Electroporation systems and methods

Abstract

Disclosed herein is an electroporation system comprising: a catheter shaft, at least one electrode coupled to the catheter shaft at its distal end, and an electroporation generator coupled in communication with the at least one electrode. The electroporation generator is configured to provide a biphasic pulse signal to the at least one electrode. The biphasic pulse signal comprises a first phase having a first polarity and a first pulse duration, and a second phase having a second polarity opposite to the first polarity and a second pulse duration. Each of the first phase and the second phase has a voltage amplitude of at least 500 volts and a pulse duration of less than 20 microseconds. The second phase is generated at a non-zero interval after the first phase.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application Serial No. 62 / 943,000, filed on December 3, 2019, the entire disclosure of which is incorporated herein by reference. Technical Field

[0003] The present disclosure relates generally to medical devices for use in the human body. In particular, the present disclosure relates to electroporation systems and methods of controlling electroporation systems. Background Art

[0004] A variety of therapies are used to treat a variety of conditions that plague the human anatomy. For example, ablation therapy is sometimes used to treat arrhythmias. When tissue is ablated or at least subjected to ablative energy generated by an ablation generator and delivered by an ablation catheter, damage is formed in the tissue. Electrodes mounted on or in the ablation catheter are used to cause tissue necrosis in cardiac tissue to correct conditions such as atrial arrhythmias (including but not limited to ectopic atrial tachycardia, atrial fibrillation, and atrial flutter). Arrhythmias (i.e., irregular heart rhythms) can cause a variety of dangerous conditions, including loss of synchronized atrioventricular contraction and stagnation of blood flow, which can lead to a variety of diseases and even death. It is believed that the main cause of atrial arrhythmias is stray electrical signals in the left or right atrium of the heart. The ablation catheter applies ablation energy (e.g., radiofrequency energy, cryoablation, laser, chemicals, high-intensity focused ultrasound, etc.) to cardiac tissue to produce damage in cardiac tissue. The damage destroys the poor electrical pathways and thereby limits or prevents stray electrical signals that cause arrhythmias.

[0005] A candidate mode for the treatment of arrhythmia is electroporation. Electroporation therapy relates to the formation of holes on the cell membrane induced by an electric field. An electric field can be induced by applying a direct current (DC) signal delivered with a pulse of relatively short duration. Such pulses can be repeated to form a pulse train. When such an electric field is applied to a living tissue, the cells in the tissue are affected by the transmembrane potential, which opens the holes on the cell wall, so it is called electroporation. Electroporation can be reversible (i.e., the temporarily opened hole will reseal) or irreversible (i.e., the hole will remain open). For example, in the field of gene therapy, reversible electroporation (i.e., temporarily opening the hole) is used to transfect high molecular weight therapeutic vectors into cells. In other therapeutic applications, a pulse sequence of appropriate configuration can be used alone to cause cell destruction, for example, by causing irreversible electroporation (IRE). Summary of the invention

[0006] The present disclosure relates to an electroporation system, which includes: a catheter shaft, at least one electrode coupled to the catheter shaft at its distal end, and an electroporation generator coupled to the at least one electrode. The electroporation generator is configured to provide a biphasic pulse signal to the at least one electrode. The biphasic pulse signal includes a first phase having a first polarity and a first pulse duration, and a second phase having a second polarity opposite to the first polarity and a second pulse duration. Each of the first phase and the second phase has a voltage amplitude of at least 500 volts and a pulse duration of less than 20 microseconds. The second phase is generated at a non-zero interval after the first phase.

[0007] The present disclosure further relates to a method, which includes providing a first phase of a biphasic pulse signal to at least one electrode coupled at the distal end of a catheter shaft by an electroporation generator. The first phase has a first polarity and a first pulse duration. The method further includes providing a second phase of the biphasic pulse signal to at least one electrode. The second phase has a second polarity opposite to the first polarity and a second pulse duration. Each of the first phase and the second phase has a voltage amplitude of at least 500 volts and a pulse duration of less than 20 microseconds. The second phase is generated at a non-zero interval after the first phase.

[0008] The present disclosure further relates to an electroporation generator, the electroporation generator comprising: a positive high voltage direct current (+HVDC) power supply having a first polarity; a negative high voltage direct current (-HVDC) power supply having a second polarity opposite to the first polarity; a plurality of semiconductor switches connected in a bridge configuration, which regulate the application of the +HVDC power supply and the -HVDC power supply to the first and second conductors for the catheter; and a microcontroller, which is communicatively coupled to the plurality of semiconductor switches. The microcontroller is configured to control the commutation of the plurality of semiconductor switches to send a biphasic pulse signal through the first and second conductors for the catheter.

[0009] The present disclosure further relates to a method for generating a pulse signal. The method includes: providing a positive high voltage direct current (+HVDC) power supply having a first polarity to a plurality of semiconductor switches connected in a bridge configuration; providing a negative high voltage direct current (-HVDC) power supply having a second polarity opposite to the first polarity to a plurality of semiconductors; and commutating the plurality of semiconductor switches to apply the +HVDC power supply to a first conductor of a conduit, and applying the -HVDC power supply to a second conductor of the conduit for a first duration. The method further includes: after the first duration, commutating the plurality of semiconductor switches to electrically disconnect the first conductor and the second conductor from the +HVDC power supply and the -HVDC power supply for a second duration; and after the second duration, commutating the plurality of semiconductor switches to apply the +HVDC power supply to the second conductor, and applying the -HVDC power supply to the first conductor for a third duration. The method further includes: after the third duration, commutating the plurality of semiconductor switches to electrically disconnect the first conductor and the second conductor from the +HVDC power supply and the -HVDC power supply. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] Figure 1 is a schematic block diagram of a system for electroporation therapy.

[0011] Figure 2 is shown in the form of an electrode ring assembly suitable for Figure 1 Side view of an exemplary electrode assembly for use in a system.

[0012] Figure 3 yes Figure 2 End view of the electrode ring assembly.

[0013] Figure 4 is shown in the form of a basket electrode assembly suitable for Figure 1 A perspective view of another exemplary electrode assembly for use in a system of FIG.

[0014] Figure 5 is shown in the form of a grid electrode assembly suitable for Figure 1 A perspective view of another exemplary electrode assembly for use in a system of FIG.

[0015] Figure 6 is shown in the form of an expandable electrode assembly suitable for use in Figure 1 Side view of another exemplary electrode assembly for use in a system.

[0016] Figure 7 It shows that Figure 1 Graph of an exemplary pulse signal generated by the electroporation generator of the system.

[0017] Figure 8is a graph showing a pulse train signal including two pulse signals generated at a pulse period.

[0018] Fig. 9 is a graph showing a plurality of pulse train signals generated within a repetitive pulse train period.

[0019] Fig.10 is used for Figure 1 Schematic diagram of an exemplary electroporation generator in the system.

[0020] Fig.11 is to generate Figure 7 Flowchart of an exemplary method of pulse signaling of a pulse signal shown in .

[0021] Corresponding reference numerals indicate corresponding parts throughout the drawings. It should be understood that the drawings are not necessarily drawn to scale. DETAILED DESCRIPTION

[0022] The present disclosure generally relates to medical devices used in the human body. In particular, in many embodiments, the present disclosure relates to electroporation systems and methods for controlling such electroporation systems. The disclosed embodiments can lead to more consistent and improved patient outcomes during electroporation therapy. For example, embodiments of the present disclosure utilize electroporation pulse signals with specific parameters (e.g., voltage amplitude, pulse width or duration, pulse period, and pulse train period) that help reduce or minimize undesirable or unexpected IREs, such as excitation of skeletal muscle and generation of gas in the patient's body. However, it is contemplated that the features and methods of the present disclosure as described herein can be incorporated into any number of systems, as understood by those of ordinary skill in the art based on the disclosure herein.

[0023] Now referring to the accompanying drawings, Figure 1 An exemplary embodiment of a system 10 for electroporation therapy is shown. Typically, various embodiments include an electrode assembly disposed at the distal end of a catheter. As used herein, "proximal" refers to the direction toward an end of the catheter that is close to the clinician, while "distal" refers to the direction away from the clinician and (usually) within the patient's body. The electrode assembly includes one or more separate electrically insulated electrode elements. In some embodiments, each electrode element (also referred to herein as a catheter electrode) is individually wired so that it can be selectively paired or combined with any other electrode element to act as a bipolar or multipolar electrode.

[0024] System 10 can be used for irreversible electroporation (IRE) to destroy tissue. In particular, system 10 can be used for electroporation-induced primary necrosis therapy, which refers to the effect of delivering current in a manner that directly causes irreversible loss of plasma membrane (cell wall) integrity that causes its decomposition and cell necrosis. The mechanism of cell death can be seen as an "outside-in" process, which means that the destruction of the outer wall of the cell will have an adverse effect on the inside of the cell. Typically, for typical plasma membrane electroporation, current is delivered as a pulsed electric field in the form of short-duration direct current (DC) pulses between closely spaced electrodes, and the electrode is capable of delivering an electric field intensity sufficient to cause irreversible electroporation in target cells. As described in more detail herein, compared to at least some existing electroporation systems, system 10 is configured to deliver an electroporation pulse signal with a relatively high voltage and a low pulse duration. The waveform generated by system 10 and applied to the catheter electrode helps to reduce and / or prevent skeletal muscle stimulation during IRE therapy.

