Oriented irreversible electroporation (IRE) pulses to correct cell size and orientation

Abstract

To provide a catheter system for irreversible electroporation.SOLUTION: A system includes an irreversible electroporation (IRE) pulse generator, a switching assembly, and a processor. The IRE pulse generator is configured to generate IRE pulses. The switching assembly is configured to deliver the IRE pulses to multiple electrodes 50 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 50 that 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 50.SELECTED DRAWING: Figure 2

Description

[Technical field]

[0001] The present invention relates generally to invasive medical probes, and more particularly to balloon catheters for irreversible electroporation. [Background technology]

[0002] Delivery of irreversible electroporation (IRE) energy to tissue using multi-electrode catheters has been previously proposed in the patent literature. For example, U.S. Patent No. 9,289,606 describes a catheter system including an orientation-sensing multipolar tip electrode assembly for electroporation-mediated therapy, electroporation-induced primary necrosis therapy, and electric field-induced apoptosis therapy, including configurations for generating narrow linear lesions and distributed widespread lesions.

[0003] As another example, U.S. Patent Application Publication No. 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 configured to deliver electroporation energy to the area of ​​tissue.

[0004] US Patent No. 8,992,517 describes a method, device, and system for the in vivo treatment of cell proliferation disorders. The invention can be used to treat solid tumors, such as brain tumors. The method relies on non-thermal irreversible electroporation (IRE) to cause cell death in the treated tumor. The method involves the use of multiple electrodes and the application of different voltages to 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 the tissue to be treated allows the practitioner to finely tune the three-dimensional shape of the electric field that irreversibly disrupts cell membranes and causes cell death. Similarly, the polarity of the electrodes can be changed to obtain different three-dimensional electric fields. Summary of the Invention [Means for solving the problem]

[0005] 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 an IRE pulse. The switching assembly is configured to deliver the IRE pulse to a plurality of electrodes disposed on an expandable distal end of a catheter placed in contact with the tissue to apply the IRE pulse to tissue of an organ. The processor is configured to (a) receive one or more pre-specified orientations in which an electric field in the tissue will be generated by the IRE pulse, (b) select one or more pairs of electrodes to apply the IRE pulse in the pre-specified orientations, and (c) connect the IRE pulse generator to the selected pairs of electrodes using the switching assembly.

[0006] In some exemplary embodiments, each of the electrodes includes a plurality of electrode segments, and the switching assembly and processor are configured to individually switch between either one or more pairs of the electrode segments.

[0007] In some exemplary embodiments, the electrodes are equiangularly disposed about the longitudinal axis of the distal end.

[0008] In an exemplary embodiment, the processor is configured to select the first and second pairs of electrodes along mutually orthogonal orientations, hi another exemplary embodiment, the one or more pre-specified orientations are pre-specified relative to a longitudinal axis of the distal end.

[0009] In some exemplary embodiments, the processor is configured to apply the IRE pulse by applying a biphasic IRE pulse.

[0010] According to an exemplary embodiment of the present invention, there is additionally provided a method that includes placing a plurality of electrodes of an expandable distal tip of a catheter in contact with tissue of an organ and applying an IRE pulse to the tissue. An irreversible electroporation (IRE) pulse is generated using an IRE pulse generator. One or more pre-specified orientations in which an electric field in the tissue will be generated by the IRE pulse are received. One or more pairs of electrodes are selected that apply the IRE pulse in the pre-specified orientation. The IRE pulse is applied to the tissue in the pre-specified orientation by connecting the IRE pulse generator to the selected pairs of electrodes.

[0011] According to an exemplary embodiment of the present invention, there is further provided a system including an irreversible electroporation (IRE) pulse generator, a switching assembly, and a processor. The IRE pulse generator is configured to generate an IRE pulse. The switching assembly is configured to deliver the IRE pulse to a plurality of electrodes disposed on an expandable distal end of a catheter placed in contact with the tissue to apply the IRE pulse to tissue of the organ. The processor is configured to select a first pair and a second pair of electrodes that apply the IRE pulse to the same region of the tissue in two orientations that are not parallel to each other, and connect the IRE pulse generator to the selected first pair and second pair of electrodes using the switching assembly. [Brief description of the drawings]

[0012] The invention will be more fully understood from consideration of the following detailed description taken in conjunction with the drawings, in which: [Figure 1] 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. [Diagram 2] 2 is a schematic side depiction of the irreversible electroporation (IRE) balloon catheter of FIG. 1 deployed in the region of a pulmonary vein (PV) and its ostium, in accordance with an exemplary embodiment of the present invention. [Diagram 3] FIG. 3 is a flow diagram that illustrates a schematic of 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 THE PREFERRED EMBODIMENTS

[0013] Overview Irreversible electroporation (IRE), also called Pulsed Field Ablation (PFA), can be used as an invasive treatment modality to kill tissue cells by exposing them to high voltage pulses. IRE can be associated with DC pulses or monophasic pulses, and when IRE ablation is called PFA (Pulsed Field Ablation), biphasic IRE pulses are used. However, the term IRE can be used to refer to any type of the above-mentioned pulse shapes.

