System and method for electroporation using waveforms that reduce electrical stimulation

Abstract

A pulse generator for use with an electroporation system is provided. [Solution] The pulse generator is configured to be connected to a catheter containing multiple electrodes and is configured to generate a waveform that is transmitted using at least one of the multiple electrodes. The waveform includes a pulse train 252 having positive pulses 260 and negative pulses 254, and the average charge of the pulse train is zero.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of priority of U.S. Provisional Patent Application No. 63 / 304,321, filed on January 28, 2022, the entire content and disclosure of which are incorporated herein by reference.

[0002] This disclosure generally relates to waveform generation. In particular, this disclosure relates to electroporation waveforms that reduce electrical stimulation.

Background Art

[0003] Generally, ablation therapy is known to treat various diseases that afflict the human body structure. For example, ablation therapy is used in the treatment of atrial arrhythmias. When tissue is ablated or at least receives ablation energy generated by an ablation generator and delivered by an ablation applicator (e.g., a catheter), damage is formed in the tissue. By locally destroying heart tissue, diseases such as atrial arrhythmias (including, but not limited to, ectopic atrial tachycardia, atrial fibrillation, atrial flutter, etc.) can be improved.

[0004] Arrhythmias (i.e., irregular heart rhythms) can cause various dangerous diseases such as loss of synchronized atrioventricular contractions and blood flow stagnation, and can even lead to various illnesses and death. The main cause of atrial arrhythmias is thought to be vagus electrical signals within the left atrium or right atrium of the heart. An ablation catheter applies ablation energy (e.g., high - frequency energy, cryoablation, laser, chemical agents, high - density focused ultrasound, etc.) to heart tissue to form damage in the heart tissue. By severing unwanted electrical pathways due to this damage, vagus electrical signals that can cause arrhythmias are restricted or blocked.

[0005] Electroporation is a non-thermal ablation technique that involves applying a strong electric field to create pores in the cell membrane. For example, an electric field can be induced by applying pulses with relatively short durations, ranging from nanoseconds to milliseconds. These pulses can be repeated to form a pulse train. When such an electric field is applied to tissue in vivo, the cells in the tissue are exposed to transmembrane potential, creating pores that open the cell wall. Electroporation can be reversible (i.e., the temporarily opened pores then close again) or irreversible (i.e., the pores remain open). For example, in the field of gene therapy, reversible electroporation (i.e., temporarily opened pores) is used to introduce high molecular weight therapeutic vectors into cells. In other therapeutic applications, irreversible electroporation using only appropriately configured pulse trains can cause cell destruction. [Overview of the project] [Problems that the invention aims to solve]

[0006] In electroporation applications, various waveforms may be used to achieve different objectives. For example, some waveforms produce larger or smaller damage compared to others. Furthermore, some waveforms deliver more or less overall energy compared to others (generally, less overall energy delivery results in less heating of the target tissue). Another example is that some waveforms are more likely to induce muscle contractions in patients. However, generally, it is desirable to reduce the electrical stimulation from a waveform to cause little to no skeletal muscle contraction (i.e., to avoid muscle contractions). [Means for solving the problem]

[0007] In one embodiment, a pulse generator is provided for use with an electroporation system. This pulse generator is configured to be connected to a catheter containing multiple electrodes and is configured to generate a waveform that is delivered using at least one of the multiple electrodes. This waveform includes a pulse train having positive and negative pulses, and the average charge of the pulse train is zero.

[0008] In another embodiment, a pulse generator is provided for use with an electroporation system. This pulse generator is configured to be connected to a catheter containing multiple electrodes and is configured to generate a waveform that is delivered using at least one of the multiple electrodes. The waveform comprises a pulse train having positive and negative pulses, the pulse train comprising a first pulse, a last pulse, and at least one intermediate pulse between the first and last pulses, and in order to facilitate the reduction of the maximum absolute charge of the pulse train, the first pulse and the last pulse have at least one of different amplitudes and different pulse widths from the at least one intermediate pulse.

[0009] In yet another embodiment, a method for controlling an electroporation system is provided. This method includes generating a waveform using a pulse generator, which includes a pulse train having positive and negative pulses, wherein the average charge of the pulse train is zero, and sending the generated waveform to a target tissue using one or more electrodes on a catheter connected to the pulse generator.

