Stimulation for delivery of molecular therapy

Abstract

The present invention provides a novel stimulatory device for the controlled production of angiogenic growth factors. More specifically, the present invention provides a subthreshold pulse generator for the local production of vascular endothelial growth factor.

1 . A subthreshold pulse generator comprising: 
 a.) a power supply; and    b a control mechanism interconnected with the power supply to deliver a subthreshold pulse to a targeted cell or tissues    wherein the subthreshold stimulus is less than or equal to about 1 volt.    
   
   
       2 . A subthreshold pulse generator of  claim 1 , wherein the control mechanism controls at least one additional set of components selected from a stimulus timer, output amplitude control, charge balanced pulse timer, stimulation threshold monitor, and a lead continuity monitor.  
   
   
       3 . A subthreshold pulse generator of  claim 1 , wherein the control mechanism has at least one additional set of components selected from a stimulus timer, output amplitude control, charge balanced pulse timer, stimulation threshold monitor, and a lead continuity monitor.  
   
   
       4 . A subthreshold pulse generator of  claim 1  wherein the the power supply provides either a constant or variable voltage.  
   
   
       5 . A subthreshold pulse generator of  claim 1  wherein the amplitude of the delivery of the electrical pulse from the power supply has an electrical field of about 1 V/cm.  
   
   
       6 . A subthreshold pulse generator of  claim 1  wherein the amplitude of the delivery of the electrical pulse from the power supply has an electrical field of about 0.5 V/cm.  
   
   
       7 . A subthreshold pulse generator of  claim 1  wherein the amplitude of the delivery of the electrical pulse from the power supply has electrical field of about 0.1 V.  
   
   
       8 . A subthreshold pulse generator of any one of claims  5 ,  6 , or  7  wherein the electrical field is ±about 30%.  
   
   
       9 . A subthreshold pulse generator of any one of claims  5 ,  6 , or  7  wherein the electrical field is ±about 20%.  
   
   
       10 . A subthreshold pulse generator of any one of claims  5 ,  6 , or  7  wherein the variable electrical field is ±about 10%.  
   
   
       11 . A subthreshold pulse generator of any one of claims  5 ,  6 , or  7  wherein the variable electrical field is ±about 5%.  
   
   
       12 . A subthreshold pulse generator of  claim 1  wherein the stimulation period of the subthreshold pulse from the power supply is less than about 20 msec.  
   
   
       13 . A subthreshold pulse generator of  claim 1  wherein the stimulation period of the subthreshold pulse from the power supply is less than about 10 msec,  
   
   
       14 . A subthreshold pulse generator of  claim 1  wherein the stimulation period of the subthreshold pulse from the power supply is less than about 5 msec.  
   
   
       15 . A subthreshold pulse generator of  claim 1  wherein the stimulation period of the subthreshold pulse from the power supply is less than about 1 msec.  
   
   
       16 . A subthreshold pulse generator of  claim 1  wherein the stimulation period of the subthreshold pulse from the power supply is less than about 0.3 msec.  
   
   
       17 . A subthreshold pulse generator of  claim 1  wherein the frequency of stimulation is about 10 Hz.  
   
   
       18 . A subthreshold pulse generator of  claim 1  wherein the frequency of stimulation is about 25 Hz.  
   
   
       19 . A subthreshold pulse generator of  claim 1  wherein the frequency of stimulation is about 40 Hz.  
   
   
       20 . A subthreshold pulse generator of  claim 1  wherein the frequency of stimulation is about 50 Hz.  
   
   
       21 . A subthreshold pulse generator of  claim 1  wherein the frequency of stimulation is about 70 Hz.  
   
   
       22 . A subthreshold pulse generator of  claim 1  wherein the frequency of stimulation is about 85 Hz.  
   
   
       23 . A subthreshold pulse generator of  claim 1  wherein the frequency of stimulation is about 100 Hz.  
   
   
       24 . A subthreshold pulse generator of  claim 1 , further comprising a plurality of electrodes for delivery of said subthreshold pulse to the targeted cells or tissue.  
   
   
       25 . A subthreshold pulse generator of  claim 1 , further comprising at least one electrode is capable of being placed on a catheter and delivered to a target organ transluminally.  
   