[0014] Specifically, IRE pulses have potential applications in killing myocardial tissue cells to treat cardiac arrhythmias. Of particular note is the use of bipolar electrical pulses (e.g., using a pair of electrodes in contact with tissue) to kill tissue cells between the electrodes. Cell destruction occurs when the transmembrane potential exceeds a threshold, resulting in cell death and thus the development of tissue damage.

[0015] Cardiac muscle tissue contains specialized cardiomyocytes that conduct electrophysiological signals. For example, the sinus node, a collection of these specialized cardiomyocytes, initiates the heartbeat. Each cardiomyocyte is typically long and thin. Cardiac tissue contains multiple cardiomyocytes that are aggregated into so-called myofibers of conductive tissue. The spatial alignment of the myofibers of conductive tissue (i.e., the orientation of the cardiomyocytes) depends heavily on their location within the heart.

[0016] Cell death is triggered by an applied electric field, and different cells respond differently to different field levels, i.e., have different thresholds for killing. In addition, the way in which non-spherical cells respond to an applied electric field depends on the geometric orientation of the cell relative to the electric field. Cardiomyocytes have a relatively large elliptical eccentricity, approximately 100 µm long and 10-25 µm in diameter. Thus, while IRE can be used to kill cardiomyocytes, the non-spherical cell shape of the cells means that knowledge of the cell orientation is required to set the optimal lethal electric field.

[0017] Exemplary embodiments of the invention described below use a catheter with multiple electrodes that can be selected to generate different electric fields (in magnitude and direction). To overcome not knowing the orientation of the cardiomyocytes near the electrodes, in some exemplary embodiments, the electric field is applied in at least two different orientations, typically perpendicular to each other. This reduces the required pulse voltage amplitude, as high pulse voltages would otherwise be required to overcome the "worst case" scenario of electric field cell alignment along the elongated direction of the cells. If the orientation of the cardiomyocytes is known (typically by other means), the configuration of the electrodes used to generate the killing electric field can be optimized.

[0018] In some exemplary embodiments, a medical probe having an expandable frame on which multiple electrodes are disposed, such as a balloon catheter or basket catheter, is used to apply high voltage pulses along two approximately orthogonal directions at multiple locations on the expandable frame, as described below. To enable application of a directional electric field, the multiple electrodes are connected to the output of an IRE pulse generator via a processor-controlled switching box (also called a switching assembly).

[0019] As used herein, the term "about" or "approximately" in relation to any numerical value or range is intended to indicate a suitable tolerance that enables a portion or collection of components to function for the intended purpose described herein. More specifically, "about" or "approximately" may refer to a range of values ​​of ±20% of the recited value, e.g., "about 90%" may refer to a range of values ​​of 71% to 99%.

[0020] In one embodiment, prior to application of a bipolar IRE pulse by a plurality of electrode pairs, the processor receives one or more pre-specified orientations (e.g., relative to the longitudinal axis of the distal end) along which an electric field in tissue will be generated by the IRE pulse. In response, the processor determines a configuration of electrode pairs on the expandable frame. The processor then controls a switching box to connect the electrodes according to the determined configuration, i.e., to connect the electrodes to an IRE pulse generator, and applies an IRE pulse between the electrodes along the one or more pre-specified orientations.

[0021] For example, if it is known that the muscle fibers of the tissue of the lumen of a blood vessel are aligned longitudinally (i.e., along the lumen) all around the luminal wall tissue, the electrode pairs are configured to generate a localized transverse electric field between each electrode pair.

[0022] By applying IRE pulses of an electric field along orthogonal orientations or along a pre-specified direction, the disclosed catheter-based IRE treatment techniques may increase tissue selectivity for treatment and thus improve clinical outcomes of invasive IRE treatments, such as IRE treatment of cardiac arrhythmias.