[0010] The aforementioned and other aspects, features, details, usefulness, and advantages of this disclosure will become apparent from reading the following description and claims, as well as from looking at the accompanying drawings. [Brief explanation of the drawing]

[0011] [Figure 1] These are schematic and block diagrams of an electroporation therapy system. [Figure 2A]This is one embodiment of a waveform that can be transmitted using the system shown in Figure 1. [Figure 2B] This is one embodiment of a waveform that can be transmitted using the system shown in Figure 1. [Figure 2C] This is one embodiment of a waveform that can be transmitted using the system shown in Figure 1. [Figure 3A] This is one embodiment of a waveform that can be transmitted using the system shown in Figure 1. [Figure 3B] This is one embodiment of a waveform that can be transmitted using the system shown in Figure 1. [Figure 4] This is one embodiment of a waveform that can be transmitted using the system shown in Figure 1. [Modes for carrying out the invention]

[0012] This disclosure provides a pulse generator for use in conjunction with an electroporation system. The pulse generator is configured to be connected to a catheter containing multiple electrodes and is configured to generate a waveform delivered using at least one of the multiple electrodes. The waveform comprises a pulse train having positive and negative pulses, the pulse train having at least one of a reduced maximum absolute charge and a zero-mean charge of the pulse train.

[0013] Figure 1 is a schematic and block diagram of system 10 for electroporation therapy. Generally, system 10 includes a catheter electrode assembly 12 positioned at the distal end 48 of a catheter 14. In this specification, “proximal” refers to the direction toward the catheter end closer to the clinician, and “distal” refers to the direction toward the patient’s body, away from the clinician. The electrode assembly includes one or more electrically insulated individual electrode elements. Each of the electrode elements, also referred to herein as a catheter electrode, is individually wired to be selectively paired with or combined with other electrode elements to function as a bipolar or multipolar electrode.

[0014] System 10 may be used for irreversible electroporation (IRE) that destroys tissue. In particular, System 10 may be used for electroporation-induced therapies that involve delivering an electric current to cause destruction and cell disruption by directly and irreversibly losing the integrity of the cell membrane (cell wall). The mechanism of this cell disruption can be thought of as an "outside-in" process, meaning that the destruction of the outer wall of the cell has a detrimental effect on the inside of the cell. Typically, in classical cell membrane electroporation, the current is delivered as a pulsed electric field in the form of short-duration pulses (e.g., pulses with a duration of 500 nanoseconds (ns) to 20 microseconds (μs)) between closely spaced electrodes capable of delivering an electric field strength of about 0.1 to 1.0 kilovolts / centimeter (kV / cm). System 10 may be used for high-power (e.g., high voltage and / or high current) electroporation procedures. Furthermore, System 10 may be used with a loop catheter and / or basket catheter.

[0015] In one embodiment, the stimulus is selectively transmitted on the catheter 14 (for example, between a pair of bipolar electrodes). Furthermore, the electrodes on the catheter 14 may be switchable between being connected to a 3D mapping system and being connected to an electroporation generator.

[0016] Although the energization method is described as involving DC electroporation pulses (i.e., square wave pulses), embodiments may be modified and should be understood to remain within the spirit and scope of this disclosure. For example, AC pulses (i.e., sinusoidal pulses), RF pulses, sequences of RF bursts, asymmetric pulses, and combinations thereof may be used. Furthermore, embodiments described herein may be performed in medical therapies other than electroporation therapy (e.g., electrosurgery, electrochemotherapy, cancer treatment, diathermy, etc.).

[0017] For example, although the methods and systems disclosed herein are described in terms of electroporation applications, those skilled in the art will understand that the techniques described herein can be implemented in any suitable application.

[0018] Furthermore, it should be understood that the mechanism of cell destruction in electroporation is not primarily due to a heating effect, but rather to the destruction of the cell membrane by applying a high-voltage electric field. Therefore, electroporation can avoid the thermal effects that can occur when other energy sources are applied. Thus, this "hypotherapy" has desirable characteristics.

[0019] With this background in mind, referring again to Figure 1, the system 10 comprises a catheter electrode assembly 12 including at least one catheter electrode. The electrode assembly 12 is incorporated as part of a medical device such as a catheter 14 for electroporation therapy of tissue 16 within the patient's body 17. In exemplary embodiments, the tissue 16 includes cardiac or myocardial tissue. However, it should be understood that embodiments may be used to perform electroporation therapy on various other body tissues (e.g., kidney tissue, tumors, etc.).