[0025] Irreversible electroporation by a multi-electrode cuff catheter can isolate the pulmonary veins with only one electrical shock per vein, resulting in a much shorter procedure time than sequentially placing radiofrequency (RF) ablation tips around the veins. It should be understood that the mechanism of cell destruction in electroporation is not primarily due to heating, but rather to cell membrane disruption caused by the application of a high voltage electric field. Therefore, electroporation can avoid some of the possible thermal effects that may occur when using RF energy. Therefore, this "cold" or "non-thermal" therapy has desirable properties.

[0026] It should be understood that although the energization strategy is described as involving DC pulses, embodiments may use variations of DC pulses and remain within the spirit and scope of the present invention. For example, exponentially decaying pulses, exponentially increasing pulses, and combinations thereof may be used. Furthermore, although the system 10 is described herein with respect to IRE ablation therapy, it should be understood that the system 10 may additionally or alternatively be used for other forms of ablation therapy, including, for example, but not limited to, radiofrequency (RF) ablation.

[0027] The system 10 includes a catheter electrode assembly 12 including at least one catheter electrode configured for use as briefly summarized above and described in more detail below. The electrode assembly 12 is incorporated as part of a medical device such as a catheter 14 for performing electroporation therapy on tissue 16 in a patient's body 17. In the illustrative embodiment, the tissue 16 includes heart or myocardial tissue. However, it should be understood that embodiments may be used to perform electroporation therapy on a variety of other body tissues.

[0028] Figure 1Further shown are multiple return electrodes labeled 18, 20 and 21, which illustrate the body connection used by multiple subsystems that can be included in the overall system 10, such as an electroporation generator 26, an electrophysiology (EP) monitor (such as an ECG monitor 28), a visualization, navigation and / or mapping system 30 for visualizing, mapping and navigating internal body structures. In the illustrated embodiment, the return electrodes 18, 20 and 21 are patch electrodes. It should be understood that the illustration of a single patch electrode is only schematic (for clarity), and such subsystems to which these patch electrodes are connected can and usually will include more than one patch (body surface) electrode. In other embodiments, the return electrodes 18, 20 and 21 can be any other type of electrode suitable for use as a return electrode, including, for example, one or more catheter electrodes. The return electrode as a catheter electrode can be part of the electrode assembly 12, or part of a separate catheter (not shown). In some embodiments, for example, the system 10 includes a bipolar catheter electrode assembly, which includes a plurality of electrode pairs, each of which includes two electrodes, one of which is used as a return electrode.

[0029] The system 10 may further include a host computer system 32 (including an electronic control unit 50 and data storage-memory 52), which in certain embodiments may be integrated with the system 30. The system 32 may further include conventional interface components, such as various user input / output mechanisms 34a and a display 34b, as well as other components.

[0030] In some embodiments, the electroporation generator 26 and / or the computer system 32 may be programmed or otherwise configured to run an algorithm that identifies and / or selects which electrodes or electrode pairs of the electrode assembly 12 are to be energized. That is, the electrodes or electrode pairs of the electrode assembly 12 may be selectively energized based on, for example, the anatomical position of the electrode and / or the contact between the electrode and the tissue 16. For example, the system 10 may include suitable detectors and tissue sensing circuits that identify which electrodes of the electrode assembly 12 have characteristics indicating contact with the tissue 16 (e.g., if it is an electrical characteristic, then, for example, impedance, phase angle, reactance, etc.). The electroporation generator 26 and / or the computer system 32 may then select which electrodes or electrode pairs of the catheter assembly 12 are to be energized based on the electrodes identified as being in contact with the tissue 16. For example, if a basket catheter is inserted into the pulmonary vein sinus, the electroporation generator 26 and / or the computer system 32 may determine which electrode to activate based on contact with the tissue 16 or even a specific anatomical position within the heart. Suitable components and methods for identifying electrodes in contact with tissue are described, for example, in US Pat. No. 9,289,606, the disclosure of which is incorporated herein by reference in its entirety.

[0031] In the illustrative embodiment, the catheter 14 includes a cable connector 40 or interface, a handle 42, and a shaft 44 having a proximal end 46 and a distal end 48. The catheter 14 may also include other conventional components not shown herein, such as a temperature sensor, additional electrodes, and corresponding conductors or wires. The connector 40 provides mechanical and electrical connections for a cable 56 extending from the generator 26. The connector 40 may include conventional components known in the art and, as shown, is disposed at the proximal end of the catheter 14.

[0032] The handle 42 provides a position for the clinician to hold the catheter 14, and can further provide a tool for manipulating or guiding the shaft 44 in the body 17. For example, the handle 42 may include a tool for changing the length of the guidewire extending through the catheter 14 to the distal end 48 of the shaft 44, or a tool for manipulating the shaft 44. In addition, in some embodiments, the handle 42 may be configured to change the shape, size and / or orientation of a portion of the catheter. The handle 42 is also conventional in the art, and it will be understood that the structure of the handle 42 can vary. In an alternative exemplary embodiment, the catheter 14 can be driven or controlled by a robot. Therefore, the robot is used to operate the catheter 14, rather than the clinician operating the handle to advance / retract and / or manipulate or guide the catheter 14 (particularly its shaft 44). The shaft 44 is a slender, tubular, flexible member configured for movement in the body 17. The shaft 44 is configured to support the electrode assembly 12, and contains associated conductors, and possible additional electronic devices for signal processing or conditioning. Axis 44 can also allow for transport, delivery and / or removal of fluids (including flushing fluids and body fluids), drugs and / or surgical tools or instruments. Axis 44 can be made of conventional materials such as polyurethane and define one or more lumens that are configured to accommodate and / or transport electrical conductors, fluids or surgical tools. Axis 44 can be introduced into a blood vessel or other structure in the body 17 by a conventional introducer. Then, axis 44 can be advanced, retracted and / or manipulated or guided through the body 17 to a desired location such as a site of tissue 16, including by using a guide wire or other tools known in the art.

[0033] In some embodiments, catheter 14 is a cuff catheter (e.g., Figure 2 and Figure 34 ), sometimes referred to as a spiral or annular catheter, has catheter electrodes distributed around one or more hoops at the distal end of shaft 44. The diameter of the hoop (sometimes referred to herein as a "ring") can be variable. In some embodiments, the hoop catheter diameter can vary between a minimum diameter and a maximum diameter of about ten millimeters (mm). In some embodiments, when manufacturing catheter 14, the minimum diameter can be selected between about thirteen millimeters and about twenty millimeters. Within the variable range of ten millimeters, such catheters will have a maximum diameter between twenty-three millimeters and thirty millimeters. In other embodiments, the ring diameter varies between about fifteen millimeters and about twenty-eight millimeters, between about thirteen millimeters and about twenty-three millimeters, or between about seventeen millimeters and about twenty-seven millimeters. Alternatively, the catheter can be a fixed diameter hoop catheter, or can vary between different diameters. In some embodiments, catheter 14 has fourteen catheter electrodes (e.g., grouped into seven pairs of catheter electrodes). In other embodiments, catheter 14 includes ten catheter electrodes, twenty catheter electrodes, or any other suitable number of electrodes for performing electroporation. In some embodiments, the catheter electrodes are annular electrodes. Alternatively, the catheter electrode may be any other suitable type of electrode, such as a single-sided electrode or an electrode printed on a flexible material. In various embodiments, the catheter electrode has a length of 1.0 mm, 2.0 mm, 2.5 mm, and / or any other suitable length for electroporation.

[0034] Figure 2 and Figure 3 An exemplary electrode assembly 12 suitable for use in the system 10 is shown in the form of an electrode band or ring assembly 200 . Figure 2 is a side view of an electrode ring assembly 200 having a variable diameter ring 202 coupled at a distal end 302 of a catheter shaft 300 . Figure 3 FIG. 2 is an end view of the variable diameter ring 202 of the electrode ring assembly 200. Figure 2 and Figure 3As shown in , the electrode ring assembly 200 extends from the proximal end 204 to the distal end 206, and includes an outer sleeve 208 formed in a ring shape and a plurality of catheter electrodes 210 mounted on the outer sleeve 208. The proximal end 204 of the electrode ring assembly 200 is coupled to the catheter shaft 300 via a suitable coupler 212. The electrode 210 can be used for a variety of diagnostic and therapeutic purposes, including, for example, but not limited to, cardiac mapping and / or ablation (e.g., IRE ablation). For example, the electrode ring assembly 200 can be configured as a bipolar electrode assembly for bipolar-based electroporation therapy. More specifically, the electrode 210 can be configured as an electrode pair (e.g., a cathode-anode electrode pair) and electrically connected to the electroporation generator 26 (e.g., via a suitable wire or other suitable electrical conductor extending through the catheter shaft 44), so that adjacent electrodes 210 are energized with opposite polarities to generate an electric potential and a corresponding electric field between adjacent electrodes 210. In other embodiments, any combination of electrodes 210 can be configured as an electrode pair (e.g., a cathode-anode electrode pair), including, for example, but not limited to, adjacent electrodes, non-adjacent electrodes, and any other combination of electrodes that enable system 10 to function as described herein. As described above, for example, electroporation generator 26 and / or computer system 32 can selectively energize certain electrodes 210 of electrode ring assembly 200 based on contact between electrode 210 and tissue 16 to form an electrode pair. In other embodiments, electrode ring assembly 200 can be configured as an electrode assembly other than a bipolar electrode assembly, such as a monopolar or monopolar electrode assembly. In such embodiments, electrode 18 can be used as a return electrode.

