Methods and apparatus for inducing controlled renal neuromodulation

Abstract

Methods and apparatus are provided for inducing, monitoring and controlling renal neuromodulation using a pulsed electric field to effectuate electroporation or electrofusion. In some embodiments, tissue impedance, conductance or conductivity may be monitored to determine the effects of pulsed electric field therapy, e.g., to determine an extent of electroporation and its degree of irreversibility. Pulsed electric field electroporation of tissue causes a decrease in tissue impedance and an increase in tissue conductivity. If induced electroporation is reversible, upon cessation of the pulsed electric field, tissue impedance and conductivity should approximate baseline levels; however, if electroporation is irreversible, impedance and conductivity changes should persist. Thus, monitoring of impedance or conductivity may be utilized to determine the onset of electroporation and to determine the type or extent of electroporation. Furthermore, monitoring data may be used in one or more manual or automatic feedback loops to control the electroporation.

1 . Apparatus for inducing, monitoring and controlling renal neuromodulation, the apparatus comprising:
 a pulsed electric field generator;   at least one electrode configured for placement proximate a neural fiber that contributes to renal function,   wherein the electrode is electrically coupled to the pulsed electric field generator for delivering a pulsed electric field to the neural fiber while the electrode is located proximate the neural fiber and/or is configured to monitor electroporation in tissue exposed to the pulsed electric field; and   a module operatively coupled to the electrode and configured to output data indicative of electroporation.   
     
     
         2 . The apparatus of  claim 1 , wherein the electrode comprises at least one pulsed electric field-delivery electrode and at least one monitoring electrode. 
     
     
         3 . The apparatus of  claim 2 , wherein the pulsed electric field-delivery electrode comprises a bipolar electrode pair. 
     
     
         4 . The apparatus of  claim 2 , wherein the monitoring electrode comprises a pair of monitoring electrodes. 
     
     
         5 . The apparatus of  claim 1 , wherein the electrode is configured to monitor electroporation in target tissue exposed to the pulsed electric field. 
     
     
         6 . The apparatus of  claim 5 , wherein the electrode is configured to monitor electroporation induced in the neural fiber by the pulsed electric field. 
     
     
         7 . The apparatus of  claim 1 , wherein the electrode is configured to monitor electroporation in non-target tissue exposed to the pulsed electric field. 
     
     
         8 . The apparatus of  claim 7 , wherein the electrode is configured to monitor electroporation in wall tissue of renal vasculature. 
     
     
         9 . The apparatus of  claim 1 , wherein the electrode is configured to monitor impedance, conductance or conductivity in tissue exposed to the pulsed electric field. 
     
     
         10 . The apparatus of  claim 1 , wherein the electrode is configured for placement adjacent renal vasculature. 
     
     
         11 . The apparatus of  claim 10 , wherein the electrode is configured for placement external to the renal vasculature. 
     
     
         12 . The apparatus of  claim 10 , wherein the electrode is configured for placement within the renal vasculature. 
     
     
         13 . The apparatus of  claim 10 , wherein the electrode is configured for placement across a wall of the renal vasculature. 
     
     
         14 . The apparatus of  claim 1  further comprising a feedback mechanism for altering delivery of the pulsed electric field in response to electroporation monitoring data collected with the electrode. 
     
     
         15 . The apparatus of  claim 14 , wherein the feedback mechanism is configured to halt delivery of the pulsed electric field in response to monitoring data indicative of undesirable electroporation. 
     
     
         16 . The apparatus of  claim 14 , wherein the feedback mechanism is configured to vary at least one parameter of the pulsed electric field in response to the monitoring data. 
     
     
         17 . The apparatus of  claim 16 , wherein the parameter is chosen from the group consisting of voltage, field strength, pulse width, pulse duration, pulse shape, pulse interval, duty cycle, number of pulses, and combinations thereof. 
     
     
         18 . The apparatus of  claim 1 , wherein the apparatus is configured to orient a longitudinal portion of the pulsed electric field with a longitudinal dimension of the neural fiber that contributes to renal function. 
     
     
         19 . The apparatus of  claim 1 , wherein the pulsed electric field generator is configured to produce a pulsed electric field that induces irreversible electroporation in the neural fiber that contributes to renal function. 
     
     
         20 . A method for inducing, monitoring and controlling renal neuromodulation, the method comprising:
 positioning at least one electrode proximate to a neural fiber that contributes to renal function of a patient;   delivering a pulsed electric field to modulate the neural fiber; and   monitoring electroporation via the electrode in tissue exposed to the pulsed electric field.   
     
     
         21 . The method of  claim 20 , wherein positioning the electrode further comprises positioning at least one pulsed electric field-delivery electrode and at least one monitoring electrode;
 wherein delivering the pulsed electric field further comprises delivering the pulsed electric field via the pulsed electric field-delivery electrode; and   wherein monitoring electroporation further comprising monitoring electroporation via the monitoring electrode.   
     
     
         22 . The method of  claim 21 , wherein delivering the pulsed electric field further comprises delivering the pulsed electric field across a bipolar electrode pair. 
     
     
         23 . The method of  claim 21 , wherein monitoring electroporation further comprises monitoring electroporation across a pair of monitoring electrodes. 
     