[0023] System Description 1 is a schematic, pictorial diagram of a catheter-based irreversible electroporation (IRE) system 20, in accordance with an exemplary embodiment of the invention. System 20 includes a catheter 21, the shaft 22 of which is inserted through a sheath 23 into a heart 26 of a patient 28. The proximal end of catheter 21 is connected to a console 24.

[0024] Console 24 includes an IRE generator 38 configured to generate an IRE pulse that is delivered via catheter 21 to ablate tissue within left atrium 45 of heart 26. For example, the IRE pulse may be a biphasic pulse formed as a positive pulse section (e.g., +1000V) followed by a negative pulse section (e.g., −1000V).

[0025] In the exemplary embodiments described herein, the catheter 21 may be used for any suitable therapeutic and / or diagnostic purpose, such as electrical sensing and / or IRE isolation of tissue at the ostium 51 of the pulmonary vein in the left atrium 45 of the heart 26.

[0026] Physician 30 inserts shaft 22 through the vascular system of patient 28. As seen in inset 25, an expandable balloon catheter 40 attached to distal end 22a of shaft 22 includes a plurality of IRE electrodes 50, further described in FIG. 2. During 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 path to the target location. Physician 30 navigates the distal end of shaft 22 to the target location within heart 26.

[0027] Once the distal end 22a of shaft 22 reaches the target location, physician 30 retracts sheath 23 and expands balloon 40, typically by pumping saline into balloon 40. Physician 30 then manipulates shaft 22 so that electrode 55 disposed on balloon catheter 40 engages the inner wall of the ostium and applies a directional high-voltage IRE pulse to tissue at ostium 51 via electrode 50. To apply the directional IRE pulse, electrode 50 is divided into segments 55 to form a primarily two-dimensional array of electrode segments around each location on balloon 40, as further described in FIG.

[0028] The console 24 includes a switching box 46 (also called a switching assembly) that can switch any segment 55 of the segmented electrode 50 between acting as part of a pair of electrode segments that apply an electric field in a given direction or in a direction approximately perpendicular to a given direction, as described below.

[0029] The electrodes 50 are connected by wires through shaft 22 to a processor 41 that controls a switching box 46 of interface circuitry 37 in console 24. A directional IRE protocol, including IRE parameters such as electrode segment pair configuration, is stored in memory 48 of console 24.

[0030] Console 24 comprises a processor 41, typically a general purpose computer, with suitable front end and interface circuitry 37 for receiving signals from catheter 21 and external electrodes 49, which are typically positioned around the chest of patient 28. To this end, processor 41 is connected to external electrodes 49 by wires running through cable 39.

[0031] The processor 41 is typically programmed (is software) to carry out the functions described herein. The software may be downloaded to the computer in electronic form, for example over a network, or alternatively or additionally may be provided and / or stored on a non-transitory tangible medium, such as a magnetic, optical, or electronic memory.

[0032] Although the illustrated exemplary embodiment relates specifically to the use of a balloon for IRE of cardiac tissue, the elements and methods of system 20 described herein may alternatively be applied to control ablation using other types of multi-electrode ablation devices, such as a basket catheter carrying multiple electrodes on the back of an expandable frame.

[0033] Oriented IRE pulses to correct for cell size and orientation 2 is a schematic side-view depiction of the irreversible electroporation (IRE) balloon catheter 40 of FIG. 1 deployed in the 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 tissue at the ostium 51 to isolate the source of the arrhythmia. The balloon 40 includes ten segmented electrodes 50 (501...50) disposed on the membrane 71 of the balloon. 10 ).

[0034] A bipolar IRE pulse can be delivered independently from the IRE generator 38 to each pair of segments 55 (551...554) of each of the ten electrodes 50, either between segments of the same electrode or between segments of adjacent electrodes. When a bipolar IRE pulse is applied between segments of the same electrode 50, it creates an electric field that is generally parallel to the longitudinal axis 61 defined by the distal end 22a of the shaft 22. For example, the electrodes 50 10 The bipolar pulse applied between segments 552 and 553 of electrode 501 and between segments 552 and 553 of electrode 502 creates an electric field Ex 60. Both of these electric fields are parallel to the longitudinal axis 61.

[0035] When a bipolar IRE pulse is applied between corresponding segments 55 of adjacent electrodes 50, the bipolar IRE pulse creates an electric field that is approximately parallel to the azimuthal axis or locally the transverse axis y. 10 A bipolar pulse is applied between the segment 552 of electrode 501 and the segment 552 of electrode 50 10 A bipolar pulse applied between segment 553 of electrode 501 and segment 553 of electrode 502 creates an electric field E y 62. Both of these fields are perpendicular to the longitudinal axis 61.