[0035] In the illustrated embodiment, the variable diameter ring 202 includes fourteen catheter electrodes 210 evenly spaced around the circumference of the variable diameter ring 202. In other embodiments, the variable diameter ring 202 may include any suitable number of catheter electrodes 210 made of any suitable material. Each catheter electrode 210 is separated from each other by an insulating gap 216. In the exemplary embodiment, each catheter electrode 210 has the same length 218 ( Figure 3 216 ), and each insulating gap 216 has the same length 220 as each other gap 216. In an example embodiment, both length 218 and length 220 are about 2.5 mm. In other embodiments, length 218 and length 220 may be different from each other. Furthermore, in some embodiments, catheter electrodes 210 may not all have the same length 218, and / or insulating gaps 216 may not all have the same length 220. In some embodiments, catheter electrodes 210 are not evenly spaced around the circumference of variable diameter ring 202.

[0036] Figure 44 is a perspective view of another exemplary electrode assembly 12 suitable for use in the system 10, shown in the form of a basket electrode assembly 400. The basket electrode assembly 400 includes a basket 402 coupled to a catheter body 404 via a suitable proximal connector 406. The basket 402 includes a plurality of splines 408 and a distal coupler 410 at which each of the splines 408 terminates. In some embodiments, such as the embodiment shown, the basket electrode assembly 400 may also include an irrigation tube 412 (e.g., to provide fluid to the basket electrode assembly 400). In other embodiments, the irrigation tube 412 may be omitted. Each spline of the plurality of splines 408 includes at least one electrode 414. In the embodiment shown, although each spline of the plurality of splines includes eight electrodes 414, each spline 408 may include more or less than eight electrodes 414.

[0037] The electrodes 414 can be used for a variety of diagnostic and therapeutic purposes, including, for example, but not limited to, cardiac mapping and / or ablation (e.g., IRE ablation). For example, the basket electrode assembly 400 can be configured as a bipolar electrode assembly for electroporation based on bipolar-based electroporation. More specifically, the electrodes 414 located on adjacent splines 408 can be configured as an electrode pair (e.g., a cathode-anode electrode pair) and electrically coupled to the electroporation generator 26 (e.g., via a suitable wire or other suitable electrical conductor extending through the catheter shaft 44) so ​​that the electrodes 414 on adjacent splines 408 are energized with opposite polarities to generate an electric potential and a corresponding electric field between the electrodes 414 of the adjacent splines 408. In other embodiments, the electrodes 414 placed along the same spline 408 can be configured as an electrode pair. In other embodiments, any combination of electrodes 414 may be configured as an electrode pair, including, for example, but not limited to, adjacent electrodes, non-adjacent electrodes, electrodes on adjacent splines, electrodes on non-adjacent splines, and any other combination of electrodes that enables system 10 to function as described herein. As described above, for example, electroporation generator 26 and / or computer system 32 may selectively energize certain electrodes 414 of basket electrode assembly 400 based on contact between electrodes 414 and tissue 16 to form electrode pairs. In other embodiments, basket electrode assembly 400 may be configured as an electrode assembly other than a bipolar electrode assembly, such as a monopolar or monopolar electrode assembly. In such embodiments, electrode 18 may be used as a return electrode.

[0038] Figure 51 is a perspective view of another exemplary electrode assembly 12 suitable for use in the system 10, shown in the form of a planar or grid electrode assembly 500. The grid electrode assembly 500 includes a paddle 502 coupled to a catheter body 504. In the illustrated embodiment, the catheter body 504 includes body electrodes 506, 508, and 510 coupled thereto. In the illustrated embodiment, the paddle 502 includes a first spline 512, a second spline 514, a third spline 516, and a fourth spline 518, which are coupled to the catheter body 504 via a proximal coupler and coupled to each other via a distal coupler 520 at the distal end of the paddle 502. In one embodiment, the first spline 512 and the fourth spline 518 can be one continuous segment, while the second spline 514 and the third spline 516 can be another continuous segment. In other embodiments, the individual splines can be separate segments coupled to each other. The plurality of splines can further include different numbers of electrodes 522. In the illustrated embodiment, the electrodes can include annular electrodes evenly spaced apart along the splines. In other embodiments, the electrodes may be evenly or unevenly spaced, and the electrodes may include point electrodes or other types of electrodes.

[0039] The electrodes 522 can be used for a variety of diagnostic and therapeutic purposes, including, for example, but not limited to, cardiac mapping and / or ablation (e.g., IRE ablation). For example, the grid electrode assembly 500 can be configured as a bipolar electrode assembly for electroporation based on bipolar electroporation. More specifically, adjacent electrodes 522 can be configured as an electrode pair (e.g., a cathode-anode electrode pair) and electrically connected to the electroporation generator 26 (e.g., via a suitable wire or other suitable electrical conductor extending through the catheter shaft 44) so ​​that adjacent electrodes 522 are energized with opposite polarities to generate an electric potential and a corresponding electric field between adjacent electrodes 522. Adjacent electrodes 522 forming a bipolar pair can be located on the same spline (e.g., electrodes 522 along the first spline 512) or across adjacent splines. In one embodiment, for example, the electrode pair can be formed between an electrode 522 (e.g., cathode) located on the first spline 512 and another adjacent electrode 522 (e.g., anode) located on the adjacent second spline 514. In other embodiments, any combination of electrodes 522 can be configured as an electrode pair (e.g., a cathode-anode electrode pair), including, for example, but not limited to, adjacent electrodes, non-adjacent electrodes, electrodes on adjacent splines, electrodes on non-adjacent splines, and any other combination of electrodes that enable the system 10 to function as described herein. As described above, for example, the electroporation generator 26 and / or the computer system 32 can selectively energize certain electrodes 522 of the grid electrode assembly 500 based on contact between the electrodes 522 and the tissue 16 to form electrode pairs. In other embodiments, the grid electrode assembly 500 can be configured as an electrode assembly other than a bipolar electrode assembly, such as a monopolar or monopolar electrode assembly. In such embodiments, the electrode 18 can be used as a return electrode.

[0040] The first spline 512, the second spline 514, the third spline 516, and the fourth spline 518 are generally aligned on the same (topological) plane. Figure 5 502 is shown as relatively flat or planar, but it should be understood that paddle 502 may be bent, curled, flexed, twisted, and / or otherwise deformed. Thus, the plane defined by paddle 502 and splines 512, 514, 516, and 518 may be deformed accordingly such that the plane is a non-straight topological plane.

[0041] Figure 66 is a perspective view of another exemplary electrode assembly 12 suitable for use in the system 10, shown in the form of an expandable electrode assembly 600. The electrode assembly 600 generally extends axially along a longitudinal axis 606 from a proximal end 602 of the electrode assembly 600 to a distal end 604 of the electrode assembly 600. The proximal end 602 is coupled to the catheter shaft 44 (e.g., coupled to the distal end of the shaft 44) via a suitable coupler (not shown). In an exemplary embodiment, a guide wire 608 extends axially through the shaft 44 and through the electrode assembly 600. The guide wire 608 can be manipulated (e.g., using the handle 42) to adjust the position of the electrode assembly 600 within the body 17.

[0042] Electrode assembly 600 generally includes an expandable isolation member 610 and a pair of electrodes 612, 614. More specifically, expandable isolation member 610 extends between a proximal end 616 of expandable isolation member 610 and a distal end 618 of expandable isolation member 610. Electrodes 612, 614 are disposed adjacent proximal end 616 and distal end 618 of expandable isolation member 610, respectively, such that expandable isolation member 610 is axially disposed between electrodes 612, 614. Proximal electrode 612 is adjacent proximal end 616 of expandable isolation member 610 and is proximal to proximal end 602 of electrode assembly 600. Similarly, distal electrode 614 is adjacent distal end 618 of expandable isolation member 610 and is proximal to distal end 604 of electrode assembly 600. In an exemplary embodiment, distal end 618 of expandable isolation member 610 is proximal to distal end 604 of electrode assembly 600.

[0043] Electrodes 612, 614 can be used for a variety of diagnostic and therapeutic purposes, including, for example, but not limited to, cardiac mapping and / or ablation (e.g., IRE ablation). For example, electrode assembly 600 can be configured as a bipolar electrode assembly for use in bipolar-based electroporation therapy. Specifically, electrodes 612, 614 can be individually electrically coupled to generator 26 (e.g., via suitable wires or other suitable electrical conductors extending through catheter shaft 44), and are configured to be selectively energized with opposite polarities (e.g., by electroporation generator 26 and / or computer system 32) to generate an electric potential and a corresponding electric field therebetween for IRE therapy. That is, one of electrodes 612, 614 is configured to serve as a cathode, and the other is configured to serve as an anode. Electrodes 612, 614 can be any suitable electroporation electrodes. In an exemplary embodiment, electrodes 612, 614 are ring electrodes. Electrodes 612, 614 can have any other shape or configuration. It should be appreciated that the shape, size and / or configuration of the electrodes 612, 614 may affect various parameters of the electroporation therapy applied. For example, increasing the surface area of ​​one or both electrodes 612, 614 may reduce the applied voltage required to cause the same level of tissue damage. In addition, although each of the proximal electrode 612 and the distal electrode 614 is shown as a single electrode, either or both of the proximal electrode 612 and the distal electrode 614 may alternatively be presented as two or more discrete electrodes. In addition, although the electrode assembly 600 is described as a bipolar electrode assembly, it should be understood that in some embodiments, the electrode assembly 600 may be configured as a monopolar or monopolar electrode assembly and use a patch electrode (e.g., return electrode 18) as a return electrode or an indifferent electrode.

