Methods and systems for treating restenosis sites using electroporation

Abstract

A system is provided for reducing restenosis. A catheter apparatus is provided with at least first and second mono-polar electrodes positioned at an inflatable balloon. The balloon is sized to be positioned and expanded at a restenosis site. A voltage pulse generator is coupled to the first and second mono-polar electrodes. The voltage pulse generator is configured to apply an electric field, in a controlled manner, to the restenosis site in an amount sufficient to produce electroporation of the restenosis site, and below an amount that causes thermal damage to the restenosis site.

1 . A system for reducing restenosis, comprising: 
 a catheter apparatus including at least first and second mono-polar electrodes positioned at an inflatable balloon, the balloon being sized to be positioned and expanded at a restenosis site;    a voltage pulse generator coupled to the first and second mono-polar electrodes and configured to apply an electric field in a controlled manner to the restenosis site in an amount sufficient to produce electroporation of the restenosis site and below an amount that causes thermal damage to the restenosis site.    
   
   
       2 . The system of  claim 1 , further comprising: 
 a monitoring electrode configured to measure a test voltage delivered to cells in the restenosis site.    
   
   
       3 . The system of  claim 1 , wherein the test voltage is insufficient to create irreversible electroporation.  
   
   
       4 . The system of  claim 1 , wherein the first and second mono-polar electrodes are band electrodes that extend at least partially circumferentially around the balloon.  
   
   
       5 . The system of  claim 4 , wherein sufficient band electrodes are provided to create electroporation along a length of the restenonsis site.  
   
   
       6 . The system of  claim 1 , wherein the electroporation is performed in a controlled manner with real time monitoring.  
   
   
       7 . The system of  claim 1 , wherein the electroporation is performed in a controlled manner to provide for controlled pore formation in cell membranes.  
   
   
       8 . The system of  claim 1 , wherein the electroporation is performed in a controlled manner to create a tissue effect of cells at the restenosis site while preserving surrounding tissue.  
   
   
       9 . The system of  claim 1 , wherein the electroporation is performed in a controlled manner with monitoring of electrical impedance;  
   
   
       10 . The system of  claim 1 , further comprising: 
 detecting an onset of electroporation of cells at the restenosis tissue site.    
   
   
       11 . The system of  claim 1 , wherein the electroporation is performed in a controlled manner with controlled intensity and duration of voltage.  
   
   
       12 . The system of  claim 1 , wherein the electroporation is performed in a controlled manner with real time control.  
   
   
       13 . The system of  claim 1 , wherein the electroporation is performed in a manner to for modification and control of mass transfer across cell membranes.  
   
   
       14 . The system of  claim 1 , wherein the electroporation is performed in a controlled manner with a proper selection of voltage magnitude.  
   
   
       15 . The system of  claim 1 , wherein the electroporation is performed in a controlled manner with a proper selection of voltage application time.  
   
   
       16 . The system of  claim 1 , wherein the voltage pulse generator is configured to provide that each pulse is applied for a duration of about 5 microseconds to about 62 seconds.  
   
   
       17 . The system of  claim 1 , wherein the voltage pulse generator is configured to provide that each pulse is applied for a duration of about 90 to 110 microseconds.  
   
   
       18 . The system of  claim 1 , wherein the voltage pulse generator is configured to provide that each pulse is applied for about 100 microseconds.  
   
   
       19 . The system of  claim 17 , wherein the voltage pulse generator is configured to apply from about 1 to 15 pulses.  
   
   
       20 . The system of  claim 17 , wherein the voltage pulse generator is configured to apply about eight pulses of about 100 microseconds each in duration.  
   
   
       21 . The system of  claim 1 , wherein the voltage pulse generator is configured to provide for pulse application to produce a voltage gradient at the restenosis tissue site in a range of from about 50 volt/cm to about 8000 volt/cm.  
   
   
       22 . The system of  claim 1 , wherein a temperature of the restenosis tissue site is monitored and the pulses are adjusted to maintain a temperature of 100 degrees C. or less at the restenosis tissue site.  
   
   
       23 . The system of  claim 1 , wherein a temperature of the restenosis tissue site is monitored and the pulses are adjusted to maintain a temperature of 75 degrees C. or less at the restenosis tissue site.  
   
   
       24 . The system of  claim 1 , wherein a temperature of the restenosis tissue site is monitored and the pulses are adjusted to maintain a temperature of 60 degrees C. or less at the restenosis tissue site.  
   