[0020] FIG. 1 further shows a plurality of return electrodes 18, 20, and 21, which can be used for body connections by various subsystems included in the entire system 10, such as an electroporation generator 26, an electrophysiology (EP) monitor such as an ECG monitor 28, and a positioning and navigation system 30 for visualization, mapping, and navigation of internal structures. In the illustrated embodiment, the return electrodes 18, 20, 21 are patch electrodes. Only one patch electrode is shown for illustrative (for clarity) purposes, and the subsystems to which these patch electrodes are connected may include multiple patch (body surface) electrodes, typically include multiple patch (body surface) electrodes, and may include split patch electrodes as described herein. In other embodiments, the return electrodes 18, 20, 21 may be other types of electrodes suitable for use as return electrodes, such as, for example, one or more catheter electrodes. When the return electrode is a catheter electrode, the return electrode may be part of the electrode assembly 12 or part of another catheter or device (not shown). The system 10 may further include a main computer system 32 (including an electronic control unit 50 and a data storage memory 52), and in a particular embodiment, the main computer system 32 may be integrated with the positioning and navigation system 30. The system 32 may further include conventional interface components such as various user input / output mechanisms 34A and a display 34B among other components.

[0021] The electroporation generator 26 is configured to energize the electrode elements according to a predetermined or user-selectable electroporation energization method. For electroporation therapy, the generator 26 can transmit an electric field strength of about 0.1 to 1.0 kV / cm (at the tissue site) between closely spaced electrodes, and generate a pulsed electric field in the form of short-duration rectangular pulses (e.g., with a duration from nanoseconds to several milliseconds, or any duration suitable for electroporation), and the current sent through the electrode assembly 12 can be generated. The amplitude and pulse width required for irreversible electroporation are in an inverse proportional relationship. That is, in order to form pores, generally, the smaller the pulse width, the larger the amplitude.

[0022] The electroporation generator 26, which may also be referred to herein as a DC energy source, is configured to generate a series of DC energy pulses (i.e., rectangular pulses) that produce a two-directional current (i.e., positive and negative pulses). In other embodiments, the electroporation generator 26 is any suitable type of electroporation generator. In some embodiments, the electroporation generator 26 is configured to output energy in DC pulses at selectable energy levels such as 50 joules, 100 joules, 200 joules, etc. In other embodiments, the number of energy settings may be more or less, and the available set values may be the same or different. In order to succeed in electroporation, in some embodiments, an output level of 200 joules is utilized. For example, the electroporation generator 26 may output a DC pulse having a peak magnitude from about 300 volts (V) to about 3,200 V at an output level of 200 joules. In other embodiments, any other suitable positive or negative voltage may be output.

[0023] In some embodiments, the impedance of the system 10 can be varied by a variable impedance 27 to limit arc discharge. Furthermore, the variable impedance 27 may be used to modify one or more characteristics of the output of the electroporation generator 26, such as amplitude, duration, and pulse shape. Although the variable impedance 27 is shown as a separate component, it may be incorporated into the catheter 14 or the generator 26.

[0024] Continuing to refer to Figure 1, as described above, the catheter 14 may have an electroporation function, and in certain embodiments, it may also have an ablation function (e.g., RF ablation). However, it should be understood that in those embodiments, it is possible to change the type of ablation energy provided (e.g., cryoablation, ultrasound, etc.).

[0025] In the illustrated embodiment, the catheter 14 comprises a cable connector or interface 40, a handle 42, and a shaft 44 having a proximal end 46 and a distal end 48. The catheter 14 may also comprise other conventional components not shown, such as a temperature sensor, additional electrodes, and corresponding conductors or lead wires. The connector 40 provides mechanical and electrical connections to a cable 56 extending from the generator 26. The connector 40 may include conventional components known in the art and is located at the proximal end of the catheter 14, as shown.

[0026] The handle 42 may provide a place for the clinician to hold the catheter 14 and further provide means for maneuvering or guiding the shaft 44 within the body 17. For example, the handle 42 may include means for changing the length of a guidewire extending through the catheter 14 to the distal end 48 of the shaft 44, or means for maneuvering the shaft 44. Furthermore, in some embodiments, the handle 42 may be configured to change the shape, size, and / or orientation of a portion of the catheter, and it will be understood that the structure of the handle 42 may vary. In another embodiment, the catheter 14 may be robot-driven or robot-controlled. Thus, the catheter 14 is operated using a robot rather than the clinician operating a handle to advance / retract and / or maneuver or guide the catheter 14 (particularly its shaft 44). The shaft 44 is an elongated tubular flexible member configured to move within the body 17. The shaft 44 supports the electrode assembly 12 and is configured to include associated conductors and, optionally, additional electronics used for signal processing or adjustment. The shaft 44 may also allow for the movement, delivery, and / or removal of fluids (including irrigation fluids and body fluids), pharmaceuticals, and / or surgical tools or instruments. The shaft 44 may be made of a conventional material such as polyurethane and define one or more lumens configured to accommodate and / or move electrical conductors, fluids, or surgical tools, as described herein. The shaft 44 may be introduced into a blood vessel or other structure within the body 17 using a conventional introducer. The shaft 44 may then be advanced / retracted and / or guided or directed within the body 17 to a desired location, such as a site of tissue 16, by means of a guidewire or other means known in the art.