[0044] In an exemplary embodiment, expandable isolation member 610 can be in a collapsed configuration (not shown) and an expanded configuration (e.g. Figure 6 ) between the expandable isolation member 610 and the proximal electrode 614. For example, the expandable isolation member 610 is delivered to a target location (e.g., axially disposed within the catheter shaft 44) of the tissue 16 within the body 17 in a contracted configuration and is transformed into an expanded configuration at the target location. The expandable isolation member 610 is configured to sealingly engage with the tissue 16 at the target location and inhibit electrical communication between the electrodes 612, 614 (e.g., by at least partially insulating the distal electrode 614 from the proximal electrode 612). More specifically, the expandable isolation member 610 is formed of an electrically insulating material. Therefore, the current 622 between the proximal electrode 612 and the distal electrode 614 is transferred around the expandable isolation member 610. Figure 6 Multiple currents 622 of varying shapes and amounts of diversion are depicted about expandable isolation member 610. In some embodiments, the shape and size of expandable isolation member 610 can be selected to affect current 622 thereabout (e.g., amount of diversion, shape or direction of current 622 generated, etc.).

[0045] In addition, the expandable isolation member 610 is configured to sealingly engage the tissue 16 when in the expanded configuration. In an exemplary embodiment, the expandable isolation member 610 includes a circumferential sealing surface 620 configured for sealing engagement with the tissue 16, such that when engaged with the patient's tissue, the expandable isolation member 610 inhibits fluid communication between the electrodes 612, 614, and thus inhibits electrical communication (e.g., electrical current). For example, in the case where the expandable isolation member 610 is used for pulmonary vein isolation (PVI) or isolation of other cylindrical or tubular tissue (e.g., other vascular system tissue), the expandable isolation member 610 inhibits or substantially prevents the surrounding blood flow. Therefore, when the electrodes 612, 614 are energized, the current 622 flows between them through the tissue 16 adjacent to the expandable isolation member 610, rather than through the blood. In this way, electroporation therapy can be more localized and thus require a reduced applied voltage to cause the desired amount of cell destruction. Specifically, fluids (e.g., blood) are more conductive than tissue, so current flows more easily through blood than through tissue, and electroporation therapy is less effective. By blocking blood flow, the current 622 between electrodes 612, 614 is diverted through adjacent tissue 16, thereby increasing the effectiveness of electroporation therapy at a given voltage.

[0046] In an exemplary embodiment, expandable isolation member 610 includes an outer layer 624 formed or constructed of an electrically insulating material. For example, outer layer 624 may include polyethylene terephthalate (PET). Outer layer 624 is made of any other suitable material that is electrically insulating and capable of accommodating expansion and contraction of electrode assembly 600. In some embodiments, such as Figure 6 , the expandable isolation member 610 is embodied as an inflatable balloon. In such embodiments, the expandable balloon is coupled to a fluid source 626 to selectively expand the balloon (e.g., when the electrode assembly 600 has advanced to a target location in the body 17 and has been deployed from the catheter shaft 44). In some embodiments, the fluid source includes a dielectric fluid, such as deionized water, saline, carbon dioxide gas, nitrous oxide gas, and / or air. In other embodiments, the expandable isolation member 610 can be selectively expanded using other means (such as an expandable frame (e.g., a frame formed of a shape memory material) retained within the outer layer 624).

[0047] Despite Figure 6The expandable isolation member 610 is shown as having an elongated spherical shape, but the expandable isolation member 610 can have any other shape or configuration that can seal and thereby inhibit fluid and / or electrical communication between the electrodes 612, 614. A specific shape and / or configuration can be selected for the specific tissue isolation required. For example, in other embodiments, isolation and tissue destruction within a solid or planar tissue such as a cardiac chamber wall (as opposed to the relatively cylindrical isolation of a blood vessel) may be desired. In such embodiments, the distal end 618 of the expandable isolation member 610 can be inverted and recessed, and the distal electrode 614 is placed in a recess of the distal end 618. The distal end 618 can be engaged or pressed against the tissue to seal or isolate the distal electrode 614 from the proximal electrode 612, so that the current 622 between the electrodes 612, 614 is transferred through the tissue (e.g., the cardiac chamber wall) engaged with the distal end 618.

[0048] It is expected that a complete seal between the expandable isolation member 610 and the adjacent tissue 16 may not occur. For example, the circumferential sealing surface 620 may not be fully engaged with the tissue 16, and some fluid (blood) may flow through the circumferential sealing surface 620. In some embodiments, complete engagement or sealing is not required for successful electroporation therapy. A variety of methods can be used to determine the level of seal. In some embodiments, a fluoroscopic contrast agent is introduced into the blood flow upstream of the expandable isolation member 610, and the presence or amount of contrast agent downstream of the expandable isolation member 610 is determined using x-rays. In other embodiments, Doppler ultrasound is used to determine the level of fluid flowing through the expandable isolation member 610. Still in other embodiments, the impedance between the electrodes 612, 614 is measured before and after the electrode assembly 600 is placed at the target location; a threshold shift in impedance reflects sufficient sealing. Still in other embodiments, the electrode assembly 600 includes a pressure sensor (not shown) on the distal end 604, which is used to measure fluid pressure to reflect the level of seal between the expandable isolation member 610 and the tissue 16. Additional and / or alternative methods of determining the seal level may be used. Furthermore, any of the above methods may be employed iteratively. Specifically, an initial level of seal may be determined, and in response, the position of the electrode assembly 600 may be adjusted. Subsequent seal levels may be determined, and so on, until a sufficient or adequate seal level is reached (e.g., based on a threshold value and / or physician determination).

[0049] Furthermore, based on the seal level determined using any of the above methods (or any other suitable method), a suitable voltage level to be applied may be selected.A reduced seal level may require an increased applied voltage.

[0050] It should be understood that the electrode assembly 12 is not limited to the specific structure shown and described herein, and may include any other suitable electrode assembly and have any other suitable structure that enables the system 10 to function as described herein. For example, the electrode assembly 12 may have a structure that is the same or similar to the electrode assemblies described in U.S. Patent No. 10,136,829, U.S. Patent Application Publication Nos. 2018 / 0014751 and 2019 / 0201688, International Patent Application Publication No. WO2018 / 208795, and U.S. Provisional Patent Application Serial Nos. 62 / 861,135, 62 / 842,654, and 62 / 983,200, the disclosures of which are incorporated herein by reference in their entirety.

[0051] Reference again Figure 1 The visualization, navigation and / or mapping system 30 may include an electric field based system, or sometimes referred to as an impedance based system, such as, for example, a system having a model designation of EnSite NAVX TM The system may be commercially available from Abbott Laboratories and as generally referenced in U.S. Patent No. 7,263,397 entitled "Method and Apparatus for Catheter Navigation and Positioning and Mapping in the Heart," the entire disclosure of which is incorporated herein by reference. The visualization, navigation and / or mapping system 30 may also include other types of commercially available systems, including Abbott Laboratories' EnSite TM Velocity TM or EnSite Precision TM Cardiac Mapping and Visualization System. In other exemplary embodiments, the visualization, navigation and / or mapping system 30 may include other types of systems, such as, for example but not limited to: magnetic field-based systems, such as the CARTO system available from Biosense Webster (now in a hybrid form with impedance and magnetic drive electrodes), or the gMPS system available from MediGuide Ltd. According to a combination electric field-based and magnetic field-based system, the catheter may include two electrodes as impedance-based electrodes and one or more magnetic field sensing coils. Commonly used fluoroscopy, computed tomography (CT), and magnetic resonance imaging (MRI)-based systems may also be used.

[0052] The electroporation generator 26 is configured to energize the electrode elements according to an electroporation energization strategy, which may be predetermined or user-selectable. For primary necrosis therapy caused by electroporation, the generator 26 may be configured to generate a current delivered via the electrode assembly 12 as a pulsed electric field in the form of a short-duration DC pulse, which is sent between closely spaced electrodes (e.g., an electrode pair of the electrode assembly 12) and is capable of delivering an electric field strength of about 0.1 to 1.0 Kv / cm (e.g., at a tissue site). The voltage amplitude required for irreversible electroporation is inversely proportional to the pulse duration. For example, as the pulse duration decreases, the voltage amplitude must be increased to achieve electroporation.

[0053] In some embodiments, the electrodes of the electrode assembly 12 may be energized sequentially so that only some electrodes are energized at a given time. That is, not all electrodes of the electrode assembly 12 are energized simultaneously. In some embodiments, for example, the first electrode pair may be energized according to the electroporation energization strategy, and then, the second electrode pair may be energized according to the electroporation energization strategy. The sequential energization of the electrodes may continue to the third electrode pair, the fourth electrode pair, and the like. The electrode pair may include adjacent or non-adjacent electrodes. For example, in the case where the electrode assembly includes a plurality of electrodes numbered 1 to n sequentially according to the position (i.e., the second electrode is adjacent to the first electrode and the third electrode), the electrodes may be energized sequentially in pairs by energizing the first electrode and the second electrode, the third electrode and the fourth electrode, the fifth electrode and the sixth electrode, etc., in sequence. In another example, the electrodes may be energized sequentially in pairs by energizing the first and second electrodes, the second and third electrodes, the third and fourth electrodes, etc., in sequence. In another example, the electrodes may be energized sequentially in pairs by energizing the first and third electrodes, the second and fourth electrodes, the third electrode and the fifth electrode, etc., in sequence. For example, additional systems and methods for sequentially energizing electrodes of an electrode assembly are described in U.S. Provisional Patent Application Serial No. 63 / 109,520, filed on November 4, 2020, the entire disclosure of which is incorporated herein by reference. Sequential energization can be used in monopolar and bipolar configurations.