   
       25 . The system of  claim 22 , wherein the temperature is maintained at 50 degrees C. or less.  
   
   
       26 . The system of  claim 1 , wherein a current-to-voltage ratio is adjusted based on temperature to maintain the restenosis tissue site temperature at 100 degrees C. or less.  
   
   
       27 . The system of  claim 1 , wherein a current-to-voltage ratio is adjusted based on temperature to maintain the restenosis tissue site temperature at 75 degrees C. or less.  
   
   
       28 . The system of  claim 1 , wherein a current-to-voltage ratio is adjusted based on temperature to maintain the restenosis tissue site temperature at 60 degrees C. or less.  
   
   
       29 . The system of  claim 1 , wherein a current-to-voltage ratio is adjusted based on temperature to maintain the restenosis tissue site temperature at 50 degrees C. or less.  
   
   
       30 . The system of  claim 1 , wherein the first electrode is placed at about 5 mm to 10 cm from the second electrode.  
   
   
       31 . The system of  claim 1 , wherein the first and second mono-polar electrodes are circular in shape.  
   
   
       32 . The system of  claim 1 , wherein the voltage pulse generator is configured to provide for pulse application of sufficient duration and magnitude to permanently disrupt cell membranes of cells at the restenosis tissue site.  
   
   
       33 . The system of  claim 1 , wherein a ratio of electric current through cells at the restenosis tissue site to voltage across the cells is detected and a magnitude of applied voltage to the restenosis tissue site is adjusted in accordance with changes in the ratio of current to voltage.  
   
   
       34 . A system for reducing restenosis, comprising: 
 a catheter apparatus including a bi-polar electrode positioned at a inflatable balloon, the balloon being sized to be positioned and expanded at a restenosis site;    a voltage pulse generator coupled to the bi-polar electrode and configured to apply an electric field in a controlled manner to the restenosis site in an amount sufficient to produce electroporation of the restenosis site and below an amount that causes thermal damage to the restenosis site.    
   
   
       35 . The system of  claim 34 , further comprising: 
 a monitoring electrode configured to measure a test voltage delivered to cells in the restenosis site.    
   
   
       36 . The system of  claim 34 , wherein the test voltage is insufficient to create irreversible electroporation.  
   
   
       37 . The system of  claim 34 , wherein the bipolar electrode is a band electrode that extend at least partially circumferentially around the balloon.  
   
   
       38 . The system of  claim 4 , wherein sufficient band electrodes are provided to create electroporation along a length of the restenonsis site.  
   
   
       39 . The system of  claim 34 , further comprising: 
 a second bi-polar electrode.    
   
   
       40 . The system of  claim 39 , wherein the bi-polar electrodes are band electrodes that extend at least partially circumferentially around the balloon.  
   
   
       41 . The system of  claim 34 , wherein the electroporation is performed in a controlled manner with real time monitoring.  
   
   
       42 . The system of  claim 34 , wherein the electroporation is performed in a controlled manner to provide for controlled pore formation in cell membranes.  
   
   
       43 . The system of  claim 34 , wherein the electroporation is performed in a controlled manner to create a tissue effect of cells at the restenosis site while preserving surrounding tissue.  
   
   
       44 . The system of  claim 34 , wherein the electroporation is performed in a controlled manner with monitoring of electrical impedance;  
   
   
       45 . The system of  claim 34 , further comprising: 
 detecting an onset of electroporation of cells at the restenosis site.    
   
   
       46 . The system of  claim 34 , wherein the electroporation is performed in a controlled manner with controlled intensity and duration of voltage.  
   
   
       47 . The system of  claim 34 , wherein the electroporation is performed in a controlled manner with real time control.  
   
   
       48 . The system of  claim 34 , wherein the electroporation is performed in a manner to for modification and control of mass transfer across cell membranes.  
   
   
       49 . The system of  claim 34 , wherein the electroporation is performed in a controlled manner with a proper selection of voltage magnitude.  
   
   
       50 . The system of  claim 34 , wherein the electroporation is performed in a controlled manner with a proper selection of voltage application time.  
   
   
       51 . The system of  claim 34 , wherein the voltage pulse generator is configured to provide that each pulse is applied for a duration of about 5 microseconds to about 62 seconds.  
   
   
       52 . The system of  claim 34 , wherein the voltage pulse generator is configured to provide that each pulse is applied for a duration of about 90 to 110 microseconds.  
   
