Methods and compositions for the treatment and repair of defects or lesions in cartilage

• US 5,368,858 A
• Filed: 11/23/1992
• Issued: 11/29/1994
• Est. Priority Date: 01/31/1991
• Status: Expired due to Term

• Current Assignee: Robert F. Shaw
• Original Assignee: Robert F. Shaw
• Inventors: Hunziker, Ernst B.
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): AZPURU, CARLOS A
• Application Number:
  US07/979,904
• Time in Patent Office: 736 Days
• Field of Search: 424/422, 424/423, 424/424, 424/425, 424/426, 424/450, 424/484, 424/489, 424/499, 514/2, 514/8, 514/944, 514/953, 514/965, 530/350, 530/351, 530/353, 530/354, 530/356, 530/840
• US Class Current: 424/423
• CPC Class Codes: A61F 2/30756 Cartilage endoprostheses A61F2/3603 takes precedence
• 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 38/185 Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3
• CPC Class Codes: A61K 38/51 Lyases (4)
• CPC Class Codes: A61L 2300/414 Growth factors
• CPC Class Codes: A61L 2300/426 Immunomodulating agents, i.e. cytokines, interleukins, interferons
• CPC Class Codes: A61L 2300/45 Mixtures of two or more drugs, e.g. synergistic mixtures
• CPC Class Codes: A61L 2300/626 Liposomes, micelles, vesicles
• CPC Class Codes: A61L 24/0015 Medicaments; Biocides
• CPC Class Codes: A61L 24/106 Fibrin; Fibrinogen
• CPC Class Codes: A61L 24/108 Specific proteins or polypeptides not covered by groups A61L24/102 - A61L24/106
• CPC Class Codes: A61L 2430/06 for cartilage reconstruction, e.g. meniscus
• CPC Class Codes: A61L 26/0047 Specific proteins or polypeptides not covered by groups A61L26/0033 - A61L26/0042
• CPC Class Codes: A61L 27/227 Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
• CPC Class Codes: A61L 27/54 Biologically active materials, e.g. therapeutic substances A61L27/227 takes precedence
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: Y10S 530/84 Bones; tendons; teeth; cartilage

Abstract

Methods and compositions are provided for the treatment and repair of defects or lesions in the cartilage of humans and other animals. The defect or lesion in the cartilage may be first treated with an enzyme to remove proteoglycans from the defect area. To induce cartilage formation, the defect is filled or otherwise dressed with a biodegradable matrix having pores sufficiently large to allow repair cells to populate the matrix. The matrix filling the defect contains a proliferation agent at a concentration sufficient to stimulate proliferation of repair cells and a transforming factor in an appropriate delivery system to release the transforming factor at a concentration sufficient to transform repair cells in the matrix and defect area into cartilage-producing chondrocytes. The matrix may also contain a chemotactic agent to attract repair cells. The entire treatment may be carried out in a single arthroscopic or open surgical procedure.

Claims

1. A composition for the treatment or repair of defects or lesions in cartilage comprising:

a biodegradable matrix or matrix-forming material used to dress the area of the defect or lesion in the cartilage;

a proliferation agent contained within the matrix or matrix-forming material at an appropriate concentration to stimulate the proliferation of repair cells in the matrix and the area of the defect or lesion; and

a transforming factor associated with a delivery system, the delivery system being contained within the matrix or matrix-forming material, and the transforming factor being present at an appropriate concentration such that upon subsequent delivery of the transforming factor to repair cells in the matrix and defect, the repair cells are transformed into chondrocytes that produce cartilage tissue.

2. The composition according to claim 1 further comprising a chemotactic agent at an appropriate concentration to attract repair cells to the matrix and defect area.

3. The composition according to claim 2, wherein the chemotactic agent is selected from the group consisting of TGF-β

s, FGFs, PDGF, TNF-α

, TNF-β and

proteoglycan degradation products.

4. The composition according to claim 1 or 2, wherein the proliferation agent is selected from the group consisting of TGF-β

s, FGFs, IGF I, PDGF, EGF, TGF-α

s, human growth hormone and hemopoietic growth factors.

5. The composition according to claims 1 or 2 wherein the transforming factor is selected from the group consisting of TGF-β

s, TGF-α

s, FGFs, and combinations thereof, and TGF-β

in combination with EGF.

6. The composition according to claim 1 or 2, wherein the biodegradable matrix used to fill the defect area is selected from the group consisting of fibrin, collagen, gelatin, Sepharose or combinations thereof.

7. The composition according to claim 2, wherein the proliferation agent, the chemotactic agent and the transforming factor are selected from the group consisting of TGF-β

s.

8. The composition according to claim 1 or 2, wherein the transforming factor is a mixture of one or more transforming factors.

9. The composition according to claim 7, wherein the proliferation and chemotactic agent is TGF-β

at a concentration of 2-50 ng/ml in the matrix and the transforming factor is TGF-β

associated with the delivery system which provides a concentration of TGF-β

of greater than 200 ng/ml in the matrix.

10. The composition according to claim 1 or 2, wherein the delivery system is selected from the group consisting of liposomes, bioerodible polymers, collagen fibers chemically linked to heparin sulfate proteoglycans, and carbohydrate-based corpuscles.

12. The composition according to claim 1 or 2 further comprising a cell adhesion promoting factor comprising the tripeptide Arg-Gly-Asp.

13. The composition according to claim 9 wherein the TGF-β

in the delivery system is at a concentration of 200-800 ng/ml in the matrix.

11. A composition for the treatment or repair of defects or lesions in cartilage comprising:

a fibrin matrix formed by adding thrombin to a fibrinogen solution,

TGF-β

present at a concentration of 2-10 ng/ml of fibrinogen solution, and

TGF-β

encapsulated in liposomes and present at a concentration of greater than 200 ng/ml of fibrinogen solution.

14. The composition according to claim 11 wherein the TGF-β

encapsulated in liposomes is present at a concentration of 200-800 ng/ml of fibrinogen solution.