[0054] In an exemplary embodiment, the electroporation generator 26 (sometimes also referred to herein as a DC energy source) is a biphasic electroporation generator 26 that is configured to generate a series of DC pulses having alternating polarity - i.e., continuous DC pulses that produce current in alternating directions. In other embodiments, the electroporation generator is a single-phase or multi-phase electroporation generator. In some embodiments, the electroporation generator 26 is configured to output energy with DC pulses at selectable energy levels (such as fifty joules, one hundred joules, two hundred joules, etc.). Other embodiments may have more or fewer energy settings, and the values ​​of the available settings may be the same or different. In some embodiments, electroporation generator 26 outputs or generates DC pulses having a peak amplitude between about 500 V and about 3.5 kV, between about 600 V and 2.5 kV, between about 800 V and about 3.5 kV, between about 600 V and about 2.0 kV, between about 800 V and about 2.5 kV, between about 1.0 kV and about 3.5 kV, between about 600 V and about 1.5 kV, between about 800 V and about 2.0 kV, or between about 1.0 kV and about 2.5 kV. Other embodiments may output or generate any other suitable voltage.

[0055] Variable impedance 27 allows the impedance of the system to be changed. In addition, variable impedance 27 can be used to change one or more characteristics of the output of electroporation generator 26, such as amplitude, duration, pulse shape, etc. Although shown as a separate component, variable impedance 27 can be incorporated into catheter 14 or generator 26. Variable impedance 27 includes one or more impedance elements, such as resistors, capacitors or inductors (not shown) connected in series, in parallel, or in a combination of series and / or parallel. In the illustrated embodiment, variable impedance 27 is connected in series with catheter 14. Alternatively, the impedance element of variable impedance 27 can be connected in parallel with catheter 14, or connected in series and parallel with catheter 14. In addition, in other embodiments, the impedance element of variable impedance 27 is connected in series and / or in parallel with return electrode 18. Some embodiments include more than one variable impedance 27, and each variable impedance 27 may include one or more impedance elements. In such embodiments, each variable impedance 27 can be connected to different catheter electrodes or catheter electrode groups to allow the impedance of each catheter electrode or catheter electrode group to be changed independently. In other embodiments, the impedance of system 10 may not need to be changed, and variable impedance 27 may be omitted.

[0056] The electroporation generator 26 is configured to generate and provide a pulse signal to the electrodes of the electrode assembly 12, which is configured to reduce, minimize, or prevent the adverse effects of IRE. For example, previous IRE treatment systems may cause skeletal muscle contractions due to the application of high amplitude, short duration DC electrical (IRE) pulses. Such skeletal muscle contractions are generally undesirable, for example, because they may make the electroanatomical map (e.g., collected before the IRE treatment) inaccurate by moving the patient's body. In addition, previous IRE treatment systems may generate undesirable gas in the patient's body, for example, at the electrodes.

[0057] The pulse signal generated by the electroporation generator 26 is specifically shaped (e.g., by controlling the phase, amplitude, and pulse duration) to prevent activation of skeletal muscle and nerves (e.g., peroneal nerve) as well as cardiac muscle. By avoiding activation of cardiac muscle, the pulse signal generated by the electroporation generator does not have to be timed or gated based on the cardiac cycle or heart rhythm (e.g., along the R wave). More specifically, the pulse signal generated by the electroporation generator 26 is shaped to have a pulse duration and voltage amplitude that is lower than the intensity-duration curve associated with neural stimulation or muscle activation. The pulse signal generated by the electroporation generator 26 has a relatively high intensity (i.e., voltage) and frequency (i.e., short pulse duration). For example, the pulse signal generated by the electroporation generator 26 may have a voltage amplitude in the range of 500 V to 3.5 kV, 600 V to 2.5 kV, 800 V to 3.5 kV, 600 V to 2.0 kV, 800 V to 2.5 kV, 1.0 kV to 3.5 kV, 600 V to 1.5 kV, 800 V to 2.0 kV, or 1.0 kV to 2.5 kV, and a pulse duration of 1 nanosecond to 100 microseconds (μs), 1 nanosecond to 50 μs, or 1 nanosecond to 2.5 kV. In some embodiments, the pulse signal generated by the electroporation generator 26 may have a pulse duration in the range of less than 5 μs, less than 4 μs, less than 3 μs, and less than 2 μs. In other embodiments, the pulse signal generated by the electroporation generator 26 may have a voltage amplitude of less than 500 V or greater than 3.5 kV, and may have a pulse duration of greater than 100 μs or less than 1 nanosecond. In general, the voltage amplitude and pulse duration required for effective IRE (e.g., to produce continuous injury) are inversely proportional and are selected within a voltage and duration range to avoid nerve stimulation or muscle activation.

[0058] Figure 7is a graph showing an exemplary pulse signal 700 generated by the electroporation generator 26, wherein the vertical axis represents voltage (V) and the horizontal axis represents time (T). Figure 7 As shown in , the pulse signal 700 is a two-phase pulse signal, which includes a first phase 702 having a first voltage amplitude 704 with a first polarity and a first pulse duration 706, and a second phase 708 having a second voltage amplitude 710 with a second polarity opposite to the first polarity and a second pulse duration 712. The pulse signal 700 shown also includes a third zero voltage phase 714 separating the second phase 708 from the first phase 702 (i.e., the pulse signal 700 has a zero voltage output), so that the second phase 708 is generated after the first phase 702 with a non-zero interval 716. In other embodiments, the pulse signal 700 may not include the third phase 714, so that the second phase 708 is generated immediately after the first phase 702.

[0059] In the illustrated embodiment, the first phase 702 has a positive voltage and the second phase 708 has a negative voltage. In other embodiments, the first phase 702 may have a negative voltage and the second phase 708 may have a positive voltage. Additionally, although the pulse signal 700 is shown and described as a bi-phase signal in the illustrated embodiment, in other embodiments, the pulse signal 700 may be different from a bi-phase signal (e.g., the pulse signal 700 may be single-phase or multi-phase).

[0060] In addition, in the illustrated embodiment, the first phase 702 and the second phase 708 have the same voltage amplitude or size and have the same pulse duration (i.e., the first pulse duration 706 is equal to the second pulse duration 712). In other words, the pulse signal 700 is a symmetrical pulse signal. In other embodiments, the first phase 702 can have a different voltage amplitude or size and / or pulse duration than the second phase 708, so that the pulse signal 700 is asymmetrical.

[0061] The first phase 702 and the second phase 708 may generally have any suitable voltage amplitude and pulse duration sufficient to cause ablation due to IRE while avoiding skeletal muscle stimulation. In some embodiments, for example, each of the first voltage amplitude 704 and the second voltage amplitude 710 is in the range of 500V to 3.5kV, 600V to 2.5kV, 800V to 3.5kV, 600V to 2.0kV, 800V to 2.5kV, 1.0kV to 3.5kV, 600V to 1.5kV, 800V to 2.0kV, or 1.0kV to 2.5kV, and each of the first pulse duration 706 and the second pulse duration 712 is in the range of 1.0kV to 2.5kV, 1.0kV to 3.5kV, 600V to 1.5kV, 800V to 2.0kV, or 1.0kV to 2.5kV. Each pulse duration is between 1 nanosecond to 100 μs, 1 nanosecond to 50 μs, 0.1 μs to 100 μs, 1 nanosecond to 20 μs, 0.1 μs to 50 μs, 1 μs to 100 μs, 1 nanosecond to 15 μs, 0.1 μs to 20 μs, 0.5 μs to 50 μs, 1 nanosecond to 10 μs, 0.1 μs to 15 μs, 1 nanosecond to 5 μs, 0.1 μs to 10 μs, 0.1 μs to 5 μs, less than 5 μs, less than 4 μs, less than 3 μs, and less than 2 μs. In a specific embodiment, each of the first voltage amplitude 704 and the second voltage amplitude 710 is approximately 1.0 kV, and each of the first pulse duration 706 and the second pulse duration 712 is approximately 2 μs. In another specific embodiment, each of the first voltage amplitude 704 and the second voltage amplitude 710 is approximately 1.4 kV, and each of the first pulse duration 706 and the second pulse duration 712 is approximately 2 μs.

[0062] The interval 716 of the third phase 714 is typically selected to be a duration sufficient to prevent or avoid the first phase 702 and the second phase 708 of the pulse signal 700 from activating or stimulating skeletal muscle. The interval 716 is typically less than 50 μs, and may be, for example but not limited to, less than 30 μs, less than 20 μs, less than 15 μs, less than 10 μs, less than 5 μs, less than 4 μs, less than 3 μs, less than 2 μs, and even less than 1 μs. In the illustrated embodiment, the interval 716 is about 2.5 μs. In another specific embodiment, the interval 716 is about 2 μs.

[0063] In some embodiments, the voltage amplitude of the pulse signal 700 (i.e., the first phase 702 and the second phase 708) can be selected based on the type of electrode assembly 12 used in the system 10. More specifically, certain types of electrode assemblies can be rated for higher voltages than other electrode assemblies, and the pulse signal 700 can be adjusted accordingly. In some embodiments, for example, with a basket-type electrode assembly (e.g., Figure 4 ) when compared to a ring electrode assembly (e.g., Figure 2 and Figure 3 ), the pulse signal 700 (i.e., the first phase 702 and the second phase 708) can have a higher voltage amplitude. In a specific embodiment, the voltage amplitude of the pulse signal 700 is in the range of 1 kV to 2.5 kV when used with a ring electrode assembly, and in the range of 800 V to 1.5 kV when used with a basket electrode assembly.

