Regulation of type II collagen gene expression using specific and selective electrical and electromagnetic signals

Abstract

Methods and devices for the regulation of type II collagen gene expression in cartilage cells via the application of specific and selective fields generated by specific and selective electric and electromagnetic signals in the treatment of diseased or injured articular cartilage. By gene expression is meant the up regulation or down regulation of the process whereby specific portions (genes) of the human genome (DNA) are transcribed into mRNA and subsequently translated into protein. Methods and devices are provided for the targeted treatment of injured or diseased cartilage tissue that include generating specific and selective electric and electromagnetic signals that generate specific and selective fields optimized for type II collagen gene expression and exposing cartilage tissue to the specific and selective fields generated by specific and selective signals so as to regulate type II collagen gene expression in such cartilage tissue. The resulting methods and devices are useful for the targeted treatment of osteoarthritis, rheumatoid arthritis, cartilage injury, and cartilage defects.

1. A method of specifically and selectively  up-regulating the gene expression of type II collagen mRNA in cartilage tissue, comprising the steps of:
 generating at least one specific and selective signal that is selected from possible signals by determining sequential dose response curves for gene expression of type II collagen mRNA in response to respective signal characteristics of said possible signals and selecting a signal from said possible signals that provides  has a frequency of about  30  kHz to about  120  kHz and that, when applied to a field generating device operatively disposed with respect to the cartilage tissue causes the generation of a substantially optimized dose response curve  electric field having an amplitude of about  0 . 2 - 40  mV/cm in the cartilage tissue for the up-regulation of the gene expression of type II collagen mRNA when said field is applied to the cartilage tissue; and  
 exposing the cartilage tissue to a specific and selective  the substantially optimized electric field generated by the  said field generating device upon the application of said at least one specific and selective signal thereto for a predetermined duration of time of about  1 / 2  to about  24  hours per  24  hour period at a predetermined intervals  duty cycle from approximately  4 . 2 %-   100   % so as to selectively up-regulate the gene expression of type II collagen mRNA in the cartilage tissue.  
 
     
     
       2. The method of  claim 1  wherein the generating step comprises the step of selectively varying the amplitude, duration, duty cycle, frequency, and/or waveform of the specific and selective signal until the magnitudes of the corresponding dose response curves are substantially optimized for up-regulation of the gene expression of type II collagen mRNA in the cartilage tissue by the generated field. 
     
     
       3. The method of  claim 1  wherein the exposing step comprises the step of exposing an articular cartilage chrondrocyte to the specific and selective  electric field generated by the  said field generating device upon the application of said at least one specific and selective signal thereto for the predetermined duration of time at predetermined intervals of once per day. 
     
     
       4. The method of  claim 1  wherein said generating step comprises the step of generating the at least one specific and selective signal at a remote source and said exposing step comprises the step of applying to the cartilage tissue the specific and selective  electric field generated by the  said field generating device upon the application of said at least one specific and selective signal to the cartilage tissue  thereto. 
     
     
       5. The method of  claim 4  wherein the exposing step comprises the step of applying the at least one specific and selective signal to either electrodes or at least one coil located near the cartilage tissue. 
     
     
       6. The method of  claim 5  wherein the exposing step comprises the step of applying to the cartilage tissue the specific and selective  electric field generated by the electrodes or at least one coil as a result of application of said at least one specific and selective signal to the cartilage tissue through one of  either capacitive coupling and  or inductive coupling. 
     
     
       7. The method of  claim 6  wherein the at least one specific and selective signal when applied to electrodes causes the electrodes to generate one of  a capacitive coupling electric field, and when applied to the coil( s )  causes the coil ( s )  to generate  an electromagnetic field, and  or a combined field. 
     
     
       8. A method for treating at least one of  osteoarthritis, rheumatoid arthritis, cartilage injury, and/or cartilage defects, comprising the steps of:
 generating at least one specific and selective signal having a frequency from about  30  kHz to about  120  kHz that up-regulates  when applied to a field generating device operatively disposed with respect to target cartilage tissue causes the generation of an electric field having an amplitude of about  0 . 2 - 4 . 0  mV/cm in the target cartilage tissue that is specific and selective for up- regulating  the gene expression of type II collagen mRNA when said electric field is applied to the target cartilage tissue; and  
 exposing the cartilage tissue to a specific and selective  the electric field generated by the  said field generating device upon the application of said at least one specific and selective signal thereto for a predetermined duration of time of about  1 / 2  to about  24  hours per  24  hour period at a predetermined intervals  duty cycle from approximately  4 . 2 %-   100   % so as to selectively up-regulate gene expression of type II collagen mRNA in the target cartilage tissue.  
 
     
     
       9. The method of  claim 8  wherein the exposing step comprises the step of capacitively coupling the specific and selective  electric field to the target cartilage tissue. 
     
     
       10. The method of  claim 8  wherein the exposing step comprises the step of applying one of  either an electromagnetic field and  or a combined field generated by one or more coils to the target cartilage tissue. 
     
     
       11. The method of  claim 8  wherein the generating step comprises the step of generating a specific and selective  an electric field having an amplitude of approximately 20 mV/cm,  in the target cartilage tissue from a specific and selective signal having a sine wave configuration, a duty cycle of approximately 1/12, and a frequency of approximately 60 kHz. 
     