   
       26 . A subthreshold pulse generator of  claim 1 , wherein the subthreshold pulse generator provides stimulation to the cells or tissue when the electrodes are in contact with or in proximity of the targeted cells or tissue.  
   
   
       27 . A subthreshold pulse generator of  claim 1 , wherein the amplitude and duration period of the delivery is sufficient to stimulate angiogensis.  
   
   
       28 . A subthreshold pulse generator of  claim 1 , wherein the delivered subthreshold pulse is charge balanced.  
   
   
       29 . A subthreshold pulse generator of  claim 1 , additionally comprising a computer processing unit in electronic communication with the power supply, the computer being programmable to cause the subthreshold pulse generator to deliver a predetermined amount of electrical current or voltage over a predetermined period of delivery to said targeted cells or tissue.  
   
   
       30 . A subthreshold pulse generator of  claim 1 , wherein the electrical pulse generator is implanted in the body.  
   
   
       31 . A subthreshold pulse generator of  claim 1 , wherein the electrical pulse generator is external to the body.  
   
   
       32 . A subthreshold pulse generator of  claim 1 , for delivering an electrical field over a predetermined period of time to a targeted tissue or cell to stimulate the production of VEGF expression.  
   
   
       33 . A subthreshold pulse generator of  claim 1 , wherein the electrical pulse generator is externally controlled.  
   
   
       34 . A therapeutic delivery system comprising a subthreshold pulse generator of  claim 1 , operably linked with mammalian cells or tissue.  
   
   
       35 . A therapeutic delivery system of  claim 34  wherein the subthreshold pulse generator provides a subthreshold stimulation.  
   
   
       36 . A therapeutic delivery system of  claim 34  further comprising a plurality of electrodes wherein the subthreshold pulse generator provides stimulation to the cells or tissue from a plurality of electrodes.  
   
   
       37 . A therapeutic delivery system of  claim 34  wherein the electrical pulse generator provides stimulation to the cell or tissue when the electrodes are in contact with or in proximity of the targeted cells or tissue.  
   
   
       38 . A therapeutic delivery system of one of claims  34 - 37  wherein the stimulated tissue is muscle tissue.  
   
   
       39 . A therapeutic delivery system of one of claims  34 - 37  wherein the stimulated tissue is heart muscle tissue.  
   
   
       40 . A therapeutic delivery system of one of claims  34 - 37  wherein the stimulated tissue is skeletal muscle tissue.  
   
   
       41 . A therapeutic delivery system of one of claims  34 - 37  wherein the stimulated cells are smooth muscle cells.  
   
   
       42 . A therapeutic delivery system one of claims  34 - 37  wherein the stimulated cells are vascular muscle cells.  
   
   
       43 . A therapeutic delivery system of one of claims  34 - 37  wherein the stimulated cells are vascular endothelial cells.  
   
   
       44 . A therapeutic delivery system of  claim 37  wherein the electrodes are configured in a manner selected from the group consisting of unipolar, bipolar, and multiple electrode configurations.  
   
   
       45 . A therapeutic delivery system of  claim 34  wherein the electrical pulse generator is implanted.  
   
   
       46 . A therapeutic delivery system of  claim 34  wherein the electrical pulse generator is external.  
   
   
       47 . A therapeutic delivery system of  claim 34  wherein the electrical pulse generator is externally controlled.  
   
   
       48 . A therapeutic delivery system of  claim 34  additionally comprising a sensing electrode for optionally readjusting or synchronizing the period of delivery of the subthreshold pulses.  
   
   
       49 . A therapeutic delivery system of  claim 34  for delivering an electrical field over a predetermined period of time to targeted cells or tissue to stimulate the production of VEGF expression.  
   
   
       50 . A method of treating a patient comprising providing the patient with a subthreshold pulse generator operably linked with targeted mammalian cells or tissues wherein the subthreshold pulse generator comprises 
 (a) a power supply; and    (b) a control mechanism interconnected with the power supply to deliver a subthreshold pulse to a targeted cell or tissue    wherein the threshold stimulus is less than or equal to about 1 volt.    
   
