Method for in vivo ex vivo and in vitro repair and regeneration of cartilage and collagen and bone remodeling

• US 6,528,052 B1
• Filed: 09/29/2000
• Issued: 03/04/2003
• Est. Priority Date: 09/29/2000
• Status: Expired due to Term

• Current Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford University)
• Original Assignee: Board of Trustees of the Leland Stanford Junior University (Stanford University)
• Inventors: Carter, Dennis R., Schurman, David J., Smith, R. Lane
• Primary Examiner(s): Witz, Jean C.
• Application Number:
  US09/677,109
• Time in Patent Office: 886 Days
• Field of Search: 424/93.7
• US Class Current: 424/93.7
• CPC Class Codes: A61F 2/08 Muscles; Tendons; Ligaments sutures A61B17/04
• CPC Class Codes: A61F 2/28 Bones joints A61F2/30
• CPC Class Codes: A61F 2/30756 Cartilage endoprostheses A61F2/3603 takes precedence
• CPC Class Codes: A61F 2/3094 Designing or manufacturing processes
• CPC Class Codes: A61F 2240/001 Designing or manufacturing processes
• CPC Class Codes: A61F 2310/00365 Proteins; Polypeptides; Degradation products thereof
• CPC Class Codes: A61K 35/12 Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells vaccines or medicinal preparations containing antigens or antibodies A61K39/00
• CPC Class Codes: A61K 35/32 Bones; Osteocytes; Osteoblasts; Tendons; Tenocytes; Teeth; Odontoblasts; Cartilage; Chondrocytes; Synovial membrane
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: C12N 2500/02 Atmosphere, e.g. low oxygen conditions
• CPC Class Codes: C12N 2521/00 Culture process characterised by the use of hydrostatic pressure, flow or shear forces
• CPC Class Codes: C12N 5/0655 Chondrocytes; Cartilage

Abstract

A method for in vivo, ex vivo and in vitro regeneration of cartilage and collagen. In vivo, ex vivo and in vitro regeneration and de novo formation of articular cartilage and collagen by intermittently applied hydrostatic pressure. The application of external interval loading consisting of repeated periods of applied hydrostatic pressure followed and interrupted by periods of recovery. The application of the intermittent hydrostatic pressure at physiological levels 5-10 MPA for an interval of 4 hours followed by a recovery period up to about 20 hours, said pressure applied to the cartilage cells in vitro, explants of cartilage ex vivo and in vivo to cartilage that remains intact within te joint space of diarthrotic joints. The interval loading results in the selective inhibition of matrix degrading enzymes, pro-inflammatory cytokines and chemokines that attract inflammatory cells into the joint cavity and in selective decrease of gene, expression of growth factors that are inhibitory to type II collagen expression.

Claims

1. A method for in vivo, ex vivo or in vitro repair and regeneration of degenerated, diseased or injured articular cartilage or for de novo production of cartilage, collagen, ligaments, tendons or bone, said method comprising a step of subjecting the degenerated, diseased or injured cartilage, a cartilage graft or chondrocytes or other mesenchymally-derived cells to intermittently applied hydrostatic pressure (IHP) between about 0.5 and about 30 MPa for about 2 to about 8 hours daily followed by about 16 to 22 hours recovery period for period of about 4 to about 100 days or as needed.

2. The method of claim 1 wherein the pressure is applied at frequency of about 0.1-10 Hz.

3. The method of claim 2 wherein the de novo method comprises subjecting a matrix with a suspension of mesenchymal or mesenchymally-derived cells to said IHP.

4. The method of claim 2 wherein the pressure is between about 1 MPa and about 10 MPa pressure is applied intermittently for about 4 hours and the recovery period is about 20 hours.

5. The method of claim 4 wherein the pressure is about 5 MPa-10 MPa.

6. The method of claim 5 wherein the cartilage is subjected to the IHP in situ using an external device to apply such pressure.

7. The method of claim 5 wherein the cartilage is subjected to the IHP ex vivo and, following the regeneration, is returned to a treated joint.

8. The method of claim 5 wherein the cartilage is regenerated in vitro by submitting chondrocytes to IHP.

9. A method for restoration of function of degenerated, diseased or injured joint, said method comprising step of (a) subjecting the degenerated, diseased or injured cartilage or a cartilage graft removed from the joint, or chondrocytes, to intermittently applied hydrostatic pressure (IHP) between about 0.5 and about 30 MPa for about 1 to about 8 hours daily;

(b) withdrawing the IHP for about 16 to 22 hours recovery period; and

(c) repeating steps (a) and (b) for a period of about 4 to about 100 days or as needed.

10. The method of claim 9 wherein the pressure is applied at frequency of about 0.1-10 Hz.

11. The method of claim 10 wherein the function of the joints is restoration by implanting into said joint a matrix comprising regenerated chondrocytes.

12. The method of claim 11 wherein the pressure is between about 1 and about 10 MPa said pressure is applied intermittently for about 4 hours and the recovery period is about 20 hours.

13. The method of claim 12 wherein the pressure is between 5 MPa and 10 MPa.

14. The method of claim 13 wherein the cartilage is subjected to the intermittent hydrostatic pressure (IHP) in situ using an external device to apply such pressure.

15. The method of claim 14 wherein the cartilage is subjected to the IHP ex vivo for regeneration and returned to a treated joint.

16. The method of claim 15 wherein the cartilage is regenerated in vitro by submitting chondrocytes to IHP.

17. The method of claim 15 wherein the disease is osteoarthritis and osteoarthrosis.

18. The method of claim 15 wherein the degeneration is degenerative joint disease.

19. The method of claim 15 wherein the disease is a collagen deficiency.

20. The method of claim 15 wherein the joint injury is loaded or damaged cartilage.