[0027] A localization and navigation system 30 may be provided for the visualization, mapping, and navigation of internal body structures. The localization and navigation system 30 may include conventional devices commonly known in the art. For example, the localization and navigation system 30 may be substantially similar to the EnSite Precision® system, commercially available from Abbott Laboratories and described in U.S. Patent No. 7,263,397, entitled "Method and Apparatus for Catheter Navigation and Location and Mapping in the Heart," by the same applicant. The entire disclosure of this U.S. patent is incorporated herein by reference. In another embodiment, the localization and navigation system 30 may be substantially similar to the EnSite X® system, described in U.S. Patent Application No. 2020 / 0138334, entitled "Method for Medical Device Localization Based on Magnetic and Impedance Sensors." The entire disclosure of this U.S. patent application is incorporated herein by reference. However, it should be understood that the localization and navigation system 30 is illustrative and not inherently limiting. Other techniques are known for locating / navigating (and visualizing) catheters in space, such as Biosense Webster's CARTO navigation and positioning system, Boston Scientific Scimed's Rhythmia® system, Koninklijke Philips NV's KODEX® system, Northern Digital's AURORA® system, commercially available fluoroscopy systems, or magnetic positioning systems such as Mediguide's gMPS system.

[0028] In this regard, some positioning, navigation, and / or visualization systems include sensors for generating signals indicating the position of a catheter, or, for example, impedance-based positioning systems, one or more electrodes, or, for example, magnetic field-based positioning systems, one or more coils (i.e., wire windings) configured to detect one or more characteristics of a magnetic field. As yet another example, system 10 may utilize a system combining electric field-based and magnetic field-based systems, as shown with reference to U.S. Patent No. 7,536,218, entitled "Hybrid Magnetic-Based and Impedance Based Position Sensing." The disclosure of this U.S. patent is incorporated herein by reference in its entirety.

[0029] Pulse-field ablation (PFA), a method for achieving irreversible electroporation, can be performed using the systems and methods described herein. In some cases, PFA may be used to perform pulmonary vein isolation (PVI) at specific cardiac tissue sites, such as pulmonary veins. In PFA, an electric field may be applied between adjacent electrodes (bipolar approach) or between one or more electrodes and a return patch (unipolar approach). To monitor the operation of system 10, one or more impedances may be measured between electrodes on catheter 14 and / or between return electrodes 18, 20, 21. For example, for system 10, impedances may be measured as described in U.S. Patent Application Publication No. 2019 / 0117113 filed on 23 October 2018, U.S. Patent Application Publication No. 2019 / 0183378 filed on 19 December 2018, and U.S. Patent Application No. 63 / 027,660 filed on 20 May 2020. All of the above-mentioned U.S. patent applications and publications are incorporated herein by reference in their entirety.

[0030] In electroporation therapy, a pulse generator (e.g., electroporation generator 26 (shown in Figure 1)) is used to generate a waveform, which is then applied between a pair of catheter electrodes (i.e., a bipolar approach) or between a catheter electrode and a return patch (i.e., a unipolar approach). The waveform may consist of one or more pulse bursts (each burst containing multiple pulses). Furthermore, the waveform is characterized by several parameters (e.g., pulse width, pulse amplitude, frequency, etc.).

[0031] Various waveforms may be used to achieve various goals. For example, some waveforms produce larger or smaller damage compared to others. Furthermore, some waveforms deliver more or less overall energy compared to others (generally, less overall energy delivery results in less heating of the target tissue). As another example, some waveforms are more likely to induce muscle contractions in the patient. However, generally, to avoid undesirable side effects, as described herein, currents with zero overall charge may be used. Generally, electroporation therapy is desirable to be performed for a relatively short time and with relatively few treatment applications. Furthermore, it is generally desirable to avoid tissue heating and to minimize skeletal muscle gradation (avoid muscle contractions).

[0032] The systems and methods described herein utilize waveforms having zero mean charge and / or reduced maximum absolute charge to reduce muscle contraction and / or nerve stimulation. The techniques described herein can be applied to waveforms having various frequencies, amplitudes, pulse shapes, initial pulse polarities, etc. Furthermore, the embodiments described herein may be carried out using a current source, a voltage source, or an intermediate output impedance source to generate the waveform.