   
       51 . A method of treating a patient comprising providing the patient with a subthreshold pulse generator operably linked to the tissue for acute subthreshold stimulation therapy to improve angiogenesis; wherein the subthreshold pulse generator comprises 
 (a) a power supply; and    (b) a control mechanism interconnected with the power supply to deliver a subthreshold pulse to a targeted cell or tissue    wherein the subthreshold stimulus is less than or equal to about 1 volt.    
   
   
       52 . A method of treating a patient comprising using the pulse generator of  claim 1  for delivering an electrical field over a predetermined period of time to a targeted cells or tissue to stimulate the production of VEGF expression.  
   
   
       53 . A method of increasing vascularization in a target tissue comprising providing subthreshold stimulatory pulses to the targeted muscle tissue using a subthreshold pulse generator: wherein the subthreshold pulse generator comprises 
 (a) a power supply; and    (b) a control mechanism interconnected with the power supply to deliver a subthreshold pulse to a targeted cell or tissue    wherein the subthreshold stimulus is less than or equal to about 1 volt.    
   
   
       54 . A method of increasing vascularization in a target tissue wherein the subthreshold stimulatory pulses are targeted to vascular muscle tissue using a subthreshold pulse generator; wherein the subthreshold pulse generator comprises 
 (a) a power supply; and    (b) a control mechanism interconnected with the power supply to deliver a subthreshold pulse to a targeted cell or tissue    wherein the subthreshold stimulus is less than or equal to about 1 volt.    
   
   
       55 . A method of increasing vascularization in a target tissue wherein the subthreshold stimulatory pulses are targeted to heart muscle tissue using a subthreshold pulse generator; wherein the subthreshold pulse generator comprises 
 (a) a power supply; and    (b) a control mechanism interconnected with the power supply to deliver a subthreshold pulse to a targeted cell or tissue    wherein the subthreshold stimulus is less than or equal to about 1 volt.    
   
   
       56 . A method of increasing vascularization in a target tissue wherein the subthreshold stimulatory pulses are targeted to skeletal muscle tissue using a subthreshold pulse generator; wherein the subthreshold pulse generator comprises 
 (a) a power supply; and    (b) a control mechanism interconnected with the power supply to deliver a subthreshold pulse to a targeted cell or tissue    wherein the subthreshold stimulus is less than or equal to about 1 volt.    
   
   
       57 . A method of treating a patient comprising providing the patient with a subthreshold pulse generator operably linked to a muscle tissue for subthreshold stimulation therapy using a subthreshold pulse generator; wherein the subthreshold pulse generator comprises 
 (a) a power supply; and    (b) a control mechanism interconnected with the power supply to deliver a subthreshold pulse to a targeted cell or tissue    wherein the subthreshold stimulus is less than or equal to about 1 volt.    
   
   
       58 . A method of treating a patient of  claim 57  wherein stimulated tissue is muscle tissue.  
   
   
       59 . A method of treating a patient of  claim 57  wherein stimulated tissue is heart muscle tissue.  
   
   
       60 . A method of treating a patient of  claim 57  where in stimulated tissue is skeletal muscle tissue.  
   
   
       61 . A method of treating a patient of  claim 57  where in stimulated cells are muscle cells  
   
   
       62 . A method of treating a patient of  claim 57  where in stimulated cells are heart muscle cells.  
   
   
       63 . A method of treating a patient of  claim 57  where in stimulated cells are skeletal muscle cells.  
   
   
       64 . A method of treating a patient of  claim 57  where in stimulated cells are vascular muscle cells.  
   
   
       65 . A method of treating a patient of  claim 57  where in stimulated cells are vascular endothelial cells.  
   
   
       66 . A method of improving vascularization in a targeted tissue comprising the steps of: 
 a. stimulating cultured cells with a subthreshold electrical field using the pulse generator of  claim 1 , and then subsequently    b. injecting the stimulated cells into the targeted body tissue.    
   
   
       67 . A method of improving vascularization in a target tissue of  claim 66  wherein the method additionally comprises further stimulating the injected cells.  
   
   
       68 . A method of improving vascularization in a targeted tissue comprising the steps of: 
 a. injecting cells into a targeted body tissue; and    b. b. stimulating the injected cell area with subthreshold stimulation using the pulse generator of  claim 1.