Patent Publication Number: US-2021169568-A1

Title: Oriented irreversible-electroporation (ire) pulses to compensate for cell size and orientation

Description:
FIELD OF THE INVENTION 
     The present invention relates generally to invasive medical probes, and particularly to balloon catheters for irreversible electroporation. 
     BACKGROUND OF THE INVENTION 
     Delivery of irreversible electroporation (IRE) energy to tissue using multi-electrode catheters was previously proposed in the patent literature. For example, U.S. Pat. No. 9,289,606 describes catheter systems that include direction-sensitive, multi-polar tip electrode assemblies for electroporation-mediated therapy, electroporation-induced primary necrosis therapy and electric field-induced apoptosis therapy, including configurations for producing narrow, linear lesions as well as distributed, wide area lesions. 
     As another example, U.S. Patent Application Publication 2019/0030328 describes a medical device configured to electroporate an area of tissue, the medical device including a balloon having a distal portion and a proximal portion, and a plurality of electrodes disposed on the distal portion of the balloon, each of the plurality of electrodes being configured to deliver electroporation energy to the area of tissue. 
     U.S. Pat. No. 8,992,517 describes methods, devices, and systems for in vivo treatment of cell proliferative disorders. The invention can be used to treat solid tumors, such as brain tumors. The methods rely on non-thermal irreversible electroporation (IRE) to cause cell death in treated tumors. The method encompasses the use of multiple electrodes and different voltages applied for each electrode to precisely control the three-dimensional shape of the electric field for tissue ablation. More specifically, it has been found that varying the amount of electrical energy emitted by different electrodes placed in a tissue to be treated allows the practitioner to finely tune the three-dimensional shape of the electrical field that irreversibly disrupts cell membranes, causing cell death. Likewise, the polarity of electrodes can be varied to achieve different three-dimensional electrical fields. 
     SUMMARY OF THE INVENTION 
     An exemplary embodiment of the present invention provides a system including an irreversible electroporation (IRE) pulse generator, a switching assembly, and a processor. The IRE pulse generator is configured to generate IRE pluses. The switching assembly is configured to deliver the IRE pulses to multiple electrodes that are disposed on an expandable distal end of a catheter that is placed in contact with tissue in an organ, for applying the IRE pulses to the tissue. The processor is configured to (a) receive one or more prespecified orientations along which electric fields in the tissue are to be generated by the IRE pulses, (b) select one or more pairs of the electrodes that would apply the IRE pulses at the prespecified orientations, and (c) connect the IRE pulse generator, using the switching assembly, to the selected pairs of the electrodes. 
     In some exemplary embodiments, each of the electrodes includes a plurality of electrode segments, and wherein the switching assembly and the processor are configured to individually include any of the electrode segments in the one or more pairs. 
     In some exemplary embodiments, the electrodes are disposed equiangularly about a longitudinal axis of the distal end. 
     In an exemplary embodiment, the processor is configured to select first and second pairs of the electrodes along mutually orthogonal orientations. In another exemplary embodiment, the one or more prespecified orientations are prespecified relative to a longitudinal axis of the distal end. 
     In some exemplary embodiments, the processor is configured to apply the IRE pulses by applying bi-phasic IRE pulses. 
     There is additionally provided, in accordance with an exemplary embodiment of the present invention, a method including placing multiple electrodes of an expandable distal end of a catheter in contact with a tissue in an organ for applying IRE pulses to tissue. Irreversible electroporation (IRE) pluses are generated using an IRE pulse generator. One or more prespecified orientations are received along which electric fields in tissue are to be generated by the IRE pulses. One or more pairs of the electrodes are selected that would apply the IRE pulses at the prespecified orientations. The IRE pulses are applied to the tissue at the prespecified orientations, by connecting the IRE pulse generator to the selected pairs of the electrodes. 
     There is further provided, in accordance with an exemplary embodiment of the present invention, a system including an irreversible electroporation (IRE) pulse generator, a switching assembly, and a processor. The IRE pulse generator is configured to generate IRE pluses. The switching assembly is configured to deliver the IRE pulses to multiple electrodes that are disposed on an expandable distal end of a catheter that is placed in contact with tissue in an organ, for applying the IRE pulses to the tissue. The processor is configured to select first and second pairs of the electrodes that would apply the IRE pulses to a same region of tissue at two orientations which are not parallel to each other, and connect the IRE pulse generator, using the switching assembly, to the selected first and second pairs of the electrodes. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       The present invention will be more fully understood from the following detailed description of the embodiments thereof, taken together with the drawings in which: 
         FIG. 1  is a schematic, pictorial illustration of a catheter-based irreversible electroporation (IRE) system, in accordance with an exemplary embodiment of the present invention; 
         FIG. 2  is a schematic, pictorial side view of the irreversible electroporation (IRE) balloon catheter of  FIG. 1  deployed in a region of a pulmonary vein (PV) and its ostium, in accordance with an exemplary embodiment of the invention; and 
         FIG. 3  is a flow chart that schematically illustrates a method for applying directional IRE pulses using the IRE balloon catheter of  FIG. 2 , in accordance with an exemplary embodiment of the present invention. 