   
       53 . The system of  claim 34 , wherein the voltage pulse generator is configured to provide that each pulse is applied for a duration of about 100 microseconds.  
   
   
       54 . The system of  claim 52 , wherein the voltage pulse generator is configured to apply from about 1 to 15 pulses.  
   
   
       55 . The system of  claim 52 , wherein the voltage pulse generator is configured to apply about eight pulses of about 100 microseconds each in duration.  
   
   
       56 . The system of  claim 34 , wherein the voltage pulse generator is configured to provide for pulse application to produce a voltage gradient at the restenosis tissue site in a range of from about 50 volt/cm to about 8000 volt/cm.  
   
   
       57 . The system of  claim 34 , wherein a temperature of the restenosis tissue site is monitored and the pulses are adjusted to maintain a temperature of 100 degrees C. or less at the restenosis tissue site.  
   
   
       58 . The system of  claim 34 , wherein a temperature of the restenosis tissue site is monitored and the pulses are adjusted to maintain a temperature of 75 degrees C. or less at the restenosis tissue site.  
   
   
       59 . The system of  claim 34 , wherein a temperature of the restenosis tissue site is monitored and the pulses are adjusted to maintain a temperature of 60 degrees C. or less at the restenosis tissue site.  
   
   
       60 . The system of  claim 57 , wherein the temperature is maintained at 50 degrees C. or less.  
   
   
       61 . The system of  claim 34 , wherein a current-to-voltage ratio is adjusted based on temperature to maintain the restenosis tissue site temperature at 100 degrees C. or less.  
   
   
       62 . The system of  claim 34 , wherein a current-to-voltage ratio is adjusted based on temperature to maintain the restenosis tissue site temperature at 75 degrees C. or less.  
   
   
       63 . The system of  claim 34 , wherein a current-to-voltage ratio is adjusted based on temperature to maintain the restenosis tissue site temperature at 60 degrees C. or less.  
   
   
       64 . The system of  claim 34 , wherein a current-to-voltage ratio is adjusted based on temperature to maintain the restenosis tissue site temperature at 50 degrees C. or less.  
   
   
       65 . The system of  claim 34 , wherein the voltage pulse generator is configured to provide for pulse application of sufficient duration and magnitude to permanently disrupt cell membranes of cells at the restenosis tissue site.  
   
   
       66 . The system of  claim 34 , wherein a ratio of electric current through cells at the restenosis tissue site to voltage across the cells is detected and a magnitude of applied voltage to the restenosis tissue site is adjusted in accordance with changes in the ratio of current to voltage.  
   
   
       67 . A method for reducing restenosis, comprising: 
 introducing a balloon with first and second mono-polar electrodes through vasculature to a restenosis site;    positioning the balloon and the first and second mono-polar electrodes at or near the restenosis site;    applying an electric field in a controlled manner to the restenosis site in an amount sufficient to produce electroporation of the restenosis site and below an amount that causes thermal damage to the restenosis site.    
   
   
       68 . The method of  claim 67 , further comprising: 
 using a monitoring electrode to measure a test voltage delivered to cells in the restenosis site.    
   
   
       69 . The method of  claim 66 , wherein the test voltage is insufficient to create irreversible electroporation.  
   
   
       70 . The method of  claim 67 , wherein the first and second mono-polar electrodes are band electrodes at least partially circumferentially positioned around the balloon.  
   
   
       71 . The method of  claim 70 , wherein sufficient band electrodes are provided to create electroporation along a length of the restenonsis site.  
   
   
       72 . The method of  claim 67 , further comprising: 
 performing the electroporation in a controlled manner with real time monitoring.    
   
   
       73 . The method of  claim 67 , further comprising: 
 performing the electroporation in a controlled manner to provide for controlled pore formation in cell membranes.    
   
   
       74 . The method of  claim 67 , further comprising: 
 performing the electroporation in a controlled manner to create a tissue effect of cells at the restenosis site while preserving surrounding tissue.    
   
   
       75 . The method of  claim 67 , further comprising: 
 performing the electroporation in a controlled manner with monitoring of electrical impedance;    
   
   
       76 . The method of  claim 67 , further comprising: 
 detecting an onset of electroporation of cells at the restenosis site.    
   
   
       77 . The method of  claim 67 , further comprising: 
 performing the electroporation in a controlled manner with controlled intensity and duration of voltage.    
   