[0064] The characteristics of the pulse signal 700 (e.g., voltage amplitude, first pulse duration 706, second pulse duration 712, etc.) may also be adjusted depending on whether the electrode assembly 12 is configured as a monopolar electrode assembly or a bipolar electrode assembly. For example, skeletal muscle recruitment may be more prominent in monopolar IRE than in bipolar IRE. Therefore, the pulse signal for monopolar IRE may have a narrower or more stringent range of acceptable pulse characteristics (e.g., voltage amplitude and pulse duration) than in bipolar IRE.

[0065] In one example, a ring electrode assembly (eg, Figure 2 and Figure 3 The electrode ring assembly 200 shown in FIG. 2 may utilize a pulse signal 700 having a voltage amplitude in the range of 500 V to 3.5 kV or in the range of 800 V to 3.0 kV, and a first pulse duration 706 and a second pulse duration 712 in the range of 0.5 μs to 3.0 μs or in the range of 0.5 μs to 1.5 μs. A ring electrode assembly configured as a bipolar electrode assembly (e.g., Figure 2 and Figure 3 The electrode ring assembly 200 shown in ) can utilize a pulse signal 700 having a voltage amplitude in the range of 500V to 3.5kV or in the range of 600V to 1.4kV, and a first pulse duration 706 and a second pulse duration 712 in the range of 0.5μs to 3μs or in the range of 1μs to 1.5μs.

[0066] In another example, a basket-type electrode assembly (e.g., Figure 4 The basket electrode assembly 400 shown in FIG. 4 may utilize a pulse signal 700 having a voltage amplitude in the range of 500 V to 3.5 kV, and a first pulse duration 706 and a second pulse duration 712 in the range of 0.5 μs to 3 μs. A basket electrode assembly configured as a bipolar electrode assembly (e.g., Figure 4The basket electrode assembly 400 shown in FIG. 4 ) can utilize a pulse signal 700 having a voltage amplitude in the range of 500 V to 3.5 kV, and a first pulse duration 706 and a second pulse duration 712 in the range of 0.5 μs to 3 μs.

[0067] In another example, a grid electrode assembly (e.g., Figure 5 The grid electrode assembly 500 shown in FIG. 5 ) can utilize a pulse signal 700 having a voltage amplitude in the range of 500 V to 3.5 kV, and a first pulse duration 706 and a second pulse duration 712 in the range of 0.5 μs to 3 μs. A grid electrode assembly configured as a bipolar electrode assembly (e.g., Figure 5 The grid electrode assembly 500 shown in FIG. 5 ) may utilize a pulse signal 700 having a voltage amplitude in the range of 500 V to 3.5 kV, and a first pulse duration 706 and a second pulse duration 712 in the range of 0.5 μs to 3 μs.

[0068] In another example, an expandable electrode assembly (e.g., Figure 6 The expandable electrode assembly 600 shown in FIG. 600 may utilize a pulse signal 700 having a voltage amplitude in the range of 500 V to 3.5 kV, in the range of 500 V to 2.5 kV, in the range of 600 V to 3.0 kV, in the range of 600 V to 2.5 kV, or in the range of 800 V to 2.5 kV, and a first pulse duration 706 and a second pulse duration 712 in the range of 400 nanoseconds to 20 μs, or in the range of 500 nanoseconds to 1.5 μs. In addition, for an expandable electrode assembly (e.g., Figure 6 The pulse signal 700 of the expandable electrode assembly 600 shown in FIG. 7A may have an interval 716 between the first phase 702 and the second phase 708 in the range of 350 nanoseconds to 1 ms or in the range of 500 nanoseconds to 1.5 μs.

[0069] The electroporation generator 26 may generate the pulse signal 700 in a repetitive pattern such that multiple pulse signals 700 are generated and applied to the electrodes of the electrode assembly 12 in a repetitive pulse cycle. Such multiple pulse signals 700 are collectively referred to herein as pulse train signals.

[0070] Figure 8An example pulse train signal 800 is shown, which includes two pulse signals 700 generated at a pulse period 802. The pulse period 802 can be any suitable period that enables the system 10 to function as described herein. For example, the pulse period 802 can be in the range of 0.5 milliseconds (ms) to 50 ms, 1 ms to 50 ms, 0.5 ms to 30 ms, 1 ms to 30 ms, 0.5 ms to 25 ms, 0.5 ms to 20 ms, 1 ms to 25 ms, 0.5 ms to 10 ms, 1 ms to 20 ms, 1 ms to 10 ms, 0.5 ms to 5 ms, and 1 ms to 5 ms. In the illustrated embodiment, the pulse period 802 is about 4 ms. In some embodiments, the pulse period 802 is selected to allow the power supply (e.g., capacitor) of the electroporation generator 26 to recharge to a sufficient voltage to maintain the voltage amplitude of the pulse signal 700 at or close to the target voltage amplitude (e.g., at least 90% of the target voltage amplitude).

[0071] In some embodiments, the electroporation generator 26 may generate a pulse train signal in a repetitive mode such that multiple pulse train signals are generated and applied to the electrodes of the electrode assembly 12 during a repetitive period (referred to as a pulse train period). Fig. 9 An example pulse train signal 900 generated within a repeated pulse train period 902 is shown. The pulse train period 902 can be any suitable period that enables the system 10 to function as described herein. For example, the pulse train period 902 can be in the range of 50ms to 5 seconds (s), 100ms to 5s, 100ms to 2s, 100ms to 1s, 200ms to 1s, 200ms to 800ms, and 300ms to 700ms. In the illustrated embodiment, the pulse train period 902 is about 500ms. In some embodiments, the pulse train period 902 is selected to allow the power supply (e.g., capacitor) of the electroporation generator 26 to recharge to a sufficient voltage to maintain the voltage amplitude of the pulse signal 700 at or close to the target voltage amplitude (e.g., at least 90% of the target voltage amplitude). Additionally or alternatively, the pulse train period 902 can be different based on the patient's cardiac cycle or heart rhythm. In one embodiment, for example, the pulse train signal 900 is generated according to an R-wave gating strategy (e.g., synchronized with the patient's heart rate). In such embodiments, the pulse train signal 900 can be generated in response to the detection of an R wave in the electrocardiogram or triggered based on the detection of an R wave in the electrocardiogram. In such embodiments, the pulse train period 902 can be variable (i.e., not fixed or constant). For example, the pulse train period 902 can vary within a range of 500 ms to 1.5 s, within a range of 600 ms and 1.2 s, or within any other suitable range that enables the system 10 to function as described herein. Such pulse train periods and gating strategies can be used in conjunction with any electrode assembly described herein.

[0072] Fig. 9 The graph shown in Figure 2 includes two pulse train signals 900, but it should be understood that the electroporation generator 26 can generate more than two pulse train signals 900. For example, the electroporation generator 26 can generate a series of pulse train signals 900 (i.e., in a repeated pulse train cycle 902), and the series of pulse train signals 900 includes at least 5 pulse train signals, at least 10 pulse train signals, at least 20 pulse train signals, at least 30 pulse train signals, at least 40 pulse train signals, at least 50 pulse train signals, at least 75 pulse train signals, at least 100 pulse train signals, or at most 200 pulse train signals. In other embodiments, the electroporation generator 26 can generate a series of more than 200 pulse train signals in a repeated pulse train cycle.

[0073] In addition, in the illustrated embodiment, the pulse train signal 900 includes 5 pulse signals 700, but it should be understood that the pulse train signal 900 may include any suitable number of pulse signals 700 that enables the system 10 to function as described herein. For example, the pulse train signal 900 may include at least 10 pulse signals, at least 15 pulse signals, at least 20 pulse signals, at least 30 pulse signals, at least 40 pulse signals, at least 50 pulse signals, at least 75 pulse signals, at least 100 pulse signals, at least 150 pulse signals, or at most 200 pulse signals. In other embodiments, the pulse train signal 900 may include less than 5 pulse signals 700 or more than 200 pulse signals 700. In one specific embodiment, the pulse train signal 900 includes 50 pulse signals 700 and has a pulse train period 902 of 0.5 s. In another specific embodiment, the pulse train signal 900 includes 1000 pulse signals 700 and has a pulse train period 902 of 0.5 s. Such pulse train signals and pulse train periods are suitable for use with any of the electrode assemblies described herein.

[0074] The relatively high voltage and short pulse duration of the pulsed signal generated by the electroporation generator 26 may result in the introduction of significant electromagnetic interference (EMI) or noise into the electroporation generator 26, its components, the catheter 14, or the patient's tissue 16, which may adversely affect the operation of the system 10. Therefore, embodiments of the present disclosure include certain features to reduce noise sources and mitigate the effects of high-frequency, high-voltage switching within the electroporation generator 26 to generate the high-amplitude, short-duration pulsed signals.

[0075] For example, Fig.10is a schematic diagram of an exemplary electroporation generator 26. The electroporation generator 26 includes a microcontroller 1002 or other programmable processing device that controls the generation of a pulse signal in response to a trigger signal 1004. The trigger signal 1004 can be generated internally to the electroporation generator 26, or externally by another system. In some embodiments, the trigger signal is a discrete logic level DC signal provided to the microcontroller 1002 due to at least momentary closure of a switch circuit by, for example, a switch or button actuated by a user. In response to the trigger signal 1004, the microcontroller 1002 initiates, for example, a single pulse, a pulse train of pulses, or a plurality of pulse trains.