[0033] This specification assumes an ideal amplifier with no startup effect (i.e., the first cycle is identical to all subsequent cycles), no close-down effect (i.e., the last cycle is identical to all preceding cycles, with no output after the last cycle), and infinite bandwidth. However, the waveforms described herein may be adapted for use with amplifiers that do not meet these criteria, and circuits for achieving these waveforms may be used to improve charge balance.

[0034] In the example waveforms described below, the horizontal axis represents time and the vertical axis represents amplitude (e.g., amperes). Note that the time scale, amplitude, and pulse shape shown are merely examples, and any appropriate parameters may be used. Furthermore, the amplitude may be expressed as a current value, an electric field value, etc. For each example waveform, the waveform signal itself and its integral value (to indicate the charge delivered by the waveform) are shown. The integral value increases when the waveform signal is positive, remains constant when the waveform signal is zero, and decreases when the waveform signal is negative.

[0035] The following exemplary waveforms include positive and negative pulses. In some embodiments (e.g., electroporation applications), the voltage amplitude of each pulse may be in the range of about 300V to about 3,200V, and more specifically, in the range of about 1,000V to about 2,000V. Furthermore, the pulse width of each pulse (i.e., one positive pulse or one negative pulse) may be in the range of about 500ns to 20μs, more specifically, in the range of about 1.0μs to about 10.0μs, and even more specifically, in the range of about 2.0μs to about 5.0μs. Of course, those skilled in the art will understand that any suitable pulse parameters may be used.

[0036] For relatively low-frequency signals, neurons may be excited by the first pulse of the burst. The neutralizing effect of subsequent reverse-polarity pulses (which return the net charge to zero) may be too late to suppress the excitation. With respect to such signals, the embodiments described herein address this problem by achieving double the current without excitation by halving the maximum absolute value of the charge in the pulse burst.

[0037] For high-frequency signals, excited tissue receives an approximately average charge, and becomes excited if the approximately average charge is above a certain level over a certain period of time. Therefore, in many embodiments described herein (as will be described in detail below), the average charge is zero, and muscles and nerves become less susceptible to stimulation by high-frequency bursts.

[0038] Figure 2A shows one embodiment of a waveform 200 that can be generated using system 10 (shown in Figure 1). The waveform 200 includes a pulse train 202 having alternating positive and negative pulses 204. The pulse train 202 includes an initial pulse 210, a final pulse 212, and a number of intermediate pulses 214. All pulses 204 have the same amplitude and pulse length. This is also called a symmetric pulse pattern.

[0039] The integrated signal 220 represents the charge delivered by waveform 200 over time. As shown in Figure 2A, the total charge delivered by waveform 200 is zero (i.e., the charge at the end of the burst is zero). However, the average charge delivered by waveform 200 is not zero at any point in the burst (i.e., the average charge is positive when calculated from the beginning of the burst to any point in the burst).

[0040] Figure 2B shows a waveform 250 of another embodiment that can be generated using system 10 (shown in Figure 1). Waveform 250 includes a pulse train 252 having alternating positive and negative pulses 254. The pulse train 252 includes an initial pulse 260, a final pulse 262, and a number of intermediate pulses 264.

[0041] In this embodiment, all intermediate pulses 264 have the same amplitude and pulse width. However, the first pulse 260 and the last pulse 262 have the same amplitude as the intermediate pulses 264 (e.g., voltage amplitude in the range of approximately 1000V to approximately 2000V), but have different pulse widths. Specifically, the pulse widths of the first pulse 260 and the last pulse 262 are half the pulse width of the intermediate pulse 264. For example, the intermediate pulse 264 may have a pulse width of approximately 3.0 μs, while the first pulse 260 and the last pulse 262 may have a pulse width of approximately 1.5 μs. Furthermore, the first pulse 260 and the last pulse 262 have the same polarity.

[0042] The integrated signal 270 represents the charge delivered by the waveform 250 over time. By halving the pulse width of the first pulse 260 and the last pulse 262 (relative to the waveform 200), the average charge delivered by the waveform 250 becomes zero. That is, the average value of the integrated signal 270 is zero over the entire burst, and also zero at regular intervals throughout the entire burst. Furthermore, the overall charge delivered by the waveform 250 is zero, as indicated by the fact that the integrated signal 270 is zero at the end of the waveform 250.

[0043] Furthermore, the maximum magnitude of the integrated signal 270 (corresponding to the maximum absolute charge value) is smaller than the maximum magnitude of the integrated signal 220. This smaller magnitude makes it less likely to cause muscle contraction and / or nerve stimulation. This smaller magnitude may also make it easier to use electrodes with smaller surface areas, depending on the application.