   
       78 . The method of  claim 67 , further comprising: 
 performing the electroporation in a controlled manner with real time control.    
   
   
       79 . The method of  claim 67 , further comprising: 
 performing the electroporation in a manner for modification and control of mass transfer across cell membranes.    
   
   
       80 . The method of  claim 67 , further comprising: 
 performing the electroporation in a controlled manner with a proper selection of voltage magnitude.    
   
   
       81 . The method of  claim 67 , wherein the electroporation is performed in a controlled manner with a proper selection of voltage application time.  
   
   
       82 . The method of  claim 67 , wherein the duration of each pulse is about 5 microseconds to about 62 seconds.  
   
   
       83 . The method of  claim 67 , wherein the duration of each pulse is about 90 to 110 microseconds.  
   
   
       84 . The method of  claim 67 , wherein the duration of each pulse is about 100 microseconds.  
   
   
       85 . The method of  claim 83 , wherein about 1 to 15 pulses are applied.  
   
   
       86 . The method of  claim 83 , wherein about eight pulses of about 100 microseconds each in duration are applied.  
   
   
       87 . The method of  claim 67 , wherein pulses are applied to produce a voltage gradient at the restenosis tissue site in a range of from about 50 volt/cm to about 8000 volt/cm.  
   
   
       88 . The method of  claim 67 , further comprising: 
 monitoring a temperature of the restenosis tissue site; and    adjusting the pulses to maintain a temperature of 100 degrees C. or less at the restenosis tissue site.    
   
   
       89 . The method of  claim 67 , further comprising: 
 monitoring a temperature of the restenosis tissue site; and    adjusting the pulses to maintain a temperature of 75 degrees C. or less at the restenosis tissue site.    
   
   
       90 . The method of  claim 67 , further comprising: 
 monitoring a temperature of the restenosis tissue site; and    adjusting the pulses to maintain a temperature of 60 degrees C. or less at the restenosis tissue site.    
   
   
       91 . The method of  claim 67 , further comprising: 
 monitoring a temperature of the restenosis tissue site; and    adjusting the pulses to maintain a temperature of 50 degrees C. or less at the restenosis tissue site.    
   
   
       92 . The method of  claim 67 , further comprising: 
 adjusting a current-to-voltage ratio based on temperature to maintain the restenosis tissue site temperature at 100 degrees C. or less.    
   
   
       93 . The method of  claim 67 , further comprising: 
 adjusting a current-to-voltage ratio based on temperature to maintain the restenosis tissue site temperature at 75 degrees C. or less.    
   
   
       94 . The method of  claim 67 , further comprising: 
 adjusting a current-to-voltage ratio based on temperature to maintain the restenosis tissue site temperature at 60 degrees C. or less.    
   
   
       95 . The method of  claim 67 , further comprising: 
 adjusting a current-to-voltage ratio based on temperature to maintain the restenosis tissue site temperature at 50 degrees C. or less.    
   
   
       96 . The method of  claim 67 , wherein the pulses applied are of sufficient duration and magnitude to permanently disrupt cell membranes of cells at the restenosis tissue site.  
   
   
       97 . The method of  claim 67 , wherein a ratio of electric current through cells at the restenosis tissue site to voltage across the cells is detected and a magnitude of applied voltage to the restenosis tissue site is adjusted in accordance with changes in the ratio of current to voltage.  
   
   
       98 . A method for reducing restenosis, comprising: 
 introducing a balloon with a bi-polar electrode through vasculature to a restenosis site;    positioning the balloon and the bi-polar electrode at or near the restenosis site;    applying an electric field in a controlled manner to the restenosis site in an amount sufficient to produce electroporation of the restenosis site and below an amount that causes thermal damage to the restenosis site.    
   
   
       99 . The method of  claim 98 , further comprising: 
 using a monitoring electrode to measure a test voltage delivered to cells in the restenosis site.    
   
   
       100 . The method of  claim 99 , wherein the test voltage is insufficient to create irreversible electroporation.  
   
   
       101 . The method of  claim 101 , wherein the bi-polar electrode is a band electrode at least partially circumferentially positioned around the balloon.  
   
   
       102 . The method of  claim 98 , wherein sufficient band electrodes are provided to create electroporation along a length of the restenonsis site.  
   
   
       103 . The method of  claim 98 , further comprising: 
 a second bi-polar electrode.    
   
