38. The polymer composition of claim 37, wherein the inorganic salts are selected from the group consisting of including sodium, chloride, potassium, calcium, magnesium, phosphate, sulfate, and carboxylate.

39. The polymer composition of claim 29, wherein said polymer composition is dissolved or suspended in a buffer containing an organic salt selected from the group consisting of glycerol-phosphate, fructose phosphate, glucose phosphate, L-Serine phosphate, adenosine phosphate, glucosamine, galactosamine, HFPES, PIPES, and MES.

40. The polymer composition of claim 29, wherein said polymer composition has a pH between 6.5 and 7.8.

41. The polymer composition of claim 29, wherein said polymer solution has an osmolarity adjusted to a physiological value between 250 mOsm/L and 600 mOsm/L.

42. The polymer composition of claim 29, wherein the blood component is selected from the group consisting of whole blood, processed blood, venous blood, arterial blood, blood from bone, blood from bone-marrow, bone marrow, umbilical cord blood, and placenta blood.

43. The polymer composition of claim 29, wherein the blood component is selected from the group consisting of erythrocytes, leukocytes, monocytes, platelets, fibrinogen, and thrombin.

44. The polymer composition of claim 29, wherein the blood component comprises platelet rich plasma free of erythrocytes.

45. The polymer composition of claim 29, wherein the blood component is anticoagulated.

46. The polymer composition of claim 45, wherein the blood component contains an anticoagulant selected from the group consisting of citrate, heparin or EDTA.

47. The polymer composition of claim 29, wherein the blood component comprises a pro-coagulant to improve coagulation/solidification at the site of introduction.

48. The polymer composition of claim 47, wherein the pro-coagulant is selected from the group consisting of thrombin, calcium, collagen, ellagic acid, epinephrine, adenosine diphosphate, tissue factor, a phospholipid, and a coagulation factor.

49. The polymer composition of claim 48, wherein the coagulation factor is factor VII.

50. The polymer composition of claim 29, wherein the blood component is autologous or non-autologous.

51. The polymer composition of claim 29, wherein the polymer composition is used in a ratio varying from 1:

100 to 100;

1 with respect to the blood component.

52. The polymer composition of claim 29, wherein said polymer composition and the blood component are mechanically mixed using sound waves, stirring, vortexing, or multiple passes in syringes.

98. The method of claim 3, wherein the site of introduction in the body has been surgically prepared to remove abnormal tissues.

99. The method of claim 98, wherein the tissue requiring repair is surgically prepared by piercing, abrading or drilling into adjacent tissue regions or vascularized regions to create channels for the polymer composition to migrate into the site requiring repair.

28. A polymer composition for use in repairing a tissue, said polymer composition comprising a polymer and a blood component.

29. A polymer composition for use in repairing a tissue of a patient, said polymer composition being mixable with at least one blood component, said polymer composition when mixed with said blood component results in a mixture, said mixture turning into a non-liquid state in time or upon heating, said mixture being retained at the site of introduction and adhering thereto for repairing the tissue.

53. The polymer composition according to any one of claims 29 to 52, wherein the tissue is selected from the group consisting of cartilage, meniscus, ligament, tendon, bone, skin, cornea, periodontal tissues, abscesses, resected tumors, and ulcers.

54. Use of a temperature-dependent polymer gel composition for tissue repair.

55. The use of claim 54, wherein the composition comprises at least one blood component.

57. The use of claim 56, wherein the polymer is a modified or natural polysaccharide.

58. The use of claim 57, wherein the polysaccharide is selected from the group consisting of chitosan, chitin, hyaluronan, glycosaminoglycan, chondroitin sulfate, keratan sulfate, dermatan sulfate, heparin, and heparin sulfate.

59. The use of claim 56, wherein the polymer composition comprises a natural, recombinant or synthetic protein or a polyamino acids.

60. The use of claim 59, wherein the polyamino acids is a polylysine.

61. The use of claim 59, wherein the natural protein is soluble collagen or gelatin.

62. The use of claim 56, wherein the polymer composition comprises polylactic acid, polyglycolic acid, a synthetic homo and block copolymers containing carboxylic, amino, sulfonic, phosphonic, phosphenic functionalities with or without additional functionalities.

63. The use of claim 62, wherein the additional functionalities are selected from the group consisting of hydroxyl, thiol, alkoxy, aryloxy, acyloxy, and aroyloxy.

64. The use of claim 56, wherein the polymer composition is initially dissolved or suspended in a buffer containing inorganic salts.

65. The use of claim 64, wherein the inorganic salts are selected from the group consisting of including sodium, chloride, potassium, calcium, magnesium, phosphate, sulfate, and carboxylate.