     
    
    
     DETAILED DESCRIPTION OF EMBODIMENTS 
     Overview 
     Irreversible electroporation (IRE), also called Pulsed Field Ablation (PFA), may be used as an invasive therapeutic modality to kill tissue cells by subjecting them to high-voltage pulses. IRE may be associated with DC pulses or mono-phasic pulses, where when IRE ablation is referred to as PFA (Pulsed Field Ablation), bi-phasic IRE pulses are used. However, the term IRE may be used to refer to any type of the above-mentioned pulse shapes. 
     Specifically, IRE pulses have a potential use to kill myocardium tissue cells in order to treat cardiac arrhythmia. Of particular interest is the use of bipolar electric pulses (e.g., using a pair of electrodes in contact with tissue) to kill tissue cells between the electrodes. Cellular destruction occurs when the transmembrane potential exceeds a threshold, leading to cell death and thus the development of a tissue lesion. 
     Myocardium tissue includes specialized myocardial cells that conduct electrophysiological signals. For example, a collection of these specialized myocardial cells, the sinus node, initiates the heartbeat. Each myocardial cell is typically long and thin. Cardiac tissue comprises multiple myocardial cells that are aggregated into so-called myofibers of conduction tissue. The alignment in space of the myofibers of conduction tissue (i.e., the orientation of the myocardial cells) largely depends on their location in the heart. 
     Cell death is caused by the applied electrical field, and different cells react differently to different field levels, i.e., have different thresholds for being killed. In addition, the way a non-spherical cell responds to the applied electrical field depends on the geometrical orientation of the cell with respect to the field. Myocardial cells have relatively large ellipsoidal eccentricity, being about 100 μm long and 10-25 μm in diameter. Therefore, while IRE may be used to kill myocardial cells, the non-spherical cell shape of cells means that knowledge of the cell orientation is needed for setting an optimal lethal electric field. 
     Exemplary embodiments of the present invention that are described hereinafter use a catheter with multiple electrodes which may be selected to generate different electric fields (in magnitude and direction). To overcome not knowing the myocardial cell orientation in the vicinity of the electrodes, in some exemplary embodiments the electric field is applied in at least two different orientations, typically orthogonal to each other. This reduces the pulse voltage amplitude needed, since otherwise, a high pulse voltage is needed to overcome a “worst case” scenario of a field-cell alignment along the elongated direction of cells. If the myocardial cell orientation is known (typically, by other means) the configuration of the electrodes used to generate the killing electrical field may be optimized. 
     In some exemplary embodiments, a medical probe having an expandable frame disposed with a plurality of electrodes, such as balloon catheter or a basket catheter, is used to apply the high voltage pulses along two approximately orthogonal orientations in multiple locations over the expandable frame, as described below. To enable the application of the directional electric fields, the plurality of electrodes is connected to an output of an IRE pulse generator via a processor-controlled switching box (also referred to as switching assembly). 
     As used herein, the terms “about” or “approximately” for any numerical values or ranges indicate a suitable dimensional tolerance that allows the part or collection of components to function for its intended purpose as described herein. More specifically, “about” or “approximately” may refer to the range of values ±20 percent of the recited value, e.g. “about 90 percent” may refer to the range of values from 71 percent to 99 percent. 
     In an embodiment, before application of bipolar IRE pulses by multiple pairs of electrodes, the processor receives one or more prespecified orientations (e.g., relative to the longitudinal axis of the distal end) along which electric fields in tissue should be generated by the IRE pulses. The processor accordingly determines a configuration of electrode pairs over the expandable frame. Then the processor controls the switching box to connect the electrodes according to the determined configuration, i.e., to connect the electrodes to the IRE pulse generator to apply the IRE pulses between the electrodes along the one or more prespecified orientations. 
     For example, if the myofibers of a tissue of a lumen of a vessel is known to be aligned longitudinally (i.e., along the lumen) over an entire perimeter of the wall tissue of the lumen, then the electrode pairs are configured to generate a locally transverse electric field between each electrode pair. 
     By applying IRE pulses of an electrical field along orthogonal orientations or along a prespecified direction, the disclosed catheter-based IRE treatment techniques increase tissue selectivity to treatment, and thus may improve the clinical outcome of invasive IRE treatments, such as of an IRE treatment of cardiac arrhythmia. 