[0076] The microcontroller 1002 generates a first pulse control signal 1006 and a second pulse control signal 1008 to control a plurality of semiconductor switches when generating a single pulse signal. The first pulse control signal 1006 and the second pulse control signal 1008 are logic level DC signals generated by the microcontroller 1002. The semiconductor switch can be any suitable power semiconductor capable of high voltage isolation, high current conduction and high frequency operation, such as an insulated gate bipolar transistor (IGBT). Fig.10 In an embodiment of the present invention, the semiconductor switches are implemented as IGBTs 1010, 1012, 1014, 1016 connected in a bridge configuration to regulate the application of a positive high voltage DC (+HVDC) power source 1018 and a negative high voltage DC (-HVDC) power source 1020 to the catheter 14 and more specifically to a first conductor 1022 and a second conductor 1024 that deliver the pulse signal to the electrode assembly 12. The microcontroller 1002 controls the IGBTs 1010, 1012, 1014, 1016 to commutate at a high frequency (e.g., about 500 kilohertz) to generate each pulse signal when generating a pulse train of the pulse signal.

[0077] The microcontroller 1002 is communicatively coupled and electrically isolated from the IGBTs 1010, 1012, 1014, 1016 by an opto-isolator 1026. The opto-isolator 1026 (also referred to as an optocoupler) prevents noise generated, for example, by high frequency switching of the IGBTs 1010, 1012, 1014, 1016 from reaching the microcontroller 1002. The opto-isolator 1026 relays the first pulse control signal 1006 and the second pulse control signal 1008 from the microcontroller 1002 to a logic circuit 1028, which converts the two logic level DC signals into four gate drive signals 1030, 1032, 1034, 1036. The logic circuit 1028 derives each of the gate drive signals 1030, 1032, 1034, 1036 from the first pulse control signal 1006 and the second pulse control signal 1008, and ensures that the gate drive signals 1030, 1032, 1034, 1036 do not momentarily connect or short the HVDC power supplies (+HVDC power supply 1018 and -HVDC power supply 1020) of opposite polarity during the transition of the pulse signal from the +HVDC phase to the -HVDC phase. For example, in some embodiments, the logic circuit 1028 derives the gate drive signals 1034 and 1036 as the inversion of the gate drive signals 1030 and 1032.

[0078] Typically, in at least some embodiments, the microcontroller 1002 does not provide enough current to drive the gates of the IGBTs 1010, 1012, 1014, 1016. The gate current of the power semiconductor switch generally increases with high voltage and high current capacity. Therefore, the electroporation generator 26 includes gate drivers 1038, 1040, 1042, 1044 for operating the IGBTs 1010, 1012, 1014, 1016, respectively. The gate drivers 1038, 1040, 1042, 1044 further isolate the microcontroller 1002 and other aspects of the digital circuit from the high voltage and high current portions of the electroporation generator 26. The gate drivers 1038, 1040, 1042, 1044 control the commutation of the IGBTs 1010, 1012, 1014, 1016 according to the gate drive signals 1030, 1032, 1034, 1036. The gate drivers 1038, 1040, 1042, 1044 drive the gates of the IGBTs 1010, 1012, 1014, 1016 through gate drive impedances 1046, 1048, 1050, 1052. The gate drive impedances 1046, 1048, 1050, 1052 are selected to produce sufficient current rise through the IGBTs 1010, 1012, 1014, 1016 and avoid oscillatory responses of the IGBTs 1010, 1012, 1014, 1016. In some embodiments, the gate drive impedances 1046, 1048, 1050, 1052 are resistors in the range of 6-8 ohms. In at least some embodiments, the gate drive impedances 1046, 1048, 1050, 1052 are 6.8 ohm resistors.

[0079] In certain embodiments, electroporation generator 26 may be implemented on one or more printed circuit boards (PCBs) on which microcontroller 1002, opto-isolator 1026, logic circuit 1028, gate drivers 1038, 1040, 1042, 1044, and IGBTs 1010, 1012, 1014, 1016 may be arranged. At least some of the traces on the PCB conduct high voltage DC that is switched at high frequency. For example, the traces connecting the +HVDC power source 1018 to the IGBTs 1010, 1012, 1014, 1016, and the traces providing current from the IGBTs 1010, 1012, 1014, 1016 to the terminals 1056 and 1058 of the first conductor 1022 and the second conductor 1024, respectively, carry pulse signals generated by the high frequency switching of the IGBTs 1010, 1012, 1014, 1016, and are therefore susceptible to introducing noise into the electroporation generator 26. In certain embodiments, such traces should be sufficiently wide and as short as possible to reduce noise introduction caused by periodic high di / dt conditions on these traces. In certain embodiments, these traces should be at least 0.12 inches wide. Likewise, at least some of the traces conduct a large amount of high frequency switching current to drive the gates of the IGBTs 1010, 1012, 1014, 1016. For example, the traces extending between the gate drivers 1038, 1040, 1042, 1044 and their respective IGBTs 1010, 1012, 1014, 1016 are also susceptible to the introduction of noise caused by high di / dt conditions on these traces. Therefore, these traces should also be sufficiently wide and as short as possible to reduce the introduction of noise. In some embodiments, for example, the traces between the gate drivers 1038, 1040, 1042, 1044 and their respective IGBTs 1010, 1012, 1014, 1016 should be at least 0.06 inches wide.

[0080] In some embodiments, the electroporation generator 26 includes additional components between each gate driver 1038, 1040, 1042, 1044 and the IGBT 1010, 1012, 1014, 1016. For example, in some embodiments, one or more capacitors are coupled in parallel with the gate of the semiconductor switch to serve as a current source to drive the gate. In some embodiments, one or more diodes are coupled in parallel with the gate of the semiconductor switch to serve as, for example, transient voltage suppression or as a current blocking device. In some embodiments, one or more EMI suppression devices are coupled to the gate drive branch to mitigate noise originating from, for example, high frequency switching of the IGBT 1010, 1012, 1014, 1016.

[0081] In certain embodiments, the electroporation generator 26 includes one or more impedance matching circuits (not shown) connected in series with the high voltage DC output (i.e., in series with the first conductor 1022 and the second conductor 1024). The impedance matching circuits can mitigate impedance discontinuities that may occur or may be inherent at various portions of the high voltage DC transmission line formed by the traces or other conductors between the +HVDC power source 1018, the -HVDC power source 1020, and the electrode assembly 12 of the catheter 14. For example, an impedance discontinuity may exist where the catheter 14 is connected to the electroporation generator 26, which may cause signal reflections within the electroporation generator 26, which ultimately manifests as noise and losses in the system 10.

[0082] +HVDC power supply 1018 and -HVDC power supply 1020 are DC voltage levels of opposite polarity. For example, in some embodiments, +HVDC power supply 1018 can be at a potential of about 3500 VDC, while -HVDC power supply 1020 can be at a potential of about zero or effectively grounded. In at least some embodiments, the electroporation generator 26 includes a high voltage capacitor 1054, which is used as a high voltage current source for the electrode assembly 12. The single pulse signal includes a first phase having a first polarity high voltage, a second phase having a potential of about zero volts, and a third phase having a second polarity high voltage. The catheter 14 provides a high voltage pulse signal on the first conductor 1022 and the second conductor 1024. Therefore, the polarity of the high voltage pulse signal can be switched by applying +HVDC power supply 1018 to the first conductor 1022 and the second conductor 1024 and -HVDC power supply 1020 to the second conductor 1024 and the first conductor 1022 alternately in time. Likewise, 0 VDC can be achieved by disconnecting both the first conductor 1022 and the second conductor 1024 and allowing their potentials to float. Thus, due to the conductive properties of the blood / saline solution in the patient's body 17, there should be no potential between the electrodes of the electrode assembly 12, and therefore no potential between the first conductor 1022 and the second conductor 1024.

[0083] For example, with +HVDC power source 1018 at a potential of about 3500 VDC and -HVDC power source 1020 at a potential of about 0 VDC, a first phase of the pulse signal is generated by turning off IGBT 1010 and turning on IGBT 1014 to apply +HVDC power source 1018 to first conductor 1022, and turning off IGBT 1012 and turning on IGBT 1016 to apply -HVDC power source 1020 to second conductor 1024, thereby generating a +3500 VDC signal for a first duration. After the first duration, IGBT 1010 and IGBT 1012 are turned on to allow the potentials of first conductor 1022 and second conductor 1024 to float, thereby generating 0 VDC for a second phase of the pulse signal for a second duration. After the second duration, IGBT 1014 is turned off to apply -HVDC power 1020 to first conductor 1022, and IGBT 1016 is turned off to apply +HVDC power 1018 to second conductor 1024, thereby generating a -3500 VDC signal for a third duration. After the third duration, IGBT 1014 and IGBT 1016 are turned on to return the potential across first conductor 1022 and second conductor 1024 to 0 VDC.