     
         24 . The method of  claim 20 , wherein monitoring electroporation further comprises monitoring electroporation in target tissue exposed to the pulsed electric field. 
     
     
         25 . The method of  claim 20 , wherein monitoring electroporation further comprises monitoring electroporation induced in the neural fiber by the pulsed electric field. 
     
     
         26 . The method of  claim 20 , wherein monitoring electroporation further comprises monitoring electroporation in non-target tissue exposed to the pulsed electric field. 
     
     
         27 . The method of  claim 26 , wherein monitoring electroporation further comprises monitoring wall tissue of renal vasculature. 
     
     
         28 . The method of  claim 20 , wherein monitoring electroporation further comprises monitoring impedance, conductance or conductivity in tissue exposed to the pulsed electric field. 
     
     
         29 . The method of  claim 20 , wherein positioning the electrode proximate to the neural fiber further comprises positioning the electrode adjacent renal vasculature. 
     
     
         30 . The method of  claim 29 , wherein positioning the electrode adjacent renal vasculature further comprises positioning the electrode external to the renal vasculature. 
     
     
         31 . The method of  claim 29 , wherein positioning the electrode adjacent renal vasculature further comprises positioning the electrode within the renal vasculature. 
     
     
         32 . The method of  claim 29 , wherein positioning the electrode adjacent renal vasculature further comprises positioning the electrode across a wall of the renal vasculature. 
     
     
         33 . The method of  claim 20  further comprising altering delivery of the pulsed electric field in response to monitoring data. 
     
     
         34 . The method of  claim 33 , wherein altering delivery of the pulsed electric field further comprises halting delivery of the pulsed electric field in response to monitoring data indicative of undesirable electroporation. 
     
     
         35 . The method of  claim 34 , wherein undesirable electroporation comprises irreversible electroporation of non-target tissue. 
     
     
         36 . The method of  claim 33 , wherein altering delivery of the pulsed electric field further comprises varying at least one parameter of the pulsed electric field in response to the monitoring data. 
     
     
         37 . The method of  claim 20 , wherein delivering the pulsed electric field further comprises orienting the pulsed electric field with a longitudinal dimension of the neural fiber that contributes to renal function. 
     
     
         38 . The method of  claim 20 , wherein delivering the pulsed electric field to modulate the neural fiber further comprises inducing irreversible electroporation in the neural fiber. 
     
     
         39 . The method of  claim 20 , wherein delivering the pulsed electric field to modulate the neural fiber further comprises denervating the neural fiber. 
     
     
         40 . The method of  claim 20  further comprising infusing an agent to protect or repair non-target cells from effects of the pulsed electric field. 
     
     
         41 . The method of  claim 40  wherein infusing the agent further comprises infusing the agent in response to monitoring data indicative of undesirable electroporation of non-target cells. 
     
     
         42 . The method of  claim 20  further comprising infusing an agent to alter the susceptibility of cells to electroporation. 
     
     
         43 . The method of  claim 20  further comprising protecting or repairing non-target cells from effects of the pulsed electric field. 
     
     
         44 . The method of  claim 31  further comprising, prior to delivering the pulsed electric field, monitoring impedance, conductance or conductivity within the vasculature via the electrode in order to determine whether the electrode is positioned in an adequately-sized vessel for delivery of the pulsed electric field. 
     
     
         45 . The method of  claim 31  further comprising monitoring patency of the renal vasculature via the electrode. 
     
     
         46 . The method of  claim 20 , wherein delivering the pulsed electric field via the electrode further comprises multiplexing delivery of the pulsed electric field between a plurality of pulsed electric field-delivery electrodes. 
     
     
         47 . The method of  claim 20 , wherein monitoring electroporation via the electrode further comprises multiplexing monitoring between a plurality of monitoring electrodes. 
     
     
         48 . The method of  claim 20 , wherein monitoring electroporation via the electrode further comprises delivering a low voltage signal across tissue exposed to the pulsed electric field, and monitoring a response of the tissue to the low voltage signal. 
     
     
         49 . The method of  claim 20 , wherein delivering the pulsed electric field and monitoring electroporation further comprises both delivering and monitoring via the at least one electrode. 
     
     
         50 . The apparatus of  claim 1 , wherein the electrode is both electrically coupled to the pulsed electric field generator for delivering a pulsed electric field to the neural fiber while the electrode is located proximate the neural fiber and configured to monitor electroporation in tissue exposed to the pulsed electric field. 
     
     
         51 . Apparatus for inducing, monitoring and controlling renal neuromodulation, the apparatus comprising:
 an electrode configured for placement proximate a neural fiber that contributes to renal function, the at least one electrode configured to deliver a pulsed electric field to the neural fiber and/or to monitor electroporation in tissue exposed to the pulsed electric field; and   a feedback mechanism for altering delivery of the pulsed electric field in response to electroporation monitoring signals sensed by the electrode.   
     
     
         52 . A method for inducing, monitoring and controlling renal neuromodulation, the method comprising:
 positioning at least one electrode proximate to a neural fiber that contributes to renal function of a patient;   delivering a pulsed electric field via the electrode to modulate the neural fiber;   monitoring electroporation in tissue exposed to the pulsed electric field; and   altering delivery of the pulsed electric field in response to monitoring data.