Methods for modulating osteochondral development using bioelectrical stimulation

• US 20060293724A1
• Filed: 05/22/2006
• Published: 12/28/2006
• Est. Priority Date: 06/03/2005
• Status: Active Grant

• Current Assignee: Medrelief, Inc.
• Original Assignee: Medrelief, Inc.
• Inventors: Gordon, Stephen L., Kronberg, James W., Ganey, Timothy
• Granted Patent: US 7,840,272 B2
• Time in Patent Office: Days
• US Class Current: 607/51
• CPC Class Codes: A61N 1/326 for promoting growth of cells, e.g. bone cells
• CPC Class Codes: A61N 1/40 Applying electric fields by inductive or capacitive coupling microwave apparatus A61N5/00; Applying radio-frequency signals
• CPC Class Codes: C12M 21/08 for producing artificial tissue or for ex-vivo cultivation of tissue prostheses A61F2/00, grafts A61L27/00
• CPC Class Codes: C12M 35/02 Electrical or electromagnetic means, e.g. for electroporation or for cell fusion

Abstract

Compositions and methods are provided for modulating the growth, development and repair of bone, cartilage or other connective tissue. Devices and stimulus waveforms are provided to differentially modulate the behavior of osteoblasts, chondrocytes and other connective tissue cells to promote proliferation, differentiation, matrix formation or mineralization for in vitro or in vivo applications. Continuous-mode and pulse-burst-mode stimulation of cells with charge-balanced signals may be used. Bone, cartilage and other connective tissue growth is stimulated in part by nitric oxide release through electrical stimulation and may be modulated through co-administration of NO donors and NO synthase inhibitors. Bone, cartilage and other connective tissue growth is stimulated in part by release of BMP-2 and BMP-7 in response to electrical stimulation to promote differentiation of cells. The methods and devices described are useful in promoting repair of bone fractures, cartilage and connective tissue repair as well as for engineering tissue for transplantation.

Claims

1. A method for modulating development or repair of bone, cartilage or other connective tissue comprising stimulating a developing or regenerating tissue with an electrical signal wherein the electrical signal comprises an A-type, B-type, C-type or D-type signal

for a time period sufficient to modulate the development or repair of the tissue.

2. The method of claim 1 further comprising stimulating a developing with a second electrical signal wherein the second electrical signal comprises an A-type, B-type, C-type or D-type signal.

3. The method of claim 2 wherein the A-type signal comprises a long component having a β

length and a short component having an α

length.

4. The method of claim 2 wherein the A-type signal comprises a long component of about 60 μ

sec in duration and a short component of about 28 μ

sec in duration.

5. The method of claim 2 wherein the B-type signal comprises a long component having a γ

length and a short having an α

length.

6. The method of claim 2 wherein the B-type signal comprises a long component of about 200 μ

sec in duration and a short component of about 28 μ

sec in duration

7. The method of claim 2 wherein the two electrical signals are administered simultaneously or sequentially to promote proliferation, differentiation, or matrix production of cells in the tissue.

8. The method of claim 1 wherein the tissue comprises progenitor cells.

9. The method of claim 8 wherein the progenitor cells are selected from stem cells, uncommitted progenitors, committed progenitors, multipotent progenitor cells, or pluripotent progenitor cells.

10. The method of claim 1 wherein the electrical stimulation increases the production of BMP-2 or BMP-7.

11. The method of claim 1 wherein the electrical stimulation modulates the production of nitric oxide.

12. A method for producing or repairing bone, cartilage, or connective tissue comprising stimulating a developing or regenerating tissue with an electrical signal wherein the electrical signal comprises an A-type, B-type, C-type or D-type electrical signal.

13. The method of claim 12 further comprising mechanical loading in combination with the electrical signal.

14. The method of claim 12 wherein the electrical stimulation is effected using a capacitively coupled electrode.

15. A method for producing or repairing bone, cartilage or other connective tissue comprising stimulating the tissue with a first electrical signal to stimulate proliferation, differentiation or matrix production of tissue-forming cells followed by stimulating the developing tissue with a second electrical signal to stimulate the proliferation, differentiation or matrix/mineral production of the tissue-forming cells.

16. The method of claim 15 wherein the first electrical signal comprises a A-type signal and the second electrical signal comprises a B-type signal.

17. The method of claim 15 wherein the A-type signal comprises a long component having a β

length and a short component having an α

length.

18. The method of claim 15 wherein the A-type signal comprises a long component of about 60 μ

sec in duration and a short component of about 28 μ

sec in duration.

19. The method of claim 15 wherein the B-type signal comprises a long component having a γ

length and a short having an α

length.

20. The method of claim 15 wherein the B-type signal comprises a long component of about 200 μ

sec in duration and a short component of about 28 μ

sec in duration.

21. A capacitively coupled bridge electrode comprising an electrode made of an anodized metal.

22. The electrode of claim 21 wherein the anodized metal is niobium, tantalum, titanium, zirconium, molybdenum, tungsten, vanadium, aluminum or stainless steels.

23. A system comprising cells and an electrical stimulator delivering a A-type signal or a B-type signal to the cells.

24. The system of claim 23 further comprising means for mechanical loading of the cells.

25. The system of claim 23 wherein the A-type signal comprises a long component between about 20 μ

sec and 100 μ

sec in duration and a short component between about 5 μ

sec and 95 μ

sec in duration.

26. The system of claim 23 wherein the A-type signal comprises a long component of about 60 μ

sec in duration and a short component of about 28 μ

sec in duration.

27. The system of claim 23 wherein the B-type signal comprises a long component between about 100 μ

sec and 1000 μ

sec in duration and a short component between about 5 μ

sec and 75 μ

sec in duration.

28. The system of claim 23 wherein the B-type signal comprises a long component of about 200 μ

sec in duration and a short component of about 28 μ

sec in duration.

29. The system of claim 23 wherein the cells are selected from stem cells, uncommitted progenitors, committed progenitor cells, multipotent progenitors, pluripotent progenitors or cells at other stages of differentiation.

30. The culture system of claim 23 further comprising a capacitively coupled bridge electrode made of an anodized metal.

31. A kit for preparing a tissue suitable for transplantation comprising cells and an electrical stimulator providing an electrical stimulus waveform wherein the electrical stimulus waveform comprises a A-type, B-type, C-type or D-type signal wherein the waveform promotes proliferation, differentiation, or matrix production of the cells into a tissue suitable for transplantation.

32. The kit of claim 31 further comprising a biodegradable or biostable scaffold.

33. The kit of claim 32 wherein the scaffold is made from a material selected from natural or synthetic polymers.

34. The kit of claim 32 wherein the scaffold is in association with growth-promoting or adhesion-promoting molecules.

35. The kit of claim 31 further comprising means for mechanical loading of the cells.