[0036] In some exemplary embodiments, the segments are connected using switching box 46 to create orthogonal fields inclined relative to longitudinal axis 61. For example, electrodes 50 10 A bipolar pulse applied between segment 552 of electrode 501 and segment 554 of electrode 501 is applied between segment 552 of electrode 501 and segment 554 of electrode 50 10 This creates an electric field 63 that is approximately orthogonal to the electric field 65 produced by the bipolar pulse applied between segments 554 of the axial segment 552, the two fields being rotated approximately (+45) degrees and (-45) degrees, respectively, relative to the longitudinal axis 61.

[0037] In the exemplary embodiment shown in FIG. 2, the balloon catheter comprises 40 segments 55 (4 per electrode), although the number and shape of the segments may vary.

[0038] Processor 41 controls switching box 46 to connect segment pairs according to a pre-specified configuration that applies, for example, to an IRE balloon treatment protocol for a given cardiac tissue.

[0039] Figure 3 is a flow diagram that illustrates a schematic of a method for applying directional IRE pulses using the balloon of Figure 2, according to an exemplary embodiment of the present invention. The algorithm according to the presented exemplary embodiment executes a process that begins in balloon catheter navigation step 80 when the physician 30 navigates the balloon catheter to a target tissue location in a patient's organ, such as the ostium 51, using, for example, electrode 50 as an ACL sensing electrode.

[0040] Next, in a balloon catheter placement step 82, physician 30 places a balloon catheter at the ostium 51. Next, in a balloon inflation step 84, physician 30 fully inflates balloon 40 to contact the target tissue with electrodes 50 around the entire circumference of the lumen.

[0041] Next, in an IRE planning step 86, the processor 41 receives one or more pre-specified orientations (e.g., relative to the longitudinal axis of the distal end) in which the IRE pulses will generate electric fields in tissue. For example, the initial orientations may be received from a protocol and adjusted by a position tracking system before being received by the processor. The pre-specified orientations may be different for different regions around the ostium 51.

[0042] Based on the required orientation, processor 41 determines the electrode connection configuration, an example of which is illustrated in FIG. 2, in an electrode configuration setup step 88 .

[0043] Next, in an electrode connection step 90, the processor 41 controls the switching box 46 to connect the electrodes according to the determined configuration.

[0044] Finally, in an IRE treatment step 92, processor 41 applies a directional IRE pulse to the tissue.

[0045] The flow diagram of FIG. 3 is an exemplary flow shown purely for clarity. In alternative embodiments, any other suitable method flow may be used. For example, the method of FIG. 2 assumes that the orientation of the cardiomyocytes is known, i.e., there is sufficient information to specify the orientation of the IRE pulses in step 86. In alternative exemplary embodiments, for example, in the absence of sufficient information regarding the orientation of the cardiomyocytes, processor 41 may control switching box 46 to apply IRE pulses in multiple (typically two) different orientations to the same region of tissue. For example, processor 41 may control switching box 46 to apply IRE pulses with orthogonal orientations, e.g., ... 10 One bipolar pulse between segment 552 of electrode 501 and segment 554 of electrode 501, and one bipolar pulse between segment 552 of electrode 501 and segment 554 of electrode 50 10 Another bipolar pulse may be applied between the first and second segments 554. Any other suitable configuration may also be applied.

[0046] Although the exemplary embodiments described herein primarily address cardiac applications, the methods and systems described herein can also be used in other medical applications, such as for treating various types of cancer, e.g., lung or liver cancer, and in neurology and otorhinolaryngology.

[0047] Therefore, it will be understood that the above-mentioned embodiments are cited by way of example, and the present invention is not limited to what has been particularly shown and described above. Rather, the scope of the present invention includes both combinations and subcombinations of the various features described in the above specification, as well as variations and modifications thereof not disclosed in the prior art that would occur to one skilled in the art upon reading the foregoing description. Documents incorporated by reference into this patent application shall be considered as an integral part of this application, but to the extent that any term is defined in these incorporated documents in a manner that is inconsistent with the definition expressly or impliedly made herein, only the definition in this specification shall be considered.

