Systems and methods for electroporation using waveforms that reduce electrical stimulation

Abstract

A pulse generator for use with an electroporation system is provided, the pulse generator configured to be coupled to a catheter including a plurality of electrodes and configured to generate a waveform delivered using at least one of the plurality of electrodes, the waveform including a pulse train having a positive pulse and a negative pulse, the average charge of the pulse train being zero.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 304,321, filed January 28, 2022, the entire contents and disclosure of which are incorporated herein by reference.

[0002] The present disclosure relates generally to waveform generation, and more particularly to electroporation waveforms that reduce electrical stimulation. [Background technology]

[0003] It is generally known to use ablation therapy to treat various diseases afflicting the human anatomy. For example, ablation therapy is used to treat atrial arrhythmias. When tissue is ablated, or at least subjected to ablation energy generated by an ablation generator and delivered by an ablation applicator (e.g., a catheter), lesions are formed in the tissue. The local destruction of cardiac tissue can ameliorate diseases such as atrial arrhythmias (including, but not limited to, ectopic atrial tachycardia, atrial fibrillation, atrial flutter, etc.).

[0004] Cardiac arrhythmias (i.e., irregular heart rhythms) can cause a variety of dangerous conditions, such as loss of synchronized atrioventricular contractions and stasis of blood flow, and can even lead to various illnesses and death. The primary cause of atrial arrhythmias is thought to be stray electrical signals within the left or right atrium of the heart. Ablation catheters deliver ablation energy (e.g., radiofrequency energy, cryoablation, laser, chemical agents, high-intensity focused ultrasound, etc.) to cardiac tissue, creating lesions in the cardiac tissue. This lesion disrupts unwanted electrical pathways, thereby limiting or preventing the stray electrical signals that could cause arrhythmias.

[0005] Electroporation is a non-thermal ablation technique that involves applying a strong electric field that creates pores in cell membranes. For example, electric fields can be induced by applying relatively short pulses, ranging from nanoseconds to milliseconds. Such pulses may be repeated to form a pulse train. When such an electric field is applied to tissue in vivo, the tissue cells are exposed to a transmembrane potential, resulting in the formation of pores that open the cell wall. Electroporation can be reversible (i.e., the temporarily opened pores subsequently reclose) or irreversible (i.e., the pores remain open). For example, in the field of gene therapy, reversible electroporation (i.e., the temporarily opened pores) is used to introduce high-molecular-weight therapeutic vectors into cells. In other therapeutic applications, irreversible electroporation can result in cell destruction using only appropriately configured pulse trains. Summary of the Invention [Problem to be solved by the invention]

[0006] In electroporation applications, different waveforms may be used to achieve different goals. For example, some waveforms produce lesions of greater or lesser size than other waveforms. Furthermore, some waveforms provide greater or lesser overall energy delivery than other waveforms (lesser overall energy delivery generally results in less heating of the target tissue). As another example, some waveforms are more likely to induce muscle contractions in a patient. However, it is generally desirable to reduce the electrical stimulation from the waveform to produce little or no skeletal muscle recruitment (i.e., avoid muscle contractions). [Means for solving the problem]

[0007] In one aspect, a pulse generator for use with an electroporation system is provided, the pulse generator being configured to be coupled to a catheter including a plurality of electrodes and configured to generate a waveform delivered using at least one of the plurality of electrodes, the waveform including a pulse train having a positive pulse and a negative pulse, the pulse train having an average charge of zero.

[0008] In another aspect, a pulse generator for use with an electroporation system is provided, the pulse generator being configured to be coupled to a catheter including a plurality of electrodes and configured to generate a waveform delivered using at least one of the plurality of electrodes, the waveform including a pulse train having a positive pulse and a negative pulse, the pulse train including a first pulse, a last pulse, and at least one intermediate pulse between the first and last pulses, the first and last pulses having a different amplitude and / or pulse width than the at least one intermediate pulse to facilitate reducing the maximum absolute charge of the pulse train.

[0009] In yet another aspect, a method of controlling an electroporation system is provided, the method including generating, with a pulse generator, a waveform including a pulse train having positive and negative pulses, where the pulse train has an average charge of zero, and delivering the generated waveform to a target tissue using one or more electrodes on a catheter coupled to the pulse generator.