[0044] Figure 2C shows a waveform 280 of another embodiment that may be generated using system 10 (shown in Figure 1). Waveform 280 includes a pulse train 282 having alternating positive and negative pulses 284. The pulse train 282 includes an initial pulse 290, a final pulse 292, and a number of intermediate pulses 294.

[0045] In this embodiment, all intermediate pulses 294 have the same amplitude and pulse width. However, the first pulse 290 and the last pulse 292 have the same pulse width as the intermediate pulse 294 (e.g., a pulse width of about 3.0 μs), but have a different amplitude. Specifically, the pulse amplitude of the first pulse 290 and the last pulse 292 is half the amplitude of the intermediate pulse 294. For example, the intermediate pulse 294 may have a voltage amplitude of about 1500 V, and the first pulse 290 and the last pulse 292 may have a voltage amplitude of about 750 V. Furthermore, the first pulse 290 and the last pulse 292 have the same polarity.

[0046] The integrated signal 296 represents the charge delivered by waveform 280 over time. By halving the amplitude of the first pulse 290 and the last pulse 292 (relative to waveform 200), the average charge delivered by waveform 280 becomes zero. That is, the average value of the integrated signal 296 is zero over the entire burst, and also zero at regular intervals throughout the entire burst. Furthermore, the overall charge delivered by waveform 280 is zero, as indicated by the fact that the integrated signal 296 at the end of waveform 280 is zero.

[0047] In this case as well, the maximum magnitude of the integrated signal 296 (corresponding to the maximum absolute charge value) is smaller than the maximum magnitude of the integrated signal 220. This smaller magnitude makes it less likely to cause muscle contraction and / or nerve stimulation. This smaller magnitude may also make it easier to use electrodes with smaller surface areas, depending on the application.

[0048] Figure 3A shows a waveform 300 of another embodiment that can be generated using system 10 (shown in Figure 1). Waveform 300 includes a pulse train 302 having alternating positive and negative pulses 304. The pulse train 302 includes an initial pulse 310, a final pulse 312, and a number of intermediate pulses 314. In one example, each of the initial pulse 310, the final pulse 312, and the intermediate pulses 314 has a voltage amplitude in the range of about 200V to about 2000V and a pulse width in the range of about 1.0μs to about 5.0μs. Alternatively, any appropriate voltage and pulse width values ​​may be used. All positive pulses in pulse train 302 have a larger amplitude and shorter pulse length than all negative pulses in pulse train 302. However, the area of ​​each positive pulse is the same as the area of ​​each negative pulse. This is sometimes called an asymmetric pulse pattern.

[0049] The integrated signal 320 represents the charge delivered by the waveform 300 over time. As shown in Figure 3A, the total charge delivered by the waveform 300 is zero because the area of ​​the positive pulse is equal to the area of ​​the negative pulse. However, the average charge delivered by the waveform 300 is not zero at any point in the burst. Thus, the waveform 300 provides the "average charge" that the tissue receives throughout the entire burst.

[0050] Figure 3B shows a waveform 350 of another embodiment that can be generated using system 10 (shown in Figure 1). Waveform 350 includes a pulse train 352 having alternating positive and negative pulses 354. The pulse train 352 includes an initial pulse 360, a final pulse 362, and a number of intermediate pulses 364. In one example, each of the initial pulse 360, the final pulse 362, and the intermediate pulses 364 has a voltage amplitude in the range of about 200V to about 2000V and a pulse width in the range of about 1.0μs to about 5.0μs. Alternatively, any appropriate voltage and pulse width values ​​may be used.

[0051] In this embodiment, the positive pulse of the intermediate pulse 364 has a larger amplitude and shorter pulse length than the negative pulse of the intermediate pulse 364. Furthermore, the first pulse 360 ​​and the last pulse 362 have the same polarity. Note that the first pulse 360 ​​and the last pulse 362 have the same amplitude as the intermediate pulse 364 of the same polarity (i.e., the negative intermediate pulse 364), but their pulse widths are different. Specifically, the pulse widths of the first pulse 360 ​​and the last pulse 362 are half the pulse width of the negative intermediate pulse 364.

[0052] The integrated signal 370 represents the charge delivered by the waveform 350 over time. By halving the pulse width of the first pulse 360 ​​and the last pulse 362 (relative to the waveform 300), the average charge delivered by the waveform 350 becomes zero. That is, the average value of the integrated signal 370 is zero over the entire burst, and also zero at regular intervals throughout the entire burst. Furthermore, the overall charge delivered by the waveform 350 is zero, as indicated by the fact that the integrated signal 370 is zero at the end of the waveform 350.