66. The use of claim 56, wherein the polymer composition is dissolved or suspended in a buffer containing an organic salt selected from the group consisting of glycerol-phosphate, fructose phosphate, glucose phosphate, L-Serine phosphate, adenosine phosphate, glucosamine, galactosamine, HEPES, PIPES, and MES.

67. The use of claim 56, wherein the polymer composition has a pH between 6.5 and 7.8.

68. The use of claim 56, wherein the polymer solution has an osmolarity adjusted to a physiological value between 250 mOsm/L and 600 mOsm/L.

69. The use of claim 56, wherein the blood component is selected from the group consisting of whole blood, processed blood, venous blood, arterial blood, blood from bone, blood from bone-marrow, bone marrow, umbilical cord blood, and placenta blood.

70. The use of claim 56, wherein the blood component is selected from the group consisting of erythrocytes, leukocytes, monocytes, platelets, fibrinogen, and thrombin.

71. The use of claim 56, wherein the blood component comprises platelet rich plasma free of erythrocytes.

72. The use of claim 54, wherein the blood component is anticoagulated.

73. The use of claim 72, wherein the blood component contains an anticoagulant selected from the group consisting of citrate, heparin or EDTA.

74. The use of claim 56, wherein the blood component comprises a pro-coagulant to improve coagulation/solidification at the site of introduction.

75. The use of claim 74, wherein the pro-coagulant is selected from the group consisting of thrombin, calcium, collagen, ellagic acid, epinephrine, adenosine diphosphate, tissue factor, a phospholipid, and a coagulation factor.

76. The use of claim 75, wherein the coagulation factor is factor VII.

77. The use of claim 56, wherein the blood component is autologous or non-autologous.

78. The use of claim 56, wherein the polymer composition is used in a ratio varying from 1:

100 to 100;

1 with respect to the blood component.

79. The use of claim 56, wherein the polymer composition and the blood component are mechanically mixed using sound waves, stirring, vortexing, or multiple passes in syringes.

56. Use of a polymer composition for repairing a tissue said polymer composition being mixable with at least one blood component, said polymer composition when mixed with said blood component results in a mixture, said mixture turning into a non-liquid state in time or upon heating, said mixture being retained at the site of introduction for repairing the tissue.

80. The use of any one claims 56 to 79, wherein the tissue is selected from the group consisting of cartilage, meniscus, ligament, tendon, bone, skin, cornea, periodontal tissues, abscesses, resected tumors, and ulcers.

81. Use of a chitosan solution for cell delivery to repair or regenerate a tissue in vivo, said chitosan solution comprising 0.5-3% w/v of chitosan and being formulated to be thermogelling, said solution being mixed with cells prior to being injected into a tissue to be repaired or regenerated.

82. The use of claim 81, wherein the chitosan composition is induced to thermogel by addition of phosphate, glycerol phosphate or glucosamine.

83. The use of claim 81, wherein the chitosan solution has a pH between 6.5 to 7.8.

84. The use of claim 81, wherein the cells are autologous or non-autologous.

85. The use of claim 81, wherein the cells are selected from the group consisting of primary cells, passaged cells, selected cells, platelets, stromal cells, stem cells, and genetically modified cells.

86. The use of claim 81, wherein the cells are suspended in a carrier solution.

87. The use of claim 86, wherein the carrier solution comprises hyaluronic acid, hydroxyethylcellulose, collagen, alginate, or a water-soluble polymer.

88. Use of a gelling chitosan solution for culturing cells in vitro, said chitosan solution comprising 0.5-3% w/v of chitosan and being formulated to be thermogelling, said solution being is mixed with cells prior to being cultured in vitro.

89. The use of claim 88, wherein the chitosan composition is induced to thermogel by addition of phosphate, glycerol phosphate or glucosamine.

90. The use of claim 89, wherein the chitosan solution has a pH between 6.5 to 7.8.

91. The use of claim 89, wherein said cells are selected from the group consisting of primary cells, passaged cells, selected cells, stromal cells, stem cells, and genetically modified cells.

92. The use of claim 89, wherein the cells are suspended in a carrier solution.

93. The use of claim 91, wherein the carrier solution comprises hyaluronic acid, hydroxyethylcellulose, collagen, alginate, or a water-soluble polymer.

94. A polymer composition containing between 0.01 and 10% w/v of 20% to 100% deacetylated chitosan with average molecular weight ranging from 1 kDa to 10 MDa and a blood component.

95. The polymer composition of claim 94, wherein the chitosan is dissolved in an organic or inorganic phosphate buffer.

96. The polymer composition of claim 95, wherein the organic or inorganic phosphate buffer is a phosphate or glycerol phosphate containing buffer.

97. The polymer composition of claim 95, wherein the chitosan in the composition is in a soluble state, said composition having a pH between 6.5 and 7.4.