     System Description 
       FIG. 1  is a schematic, pictorial illustration of a catheter-based irreversible electroporation (IRE) system  20 , in accordance with an exemplary embodiment of the present invention. System  20  comprises a catheter  21 , wherein a shaft  22  of the catheter is inserted into a heart  26  of a patient  28  through a sheath  23 . The proximal end of catheter  21  is connected to a console  24 . 
     Console  24  comprises an IRE generator  38  configured to generate IRE pulses. The IRE pulses are delivered via catheter  21  to ablate tissue in a left atrium  45  of heart  26 . For example, the IRE pulses may be bi-phasic pulses shaped as a positive pulse section (e.g., of +1000V) followed by a negative pulse section (e.g., of −1000V). 
     In the exemplary embodiment described herein, catheter may be used for any suitable therapeutic and/or diagnostic purpose, such as electrical sensing and/or IRE isolation of ostium  51  tissue of a pulmonary vein in left atrium  45  of heart  26 . 
     A physician  30  inserts shaft  22  through the vascular system of patient  28 . As seen in inset  25 , an expandable balloon catheter  40 , fitted at a distal end  22   a  of shaft  22 , comprises multiple IRE electrodes  50 , further described in  FIG. 2 . During the insertion of shaft  22 , balloon  40  is maintained in a collapsed configuration inside sheath  23 . By containing balloon  40  in a collapsed configuration, sheath  23  also serves to minimize vascular trauma along the way to target location. Physician  30  navigates the distal end of shaft  22  to a target location in the heart  26 . 
     Once distal end  22   a  of shaft  22  has reached the target location, physician  30  retracts sheath  23  and expands balloon  40 , typically by pumping saline into the balloon  40 . Physician  30  then manipulates shaft  22  such that electrodes  55  disposed on balloon catheter  40  engage an interior wall of the ostium to apply directional high-voltage IRE pulses via electrodes  50  to ostium  51  tissue. To apply directional IRE pulses, electrodes  50  are divided into segments  55 , so as to form a largely two-dimensional array of electrode segments about each location over balloon  40 , as further described in  FIG. 2 . 
     Console  24  includes a switching box  46  (also referred to as a switching assembly) that can switch any segment  55  of a segmented electrode  50  between acting as part of a pair of electrode segments that applies an electric field in a given direction or in an approximately orthogonal direction to the given direction, as described below. 
     Electrodes  50  are connected by wires running through shaft  22  to processor  41  controlling switching box  46  of interface circuits  37  in the console  24 . Directional IRE protocols comprising IRE parameters such as electrode segment pair configurations are stored in a memory  48  of the console  24 . 
     Console  24  comprises a processor  41 , typically a general-purpose computer, with suitable front end and interface circuits  37  for receiving signals from catheter  21  and from external electrodes  49 , which are typically placed around the chest of patient  28 . For this purpose, processor  41  is connected to external electrodes  49  by wires running through a cable  39 . 
     Processor  41  is typically programmed (software) to carry out the functions described herein. The software may be downloaded to the computer in electronic form, over a network, for example, or it may, alternatively or additionally, be provided and/or stored on non-transitory tangible media, such as magnetic, optical, or electronic memory. 
     Although the illustrated exemplary embodiment relates specifically to the use of a balloon for IRE of heart tissue, the elements of system  20  and the methods described herein may alternatively be applied to control ablation using other sorts of multi-electrode ablation devices, such as a basket catheter that carries multiple electrodes on spines of an expandable frame. 
     Oriented IRE Pulses to Compensate for Cell Size and Orientation 
       FIG. 2  is a schematic, pictorial side view of the irreversible electroporation (IRE) balloon catheter  40  of  FIG. 1  deployed in a region of a pulmonary vein (PV) and its ostium  51 , in accordance with an exemplary embodiment of the present invention. The balloon catheter  40  is used to ablate ostium  51  tissue to isolate a source of arrhythmia. Balloon  40  has ten segmented electrodes  50  ( 50   1  . . .  50   10 ) disposed over a membrane  71  of the balloon. 
     Bipolar IRE pulses can be delivered from IRE generator  38  independently to each pair of segments  55  ( 55   1  . . .  55   4 ) of each of the ten electrodes  50 , either between segments of the same electrode or between segments of neighboring electrodes. When the bipolar IRE pulse is applied between segments of a same electrode  50 , it creates an electric field approximately parallel with a longitudinal axis  61 , defined by distal end  22   a  of shaft  22 . For example, a bipolar pulse applied between segments  55   2  and  55   3  of electrode  50   10  and a bipolar pulse applied between segments  55   2  and  55   3  of electrode  50   1 , generate electrical fields E.  60  at different tissue locations in contact with balloon  40  over a perimeter of balloon  40 . Both these fields are parallel to longitudinal axis  61 . 