[0084] Fig.11 is a flow chart of an example method 1100 for generating a pulse signal. Fig.10 and Fig.11The method includes providing (1102) a +HVDC power source 1018 having a first polarity to a plurality of semiconductor switches, such as IGBTs 1010, 1012, 1014, 1016, connected in a bridge configuration. A -HVDC power source 1020 having a second polarity opposite to the first polarity is provided (1104) to the plurality of semiconductors. To generate a biphasic pulse signal, the microcontroller 1002 controls the commutation of the IGBTs 1010, 1012, 1014, 1016. More specifically, the plurality of semiconductors are each commutated (1106) to apply the +HVDC power source 1018 to a first conductor 1022 of the conduit 14 and the -HVDC power source 1020 to a second conductor 1024 of the conduit 14 for a first duration. Then, after the first duration, the plurality of semiconductors are each commutated (1108) to electrically disconnect the first conductor 1022 and the second conductor 1024 from the +HVDC power source 1018 and the −HVDC power source 1020 for a second duration. Then, after the second duration, the plurality of semiconductors are each commutated (1110) to apply the +HVDC power source 1018 to the second conductor 1024 and the −HVDC power source 1020 to the first conductor 1022 for a third duration. Then, after the third duration, the plurality of semiconductors are each commutated (1112) to electrically disconnect the first conductor 1022 and the second conductor 1024 from the +HVDC power source 1018 and the −HVDC power source 1020.

[0085] Although certain steps of the example methods are numbered, such numbering does not imply that the steps must be performed in the order listed. Therefore, unless such order is required for the specific description, specific steps do not need to be performed in the exact order given. The steps may be performed in the order listed or in another suitable order.

[0086] Although the embodiments and examples disclosed herein have been described with reference to specific embodiments, it should be understood that these embodiments and examples are merely illustrations of the principles and applications of the present disclosure. Therefore, it should be understood that various modifications may be made to the illustrative embodiments and examples, and other arrangements may be designed without departing from the spirit and scope of the present disclosure as defined by the claims. Therefore, the present application is intended to cover modifications and variations of these embodiments and their equivalents.

[0087] This written description uses examples to disclose the invention, including the best mode, and also enables those skilled in the art to practice the disclosure, including making and using any device or system and performing any combined methods. The patentable scope of the disclosure is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be included within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements that do not differ substantially from the literal language of the claims.

Claims

1. An electroporation system, comprising: Catheter shaft; at least one electrode coupled to the catheter shaft at its distal end; as well as an electroporation generator communicatively coupled to the at least one electrode, the electroporation generator being configured to provide a biphasic pulse signal to the at least one electrode, the biphasic pulse signal comprising: a first phase having a first polarity and a first pulse duration; and a second phase having a second polarity and a second pulse duration opposite to the first polarity, each of the first phase and the second phase having a voltage amplitude of at least 500 volts and a pulse duration of less than 20 microseconds, wherein the second phase is generated after the first phase by a non-zero interval; wherein the non-zero interval is greater than zero, and Wherein, the electroporation generator comprises: Microcontroller; a plurality of switching elements; and An opto-isolator communicatively couples the microcontroller with each of the plurality of switching elements and is configured to prevent noise generated by switching of the plurality of switching elements from reaching the microcontroller.

2. The electroporation system according to claim 1, wherein: Each of the first phase and the second phase has a voltage amplitude of at least 600 volts and a pulse duration of less than 3 microseconds.

3. The electroporation system according to claim 1, wherein: Each of the first phase and the second phase has a voltage amplitude of at least 600 volts and a pulse duration of less than 1.5 microseconds.

4. The electroporation system according to claim 1, wherein: Each of the first pulse duration, the second pulse duration, and the non-zero interval is less than 3 microseconds.

5. The electroporation system according to claim 4, wherein: Each of the first phase and the second phase has a voltage amplitude of at least 600 volts.

6. The electroporation system according to claim 1, wherein: The electroporation generator is further configured to generate a pulse train signal including a plurality of the biphasic pulse signals, wherein each of the plurality of the biphasic pulse signals is generated at a pulse period ranging from 0.5 milliseconds to 10 milliseconds.

7. The electroporation system according to claim 1, further comprising an electrode assembly coupled to the distal end of the catheter shaft, the electrode assembly comprising the at least one electrode, wherein The electrode assembly is configured as one of an electrode ring assembly, a basket electrode assembly, a planar electrode assembly, and an expandable electrode assembly including an expandable isolation member.

8. The electroporation system according to claim 7, wherein: The electrode assembly is configured as a bipolar electrode ring assembly, and wherein each of the first phase and the second phase has a voltage amplitude of at least 600 volts and a pulse duration of less than 3 microseconds.

9. The electroporation system according to claim 8, wherein: Each of the first phase and the second phase has a voltage amplitude in the range of 600 volts to 1.4 kV, and a pulse duration in the range of 1 microsecond to 1.5 microseconds.

10. The electroporation system according to claim 7, wherein: The electrode assembly is configured as a monopolar electrode ring assembly, and wherein each of the first phase and the second phase has a voltage amplitude of at least 800 volts and a pulse duration of less than 3 microseconds.

11. The electroporation system according to claim 10, wherein: Each of the first phase and the second phase has a voltage amplitude in the range of 800 volts to 3.0 kV, and a pulse duration in the range of 0.5 microseconds to 1.5 microseconds.

12. The electroporation system according to claim 7, wherein: The electrode assembly is configured as a bipolar expandable electrode assembly including an expandable isolation member, and wherein each of the first phase and the second phase has a voltage amplitude of at least 500 volts and a pulse duration of less than 20 microseconds.

13. The electroporation system according to claim 12, wherein: Each of the first phase and the second phase has a voltage amplitude in the range of 600 volts to 2.5 kV, and a pulse duration in the range of 500 nanoseconds to 1.5 microseconds.

14. An electroporation generator, comprising: a positive high voltage DC power supply having a first polarity; a negative high-voltage direct current power source having a second polarity opposite to the first polarity; a plurality of semiconductor switches connected in a bridge configuration that regulate application of the positive high voltage DC power source and the negative high voltage DC power source to first and second conductors for a conduit; a microcontroller communicatively coupled to the plurality of semiconductor switches and configured to control commutation of the plurality of semiconductor switches to send a biphasic pulse signal through the first and second conductors for the catheter; as well as an opto-isolator communicatively coupling the microcontroller with each of the plurality of semiconductor switches and configured to prevent noise generated by switching of the plurality of semiconductor switches from reaching the microcontroller; Wherein, the microcontroller is further configured to generate the bi-phase pulse signal, and the bi-phase pulse signal includes: a first phase having said first polarity and a first pulse duration; and a second phase having said second polarity and second pulse duration, each of said first phase and said second phase having a voltage amplitude of at least 500 volts and a pulse duration of less than 20 microseconds, and wherein the second phase is generated after the first phase by a non-zero interval, and wherein the non-zero interval is greater than zero.

15. The electroporation generator of claim 14, further comprising an opto-isolator coupled between the microcontroller and the plurality of semiconductor switches.

16. The electroporation generator of claim 14, further comprising a plurality of gate drivers coupled between the microcontroller and corresponding semiconductor switches of the plurality of semiconductor switches, wherein: The plurality of gate drivers are configured to provide gate drive currents based on at least one signal from the microcontroller.

17. The electroporation generator of claim 16, further comprising a gate drive impedance coupled between each of the plurality of gate drivers and a corresponding semiconductor switch of the plurality of semiconductor switches, the gate drive impedance being configured to calibrate a rise time of a high voltage DC provided through the plurality of semiconductor switches and further configured to reduce an oscillatory response of the plurality of semiconductor switches.

18. The electroporation generator according to claim 14, wherein: The plurality of semiconductor switches include a plurality of insulated gate bipolar transistors.

19. A method of generating a pulse signal, performed by an electroporation generator, the electroporation generator comprising a microcontroller, a plurality of semiconductor switches, and an opto-isolator communicatively coupling the microcontroller to each of the plurality of semiconductor switches, the method comprising: providing a positive high voltage DC power source having a first polarity to a plurality of semiconductor switches connected in a bridge configuration; providing a negative high-voltage direct current power source having a second polarity opposite to the first polarity to the plurality of semiconductors; commutating the plurality of semiconductor switches to apply the positive high voltage DC power source to a first conductor of the catheter and the negative high voltage DC power source to a second conductor of the catheter for a first duration of less than 20 microseconds to provide a first pulse signal having a voltage amplitude of at least 500 volts; After the first duration, commutating the plurality of semiconductor switches to electrically disconnect the first conductor and the second conductor from the positive high voltage DC power source and the negative high voltage DC power source for a second duration greater than zero; After the second duration, commutating the plurality of semiconductor switches to apply the positive high voltage DC power source to the second conductor and to apply the negative high voltage DC power source to the first conductor for a third duration of less than 20 microseconds to provide a second pulse signal having a voltage amplitude of at least 500 volts; After the third duration, commutating the plurality of semiconductor switches to electrically disconnect the first conductor and the second conductor from the positive high-voltage DC power source and the negative high-voltage DC power source; and Noise generated by switching of the plurality of semiconductor switches is prevented from reaching the microcontroller.

20. The method according to claim 19, wherein: Each of the first pulse signal and the second pulse signal has a voltage amplitude of at least 600 volts, and each of the first duration and the third duration is less than 3 microseconds.

21. The method according to claim 19, wherein: Each of the first pulse signal and the second pulse signal has a voltage amplitude of at least 600 volts, and each of the first duration and the third duration is less than 1.5 microseconds.

22. The method according to claim 19, wherein: Each of the first duration, the second duration, and the third duration is less than 3 microseconds.

23. The method according to claim 22, wherein: Each of the first pulse signal and the second pulse signal has a voltage amplitude of at least 600 volts.

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