     
       12. The method of  claim 11  wherein the exposing step comprises the step of applying the specific and selective  electric field to the target cartilage tissue for a duration of approximately 30 minutes every 24 hours. 
     
     
       13. The method of  claim 8  wherein the generating step comprises the steps of selectively varying the amplitude, duration, duty cycle, frequency, and/or waveform of the specific and selective signal until the magnitudes of the corresponding dose response curves are substantially optimized for up-regulation of the gene expression of type II collagen mRNA in the target cartilage tissue by the generated field. 
     
     
       14. The method of  claim 13  wherein the exposing step comprises the step of applying the specific and selective  electric field generated by said field generating device, upon the application of the specific and selective signal thereto, to the target cartilage tissue through one of  either capacitive coupling and  or inductive coupling. 
     
     
       15. The method of  claim 14  wherein application of the specific and selective signal to said field generating device causes the electrodes to generate one  generation of a capacitive coupling electric field, an electromagnetic field, and  or a combined field. 
     
     
       16. A method of  for treating at least one of  osteoarthritis, rheumatoid arthritis, cartilage injury, and/or a cartilage defect comprising the steps of:
 exposing cartilage tissue to the specific and selective field generated by a device comprising a signal source that provides at least one specific and selective signal that creates a field  and a field generating device connected to the signal source so as to receive said at least one specific and selective signal and that is operatively disposed with respect to target cartilage tissue, said field generating device upon receipt of said at least one specific and selective signal causing the generation of an electric field that is specific and selective for up-regulating gene expression of type II collagen mRNA in said target cartilage tissue, the specific and selective signal having a sine wave configuration and approximately a  1 / 12  duty cycle and generating a  said specific and selective electric field having an amplitude of about 20 mV/cm at 60 kHz with approximately a 1/12 duty cycle, and electrodes connected to the signal source that receive , said at least one  specific and selective signal for application of the  field being applied to the cartilage tissue via one of  either capacitive coupling and  or inductive coupling; and  
 selectively up-regulating gene expression of type II collagen mRNA in the target cartilage tissue for a predetermined duration at predetermined intervals using said device.  
 
     
     
       17. The method of  claim 1  wherein the generating step comprises the step of generating a specific and selective  an electric field having an amplitude of approximately 20 mV/cm,  in the target cartilage tissue from a specific and selective signal having a sine wave configuration, a duty cycle of approximately 1/12, and a frequency of approximately 60 kHz. 
     
     
       18. The method of  claim 17  wherein the exposing step comprises the step of applying the specific and selective  electric field to the target cartilage tissue for a duration of approximately 30 minutes every 24 hours. 
     
     
       19. A method of up- regulating the gene expression of type II collagen mRNA in cartilage tissue, comprising the steps of:      generating at least one specific and selective signal having a frequency of about  30  kHz to about  120  kHz that when applied to a field generating device operatively disposed with respect to the cartilage tissue causes the generation of an electric field having an amplitude of about  0 . 2 - 40  mV/cm in the cartilage tissue that is specific and selective for the up - regulation of the gene expression of type II collagen mRNA when said electric field is applied to the cartilage tissue containing said type II collagen mRNA; and        exposing the cartilage tissue to the specific and selective electric field generated by said field generating device upon the application of said at least one specific and selective signal thereto for a predetermined duration of time of about  1 / 2  to about  24  hours per  24  hour period at a predetermined duty cycle from approximately  4 . 2   %-   100   %  so as to selectively up - regulate the gene expression of type II collagen mRNA in the cartilage tissue.      
     
     
       20. The method of  claim 19  wherein the generating step comprises the step of selectively varying the amplitude, duration, duty cycle, frequency, and/or waveform of the specific and selective signal until the up- regulation of type II collagen mRNA in the cartilage tissue in response to the specific and selective electric field resulting from application of the specific and selective signal to said field generating device is substantially optimized.    
     
     
       21. The method of  claim 19  wherein the exposing step comprises the step of exposing an articular cartilage chrondrocyte to the electric field generated by said field generating device upon the application of said at least one specific and selective signal thereto for the predetermined duration of time at predetermined intervals of once per day.  
     
     
       22. The method of  claim 19  wherein said generating step comprises the step of generating the at least one specific and selective signal at a remote source and said exposing step comprises the step of applying to the cartilage tissue the electric field generated by said field generating device upon the application of said at least one specific and selective signal thereto.  
     
     
       23. The method of  claim 22  wherein the exposing step comprises the step of applying the at least one specific and selective signal to either electrodes or at least one coil located near the cartilage tissue.  
     
     
       24. The method of  claim 23  wherein the exposing step comprises the step of applying to the cartilage tissue the electric field generated by the electrodes or at least one coil as a result of application of said at least one specific and selective signal thereto through either capacitive coupling or inductive coupling.  
     
     
       25. The method of  claim 24  wherein the at least one specific and selective signal when applied to electrodes causes the electrodes to generate a capacitive coupling electric field, and when applied to the coil( s )  causes the coil ( s )  to generate an electromagnetic field or a combined field.