   
       104 . The method of  claim 103 , wherein the bi-polar electrodes are band electrodes at least partially circumferentially positioned around the balloon.  
   
   
       105 . The method of  claim 98 , further comprising: 
 performing the electroporation in a controlled manner with real time monitoring.    
   
   
       106 . The method of  claim 98 , further comprising: 
 performing the electroporation in a controlled manner to provide for controlled pore formation in cell membranes.    
   
   
       107 . The method of  claim 98 , further comprising: 
 performing the electroporation in a controlled manner to create a tissue effect of cells at the restenosis site while preserving surrounding tissue.    
   
   
       108 . The method of  claim 98 , further comprising: 
 performing the electroporation in a controlled manner with monitoring of electrical impedance;    
   
   
       109 . The method of  claim 98 , further comprising: 
 detecting an onset of electroporation of cells at the restenosis site.    
   
   
       110 . The method of  claim 98 , further comprising: 
 performing the electroporation in a controlled manner with controlled intensity and duration of voltage.    
   
   
       111 . The method of  claim 98 , further comprising: 
 performing the electroporation in a controlled manner with real time control.    
   
   
       112 . The method of  claim 98 , further comprising: 
 performing the electroporation in a manner for modification and control of mass transfer across cell membranes.    
   
   
       113 . The method of  claim 98 , further comprising: 
 performing the electroporation in a controlled manner with a proper selection of voltage magnitude.    
   
   
       114 . The method of  claim 98 , wherein the electroporation is performed in a controlled manner with a proper selection of voltage application time.  
   
   
       115 . The method of  claim 98 , wherein the duration of each pulse is about 5 microseconds to about 62 seconds.  
   
   
       116 . The method of  claim 98 , wherein the duration of each pulse is about 90 to 110 microseconds.  
   
   
       117 . The method of  claim 98 , wherein the duration of each pulse is about 100 microseconds.  
   
   
       118 . The method of  claim 116 , wherein about 1 to 15 pulses are applied.  
   
   
       119 . The method of  claim 116 , wherein about eight pulses of about 100 microseconds each in duration are applied.  
   
   
       120 . The method of  claim 98 , wherein pulses are applied to produce a voltage gradient at the restenosis tissue site in a range of from about 50 volt/cm to about 8000 volt/cm.  
   
   
       121 . The method of  claim 98 , further comprising: 
 monitoring a temperature of the restenosis tissue site; and    adjusting the pulses to maintain a temperature of 100 degrees C. or less at the restenosis tissue site.    
   
   
       122 . The method of  claim 98 , further comprising: 
 monitoring a temperature of the restenosis tissue site; and    adjusting the pulses to maintain a temperature of 75 degrees C. or less at the restenosis tissue site.    
   
   
       123 . The method of  claim 98 , further comprising: 
 monitoring a temperature of the restenosis tissue site; and    adjusting the pulses to maintain a temperature of 60 degrees C. or less at the restenosis tissue site.    
   
   
       124 . The method of  claim 98 , further comprising: 
 monitoring a temperature of the restenosis tissue site; and    adjusting the pulses to maintain a temperature of 50 degrees C. or less at the restenosis tissue site.    
   
   
       125 . The method of  claim 98 , further comprising: 
 adjusting a current-to-voltage ratio based on temperature to maintain the restenosis tissue site temperature at 100 degrees C. or less.    
   
   
       126 . The method of  claim 98 , further comprising: 
 adjusting a current-to-voltage ratio based on temperature to maintain the restenosis tissue site temperature at 75 degrees C. or less.    
   
   
       127 . The method of  claim 98 , further comprising: 
 adjusting a current-to-voltage ratio based on temperature to maintain the restenosis tissue site temperature at 60 degrees C. or less.    
   
   
       128 . The method of  claim 98 , further comprising: 
 adjusting a current-to-voltage ratio based on temperature to maintain the restenosis tissue site temperature at 50 degrees C. or less.    
   
   
       129 . The method of  claim 98 , wherein the pulses applied are of sufficient duration and magnitude to permanently disrupt cell membranes of cells at the restenosis tissue site.  
   
   
       130 . The method of  claim 98 , wherein a ratio of electric current through cells at the restenosis tissue site to voltage across the cells is detected and a magnitude of applied voltage to the restenosis tissue site is adjusted in accordance with changes in the ratio of current to voltage.