[0053] Furthermore, the maximum magnitude of the integrated signal 370 (corresponding to the maximum absolute charge value) is smaller than the maximum magnitude of the integrated signal 320. This smaller magnitude makes it less likely to cause muscle contraction and / or nerve stimulation. This smaller magnitude may also make it easier to use electrodes with smaller surface areas, depending on the application.

[0054] By using long-width polarities (i.e., negative pulses in this embodiment) for the first pulse 360 ​​and the last pulse 362, the requirements for the amplifier's bandwidth and switching speed are reduced.

[0055] Figure 4 shows a waveform 400 of another embodiment that can be generated using system 10 (shown in Figure 1). Waveform 400 includes a pulse train 402 having alternating positive and negative pulses 404. The pulse train 402 includes an initial pulse 410, a final pulse 412, and a number of intermediate pulses 414. In one example, each of the initial pulse 410, the final pulse 412, and the intermediate pulses 414 has a voltage amplitude in the range of about 200V to about 2000V and a pulse width in the range of about 1.0μs to about 5.0μs. Alternatively, any appropriate voltage and pulse width values ​​may be used.

[0056] In this embodiment, all intermediate pulses 414 have the same amplitude and pulse width. However, the first pulse 410 and the last pulse 412 have the same pulse width as the intermediate pulses 414, but have different amplitudes. Specifically, the pulse amplitudes of the first pulse 410 and the last pulse 412 are half the amplitude of the intermediate pulses 414. Therefore, waveform 400 is somewhat similar to waveform 280 (shown in Figure 3C). However, unlike waveform 280, the first pulse 410 and the last pulse 412 have different polarities.

[0057] The integrated signal 416 represents the charge delivered by waveform 400 over time. With respect to waveform 400, the average charge delivered is not zero over the entire burst, but it is still zero at regular intervals throughout the burst. Furthermore, the overall charge delivered by waveform 400 is zero, as indicated by the integrated signal 416 being zero at the end of waveform 400.

[0058] In the case of waveform 400, the average charge transmitted is not zero, but the maximum magnitude of the integrated signal 416 (corresponding to the maximum absolute charge value) is smaller than the maximum magnitude of the integrated signal 220. This smaller magnitude makes muscle contraction and / or nerve stimulation less likely. This smaller magnitude may also make it easier to use electrodes with small surface areas, depending on the application.

[0059] As those skilled in the art will understand, in order to obtain similar results, instead of the first pulse 410 and the last pulse 412 having half the amplitude of the intermediate pulse 414, the first pulse 410 and the last pulse 412 may have the same amplitude as the intermediate pulse 414, but with half the pulse width of the intermediate pulse 414.

[0060] Figures 2B, 2C, and 3B show waveforms that constitute a complete pulse burst (e.g., including multiple positive and negative pulses). However, those skilled in the art will understand that the techniques described herein (e.g., achieving zero-mean charge across a waveform) can be performed with fewer pulses. For example, a subset of pulses within a burst may constitute a zero-mean charge waveform, but the burst itself may not have a zero-mean charge.

[0061] In the embodiments disclosed herein, the short interval between the positive and negative pulses allows for timing inaccuracies in the switching components and reduces the bandwidth of the output signal. These times do not affect the overall average charge (i.e., zero) nor the reduction of the maximum absolute charge. In some embodiments, the pulse length is adjusted to account for non-ideal switching times or non-resistive loads. Furthermore, to improve charge balance, the circuits used to deliver the first and last pulses can be used to compensate for amplifier shortcomings (e.g., turn-on effects at the start of a burst and amplitude reduction as the burst approaches its end).

[0062] Those skilled in the art will understand that the specific waveforms disclosed herein are illustrative. Generally, any combination of pulse duration, pulse amplitude, or pulse shape may be used to result in a zero-mean charge in the waveform such that the first and last pulses achieve half the charge level of the intermediate pulses. That is, a waveform with zero-mean charge may be contained within a longer burst waveform and may have a shorter duration than the longer burst waveform.

[0063] The systems and methods described herein relate to pulse generators used in conjunction with electroporation systems. These pulse generators are configured to be coupled to a catheter containing multiple electrodes and to generate a waveform delivered using at least one of the multiple electrodes. The waveform comprises a pulse train having positive and negative pulses, the pulse train having at least one of a reduced maximum absolute charge and a zero-average charge across the pulse train.

