Methods for modulating osteochondral development using bioelectrical stimulation

• US 7,840,272 B2
• Filed: 05/22/2006
• Issued: 11/23/2010
• 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
• Primary Examiner(s): Patel; Niketa I
• Assistant Examiner(s): HAYES, ANDREW L
• Application Number:
  US11/444,916
• Publication Number:
  US 20060293724A1
• Time in Patent Office: 1,646 Days
• Field of Search: 607/50, 607/51
• 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:

generating a first electrical signal having a first repeating pattern of a number of pulse bursts, each of the pulse bursts comprising a plurality of individual positive pulses of a first voltage level L₁ of a first duration T₁, the individual positive pulses separated by a number of negative pulses of a second duration T₂ at a second voltage level L₂, wherein each of the pulse bursts has a third duration T₃ and are separated from each other at least by an equalizing pulse of a fourth period T₄ at the second voltage level L₂;

wherein the first duration T₁ equals 13 msec, the second duration T₂ equals 200 μ

sec, and the third duration T₃ equals 1 sec; and

applying the generated first electrical signal to the bone, cartilage, or other connective tissue to modulate development or repair of the tissue.

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

3. The method of claim 2 wherein the progenitor cells are selected from stem cells, uncommitted progenitors, committed progenitors, multipotent progenitor cells, or pluripotent progenitor cells.

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

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

6. The method of claim 1 further comprising:

mechanical loading in combination with applying the generated first electrical signal.

7. The method of claim 1 wherein applying the generated first electrical signal includes applying the generated first electrical signal using a capacitively coupled electrode.

8. The method of claim 1 wherein generating a first electrical signal includes generating the electrical signal to include an additional duration between the pulse bursts at a third voltage level L₃, the third voltage level L₃ between the first voltage level L₁ and the second voltage level L₂.

9. The method of claim 1, further comprising:

generating a second electrical signal having a first repeating pattern of a number of pulse bursts, each of the pulse bursts comprising a plurality of individual positive pulses of a first voltage level L₁ of a first duration T₁, the individual positive pulses separated by a number of negative pulses of a second duration T₂ at a second voltage level L₂, wherein each of the pulse bursts has a third duration T₃ and are separated from each other at least by an equalizing pulse of a fourth period T₄ at the second voltage level L₂, wherein the first duration T₁, the second duration T₂, and the third duration T₃ are selected from the group of triplets consisting of;

A) the first duration T₁ between 20 μ

sec and 100 μ

sec, the second duration T₂ between 5 μ

sec and 75 μ

sec, and the third duration T₃ between 0.5 msec and 500msec;

B) the first duration T₁ between 100 μ

sec and 1000 μ

sec, the second duration T₂ between 5 μ

sec and 75 μ

sec, and the third duration T₃ between 1.0 msec and 50 msec;

C) the first duration T₁ between 100 μ

sec and 1000 μ

sec, the second duration T₂ between 20 μ

sec and 100 μ

sec, and the third duration T₃ between 1.0 msec and 50 msec;

applying the generated second electrical signal to the tissue to modulate development or repair of the tissue.

10. The method of claim 9 wherein the first and the second electrical signals are administered simultaneously or sequentially to promote proliferation, differentiation, or matrix production of cells in the tissue.

11. The method of claim 9 wherein the first and the second electrical signals are applied consecutively with respect to one another.

12. The method of claim 9 wherein the first and the second electrical signals are applied concurrently with respect to one another.