[0048] [Embodiment] (1) A system for irreversible electroporation, comprising: an irreversible electroporation (IRE) pulse generator configured to generate IRE pulses; a switching assembly configured to deliver the IRE pulses to a plurality of electrodes disposed on an expandable distal end of a catheter positioned in contact with tissue of an organ to apply the IRE pulses to the tissue; 1. A processor comprising: receiving one or more pre-specified orientations at which an electric field in the tissue will be generated by the IRE pulse; selecting one or more pairs of the electrodes to which to apply the IRE pulse in the prespecified orientation; and a processor configured to connect the IRE pulse generator to the selected pair of electrodes using the switching assembly. (2) The system of embodiment 1, wherein each of the electrodes comprises a plurality of electrode segments, and the switching assembly and the processor are configured to individually include any of the electrode segments of the one or more pairs. (3) The system of embodiment 1, wherein the electrodes are equiangularly arranged around the longitudinal axis of the distal end. (4) The system of embodiment 1, wherein the processor is configured to select the first and second pairs of electrodes along mutually orthogonal orientations. (5) The system of embodiment 1, wherein the one or more pre-specified orientations are pre-specified relative to a longitudinal axis of the distal end.

[0049] (6) The system of embodiment 1, wherein the processor is configured to apply the IRE pulse by applying a biphasic IRE pulse. (7) A method for irreversible electroporation, comprising: placing a plurality of electrodes at the expandable distal end of the catheter in contact with tissue of the organ to apply an IRE pulse to the tissue; generating an irreversible electroporation (IRE) pulse using an IRE pulse generator; receiving one or more pre-specified orientations in which an electric field in tissue will be generated by said IRE pulse; selecting one or more pairs of the electrodes to which the IRE pulse is applied in the pre-specified orientation; applying the IRE pulse to the tissue in the pre-specified orientation by connecting the IRE pulse generator to the selected pair of electrodes. (8) The method of embodiment 7, wherein each of the electrodes comprises a plurality of electrode segments, and selecting the pair includes individually selecting any of the electrode segments of the one or more pairs. (9) The method of embodiment 7, wherein the electrodes are equiangularly disposed about the longitudinal axis of the distal end. (10) The method of embodiment 7, wherein selecting the pairs includes selecting the first pair and the second pair of electrodes along mutually orthogonal orientations.

[0050] (11) The method of embodiment 7, wherein applying the IRE pulse comprises applying a biphasic IRE pulse. (12) A system for irreversible electroporation, comprising: an irreversible electroporation (IRE) pulse generator configured to generate an IRE pulse; a switching assembly configured to deliver the IRE pulses to a plurality of electrodes disposed on an expandable distal end of a catheter positioned in contact with tissue of an organ to apply the IRE pulses to the tissue; 1. A processor comprising: selecting the first and second pairs of electrodes that apply the IRE pulses to the same region of tissue in two non-parallel orientations; and a processor configured to connect the IRE pulse generator to selected first and second pairs of electrodes using the switching assembly. (13) The system of embodiment 12, wherein the processor is configured to select the first pair and the second pair of electrodes along approximately mutually orthogonal orientations.

Claims

1. 1. A system for irreversible electroporation, comprising: a balloon catheter having an expandable distal end; a plurality of electrodes disposed on the expandable distal end along a length of the balloon catheter, each of the plurality of electrodes having a plurality of electrode segments; an irreversible electroporation (IRE) pulse generator configured to generate pulses for IRE; a switching assembly configured to deliver the pulses to the plurality of electrode segments disposed on the expandable distal end of the balloon catheter positioned in contact with tissue to apply an electric field to the tissue between pairs of electrode segments based on delivery of the pulses, each of the pairs of electrode segments being included in adjacent ones of the plurality of electrodes; 1. A processor comprising: receiving a first orientation and a second orientation of an electric field generated in the tissue by the pulse; selecting first and second pairs of electrode segments to generate the electric field in the first and second orientations; and a processor configured to connect the IRE pulse generator to selected of the first and second pairs of electrode segments using the switching assembly; the first orientation and the second orientation are defined to intersect with each other; The system, wherein the electric field is generated across the same region of the tissue in each of the first orientation and the second orientation.

2. The system of claim 1 , wherein the switching assembly is configured to individually include any of the electrode segments.

3. The system of claim 1 , wherein the electrodes are equiangularly disposed about a longitudinal axis of the distal end.

4. The system of claim 1 , wherein the processor is configured to select the first and second pairs of electrodes along mutually orthogonal orientations.

5. The system of claim 1 , wherein the first orientation and the second orientation are pre-specified relative to a longitudinal axis of the distal end.

6. The system of claim 1 , wherein the processor is configured to apply the pulse by applying a biphasic pulse.

Images