[0064] While specific embodiments of this disclosure have been described in some detail above, those skilled in the art will be able to make various modifications to the disclosed embodiments without departing from the spirit or scope of this disclosure. All references to directions (e.g., up, down, upward, downward, left, right, leftward, rightward, upper, lower, upper side, lower side, vertical, horizontal, clockwise, and counterclockwise) are used solely for identification purposes to aid the reader's understanding of this disclosure and are not particularly limited to the position, orientation, or use of this disclosure. References to connections (e.g., mounted, linked, connected, etc.) should be interpreted broadly and may include intermediate members between element connections and relative movement between elements. Thus, references to connections do not necessarily indicate that two elements are directly connected and in a fixed relationship with one another. All matters shown in the above description or in the accompanying drawings should be interpreted as illustrative only and not limiting. Details or structures may be modified without departing from the spirit of this disclosure as defined in the accompanying claims.

[0065] When introducing elements of this disclosure or its preferred embodiments, the articles “a,” “an,” “the,” and “said” are intended to indicate that there are one or more elements. The terms “comprising,” “including,” and “having” are intended to be comprehensive and mean that there may be further elements other than those listed.

[0066] Since various modifications can be made to the above configuration without departing from the scope of this disclosure, all matters shown in the above description or in the accompanying drawings are intended to be construed as illustrative and not as restrictive.

Claims

1. A pulse generator used in conjunction with an electroporation system, The pulse generator is configured to be connected to a catheter containing multiple electrodes, and is configured to generate a waveform that is transmitted using at least one of the multiple electrodes. The waveform includes a pulse train having positive and negative pulses, A pulse generator in which the average charge of the pulse train is zero.

2. The pulse train includes a first pulse, a last pulse, and at least one intermediate pulse between the first pulse and the last pulse. The pulse generator according to claim 1, wherein the polarity of the first pulse is the same as the polarity of the last pulse.

3. The at least one intermediate pulse has a first pulse width, The pulse generator according to claim 2, wherein the first pulse and the last pulse have a second pulse width different from the first pulse width.

4. The pulse generator according to claim 3, wherein the second pulse width is half the first pulse width.

5. The pulse generator according to claim 2, wherein the positive pulse of the at least one intermediate pulse has a different pulse width and different amplitude than the negative pulse of the at least one intermediate pulse.

6. The at least one intermediate pulse has a first pulse amplitude, The pulse generator according to claim 2, wherein the first pulse and the last pulse have a second pulse amplitude different from the first pulse amplitude.

7. The pulse generator according to claim 6, wherein the second pulse amplitude is half the first pulse amplitude.

8. The pulse train is a subset of pulses within a longer burst waveform, The pulse generator according to claim 1, wherein the average charge of the burst waveform is not zero.

9. A pulse generator used in conjunction with an electroporation system, The pulse generator is configured to be connected to a catheter containing multiple electrodes, and is configured to generate a waveform that is transmitted using at least one of the multiple electrodes. The waveform has a pulse train with positive and negative pulses, The pulse train includes a first pulse, a last pulse, and at least one intermediate pulse between the first pulse and the last pulse. A pulse generator wherein, in order to facilitate the reduction of the maximum absolute charge of the pulse train, the first pulse and the last pulse have at least one of different amplitudes and different pulse widths from the at least one intermediate pulse.

10. The pulse generator according to claim 9, wherein the first pulse and the last pulse have different polarities.

11. The first pulse and the last pulse have the same polarity. The pulse generator according to claim 9, wherein the average charge of the pulse train is zero.

12. The at least one intermediate pulse has a first pulse width, The pulse generator according to claim 9, wherein the first pulse and the last pulse have a second pulse width that is half the width of the first pulse.

13. The at least one intermediate pulse has a first pulse amplitude, The pulse generator according to claim 9, wherein the first pulse and the last pulse have a second pulse amplitude that is half the amplitude of the first pulse.

14. An electroporation system control method, Using a pulse generator, generate a waveform that includes a pulse train having positive and negative pulses, wherein the average charge of the pulse train is zero. Using one or more electrodes on a catheter connected to the pulse generator, the generated waveform is sent to the target tissue. Methods that include...

15. The pulse train includes a first pulse, a last pulse, and at least one intermediate pulse between the first pulse and the last pulse. The method according to claim 14, wherein the polarity of the first pulse is the same as the polarity of the last pulse.

16. The at least one intermediate pulse has a first pulse width, The method according to claim 15, wherein the first pulse and the last pulse have a second pulse width different from the first pulse width.

17. The method according to claim 16, wherein the second pulse width is half the first pulse width.

18. The method according to claim 15, wherein the positive pulse of the at least one intermediate pulse has a different pulse width and different amplitude than the negative pulse of the at least one intermediate pulse.

19. The at least one intermediate pulse has a first pulse amplitude, The method according to claim 15, wherein the first pulse and the last pulse have a second pulse amplitude different from the first pulse amplitude.

20. The method according to claim 19, wherein the second pulse amplitude is half the first pulse amplitude.

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