     When the bipolar IRE pulse is applied between corresponding segments  55  of neighboring electrodes  50  it creates an electric field approximately parallel with an azimuthal axis, or a locally transverse axis, y. For example, a bipolar pulse applied between segment  55   2  of electrode  50   10  and segment  55   2  of electrode  50   1 , and a bipolar pulse applied between segment  55   3  of electrode  50   10  and segment  55   3  of electrode  50   1 , generate electrical fields E y    62  at different tissue locations in contact with balloon  40  over a perimeter of balloon  40 . Both these fields are orthogonal to longitudinal axis  61 . 
     In some exemplary embodiments the segments are connected, using switching box  46 , to create orthogonal fields that are tilted relative to longitudinal axis  61 . For example, a bipolar pulse applied between segment  55   2  of electrode  50   10  and segment  55   4  of electrode  50   1  creates an electric field  63  that is approximately orthogonal to an electric field  65  created by a bipolar pulse applied between segment  55   2  of electrode  50   1  and segment  55   4  of electrode  50   10 , with the two fields rotated approximately (+45) degrees and (−45) degrees, respectively, relative to longitudinal axis  61 . 
     In the exemplary embodiment shown in  FIG. 2 , the balloon catheter comprises forty segments  55  (four per electrode), although the number and shape of the segments may differ. 
     Processor  41  controls switching box  46  to connect the segment pairs according, for example, to a prespecified configuration applied in an IRE balloon treatment protocol of a given cardiac tissue. 
       FIG. 3  is a flow chart that schematically illustrates a method for applying directional IRE pulses using the balloon of  FIG. 2 , in accordance with an exemplary embodiment of the present invention. The algorithm, according to the presented exemplary embodiment, carries out a process that begins when physician  30  navigates the balloon catheter to a target tissue location in an organ of a patient, such as at ostium  51 , using, for example, electrode  50  as ACL sensing electrodes, at a balloon catheter navigation step  80 . 
     Next, physician  30  positions the balloon catheter at ostium  51 , at a balloon catheter positioning step  82 . Next, physician  30  fully inflates balloon  40  to contact target tissue with electrodes  50  over an entire circumference of the lumen, at a balloon inflation step  84 . 
     Next, at an IRE planning step  86 , processor  41  receives one or more prespecified orientations (e.g., relative to the longitudinal axis of the distal end) along which the IRE pulses should generate an electric field in the tissue. For example, initial orientations are received from a protocol and are adjusted by the position tracking system before being received in the processor. The prespecified orientations may differ from one region to another around ostium  51 . 
     Based on the required orientations, processor  41  determines an electrode connection configuration, examples of which are described in  FIG. 2 , at an electrode configuration setup step  88 . 
     Next, processor  41  controls switching box  46  to connect the electrodes according to the determined configuration, at an electrode connecting step  90 . 
     Finally, processor  41  applies the directional IRE pulses to tissue, at an IRE treatment step  92 . 
     The flow chart of  FIG. 3  is an exemplary flow that is depicted purely for the sake of clarity. In alternative embodiments, any other suitable method flow may be used. For example, the method of  FIG. 2  assumes that the orientations of the myocardial cells are known, i.e., that there is sufficient information for specifying the IRE pulse orientations at step  86 . In alternative exemplary embodiments, e.g., in the absence of sufficient information regarding myocardial cell orientations, processor  41  may control switching box  46  to apply IRE pulses at multiple (typically two) different orientation to the same region of tissue. For example, processor  41  may control switching box  46  to apply IRE pulses having orthogonal orientations, e.g., one bipolar pulse between segment  55   2  of electrode  50   10  and segment  55   4  of electrode  50   1 , and another bipolar pulse between segment  55   2  of electrode  50   1  and segment  55   4  of electrode  50   10 . Any other suitable configuration can also be applied. 
     Although the exemplary embodiments described herein mainly address cardiac applications, the methods and systems described herein can also be used in other medical applications, such as to treat different type of cancers, for example lung cancer and liver cancer, and in neurology and otolaryngology. 
     It will thus be appreciated that the embodiments described above are cited by way of example, and that the present invention is not limited to what has been particularly shown and described hereinabove. Rather, the scope of the present invention includes both combinations and sub-combinations of the various features described hereinabove, as well as variations and modifications thereof which would occur to persons skilled in the art upon reading the foregoing description and which are not disclosed in the prior art. Documents incorporated by reference in the present patent application are to be considered an integral part of the application except that to the extent any terms are defined in these incorporated documents in a manner that conflicts with the definitions made explicitly or implicitly in the present specification, only the definitions in the present specification should be considered.