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

• US 7,148,209 B2
• Filed: 01/07/2005
• Issued: 12/12/2006
• Est. Priority Date: 06/29/2000
• Status: Expired due to Fees

• Current Assignee: Smith & Nephew Orthopaedics Ag (Smith & Nephew PLC)
• Original Assignee: Ecole polytechnique
• Inventors: McKee, Marc D., Buschmann, Michael D., Hoemann, Caroline D.
• Primary Examiner(s): Weber, Jon
• Assistant Examiner(s): Kosson, Rosanne
• Application Number:
  US11/031,325
• Publication Number:
  US 20060029578A1
• Time in Patent Office: 704 Days
• Field of Search: 514/55, 514/12, 514/515, 424/422, 606/213
• US Class Current: 514/55
• 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 repair and/or regeneration in cartilaginous tissue comprising administering at a site of the cartilaginous tissue in need of repair an effective amount of a polymer composition comprising:

a solution of a polymer; and

blood,

wherein the polymer includes at least one selected from the group consisting of a polysaccharide, a protein, and a polyamino acid, and further wherein when the polymer is combined with blood the polymer composition is converted into a non-liquid state in time or upon heating such that the polymer compositions when placed at the site in need of repair, the polymer composition will adhere to the site in need of repair to effect reconstruction or bulking of the tissue and/or regeneration thereof.

2. The method of claim 1, wherein the polysaccharide is a modified or natural polysaccharide.

3. The method of claim 2, wherein the polysaccharide is selected from the group consisting of chitosan, chitin, hyaluronan, glycosaminoglycan, chondroitin sulfate, keratan sulfate, dermatan sulfate, heparin, and heparin sulfate.

4. The method of claim 1, wherein the polysaccharide is chitosan.

5. The method of claim 1, wherein cartilaginous tissue is selected from the group consisting of cartilage, meniscus, ligament and tendon.

6. The method of claim 1, wherein the protein is a natural, recombinant or synthetic protein.

7. The method of claim 3, wherein said protein is a polyamino acid.

8. The method of claim 7, wherein the polyamino acid is a polylysine.

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

10. The method of claim 1, wherein the polymer composition is dissolved or suspended in a buffer containing organic or inorganic salts.

11. The method of claim 10, wherein the inorganic salts are selected from the group consisting of sodium chloride or phosphates, sulfates or carboxylates of potassium, calcium and magnesium.

12. The method of claim 1, wherein said polymer composition has a pH between 6.5 and 7.8.

13. The method of claim 1, wherein said polymer solution has an osmolarity adjusted to a physiological value between 250 mOsm/L and 600 mOsm/L.

14. The method of claim 1, wherein the blood is anticoagulated.

15. The method of claim 1, wherein the blood further comprises an anticoagulant selected from the group consisting of citrate, heparin or EDTA.

16. The method of claim 1, wherein the blood further comprises a pro-coagulant to improve coagulation/solidification at the site of introduction.

17. The method of claim 1, 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.

18. The method of claim 1, wherein the blood is autologous or non-autologous.

19. The method of claim 18, wherein the blood is free of at least one of erythrocytes and/or leukocytes.

20. The method of claim 18, wherein the blood is enriched in platelets.

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

100 to 100;

1 with respect to the blood.

22. The method of claim 1, wherein said polymer and blood are mechanically mixed using sound waves, stirring, vortexing, or multiple passes in syringes.

23. The method of claim 10, wherein the organic salts are selected from the group consisting of glycerol-phosphate, fructose phosphate, glucose phosphate, L-serine phosphate, adenosine phosphate, glucosamine, galactosamine, HEPES, PIPES and MES.

24. The method of claim 1, wherein the blood is selected from the group consisting of whole blood, processed blood, venous blood, arterial blood, blood from bone-marrow, umbilical cord blood and placenta blood.

25. The method of claim 17, wherein the coagulation factor is factor VII.

26. The method of claim 4, wherein the chitosan is dissolved in an organic or inorganic phosphate buffer.

27. The method of claim 26, wherein the organic or inorganic phosphate buffer is a phosphate or glycerol phosphate containing buffer.

28. The method of claim 26, wherein the chitosan in the composition is in a soluble state, said composition having a pH between 6.5 and 7.4.

29. The method of claim 1, wherein the cartilaginous tissue is selected from the group consisting of articular cartilage, nose cartilage, ear cartilage, meniscus and avascular cartilage.

30. A method for repair and/or regeneration in cartilaginous tissue comprising administering at a site of the cartilaginous tissue in need of repair an effective amount of a thermogelling composition comprising:

a solution of the polymer chitosan;

glycerol phosphate; and

blood,

wherein the thermogelling composition is converted into a non-liquid state in time or upon heating, said composition once converted into a non-liquid state adheres to the site in need of repair when placed thereon to effect reconstruction or bulking of the tissue and/or regeneration thereof.

31. The method of claim 30, wherein cartilaginous tissue is selected from the group consisting of cartilage, meniscus, ligament and tendon.

32. The method of claim 30, wherein said polymer composition has a pH between 6.5 and 7.8, and wherein said chitosan is in solution at said pH.

33. The method of claim 30, wherein said polymer solution has an osmolarity adjusted to a physiological value between 250 mOsm/L and 600 mOsm/L.

34. The method of claim 30, wherein the blood is anticoagulated.

35. The method of claim 30, wherein the blood further comprises an anticoagulant selected from the group consisting of citrate, heparin or EDTA.

36. The method of claim 30, wherein the blood further comprises a pro-coagulant to improve coagulation/solidification at the site of introduction.

37. The method of claim 30, 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.

38. The method of claim 30, wherein the blood is autologous or non-autologous.

39. The method of claim 38, wherein the blood is free of at least one of erythrocytes and/or leukocytes.

40. The method of claim 38, wherein the blood is enriched in platelets.

41. The method of claim 30, wherein said chitosan, glycerol phosphate and blood are mechanically mixed using sound waves, stirring, vortexing, or multiple passes in syringes.

42. The method of claim 30, wherein the blood is selected from the group consisting of whole blood, processed blood, venous blood, arterial blood, blood from bone-marrow, umbilical cord blood and placenta blood.

43. The method of claim 37, wherein the coagulation factor is factor VII.

44. The method of claim 30, wherein the cartilaginous tissue is selected from the group consisting of articular cartilage, nose cartilage, ear cartilage, meniscus and avascular cartilage.