[0010] The foregoing and other aspects, features, details, utilities, and advantages of the present disclosure will become apparent from reading the following description and claims, and from viewing the accompanying drawings. [Brief explanation of the drawings]

[0011] [Figure 1] 1 is a schematic and block diagram of a system for electroporation therapy. [Figure 2A]2 is an embodiment of a waveform that may be transmitted using the system shown in FIG. 1. [Figure 2B] 2 is an embodiment of a waveform that may be transmitted using the system shown in FIG. 1. [Figure 2C] 2 is an embodiment of a waveform that may be transmitted using the system shown in FIG. 1. [Figure 3A] 2 is an embodiment of a waveform that may be transmitted using the system shown in FIG. 1. [Figure 3B] 2 is an embodiment of a waveform that may be transmitted using the system shown in FIG. 1. [Figure 4] 2 is an embodiment of a waveform that may be transmitted using the system shown in FIG. 1. DETAILED DESCRIPTION OF THE INVENTION

[0012] The present disclosure provides a pulse generator for use with an electroporation system, the pulse generator configured to be coupled to a catheter including a plurality of electrodes and configured to generate a waveform delivered using at least one of the plurality of electrodes, the waveform including a pulse train having a positive pulse and a negative pulse, the pulse train having at least one of a reduced maximum absolute charge and a zero average charge of the pulse train.

[0013] FIG. 1 is a schematic and block diagram of a system 10 for electroporation therapy. Generally, the system 10 includes a catheter electrode assembly 12 disposed at the distal end 48 of a catheter 14. As used herein, "proximal" refers to the direction toward the end of the catheter closer to the clinician, and "distal" refers to the direction away from the clinician and (generally) within the patient's body. The electrode assembly includes one or more individual, electrically isolated electrode elements. Each of the electrode elements, also referred to herein as catheter electrodes, is individually wired so that it can be selectively paired or combined with other electrode elements to function as a bipolar or multipolar electrode.

[0014] System 10 may be used for irreversible electroporation (IRE) to destroy tissue. In particular, system 10 may be used for electroporation-induced treatments, which involve delivering an electric current to directly and irreversibly lose the integrity of cell membranes (cell walls), resulting in disruption and cell destruction. This mechanism of cell destruction can be considered an "outside-in" process, meaning that disruption of the cell's outer wall has a detrimental effect on the cell's interior. Typically, in classical cell membrane electroporation, the electric current is delivered as a pulsed electric field in the form of brief pulses (e.g., pulses having a duration of 500 nanoseconds (ns) to 20 microseconds (μs)) between closely spaced electrodes capable of delivering a field strength of approximately 0.1 to 1.0 kilovolts per centimeter (kV / cm). System 10 may be used for high-power (e.g., high voltage and / or high current) electroporation procedures. Additionally, system 10 may be used with loop catheters and / or basket catheters.

[0015] In one embodiment, stimulation is selectively delivered (e.g., between a pair of electrodes in bipolar mode) on catheter 14. Additionally, electrodes on 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), it should be understood that embodiments may employ variations and remain within the spirit and scope of the present disclosure. For example, AC pulses (i.e., sinusoidal pulses), RF pulses, sequences of RF bursts, asymmetric pulses, and combinations thereof may be used. Furthermore, the embodiments described herein may be practiced with medical therapies other than electroporation therapy (e.g., electrosurgery, electrochemotherapy, cancer treatment, diathermy, etc.).

[0017] For example, although the disclosed methods and systems are described herein in terms of electroporation applications, one of ordinary skill in the art will understand that the techniques described herein may 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 disruption of cell membranes by the application of a high-voltage electric field. Thus, electroporation avoids the thermal effects that can occur with other energy applications. As such, this "cold therapy" has desirable characteristics.

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

[0020] FIG. 1 further illustrates multiple return electrodes, designated 18, 20, and 21, which represent body connections that may be used by various subsystems included in the overall system 10, such as an electroporation generator 26, an electrophysiology (EP) monitor such as an ECG monitor 28, and a localization and navigation system 30 for visualizing, mapping, and navigating internal body structures. In the illustrated embodiment, the return electrodes 18, 20, and 21 are patch electrodes. The illustration of only one patch electrode is for illustrative purposes (for clarity), and it should be understood that the subsystems to which these patch electrodes are connected may include, and typically do include, multiple patch (body surface) electrodes, and may include split patch electrodes (as described herein). In other embodiments, the return electrodes 18, 20, and 21 may be other types of electrodes suitable for use as return electrodes, such as, for example, one or more catheter electrodes. If the return electrodes are catheter electrodes, they may be part of the electrode assembly 12 or 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), which in certain embodiments may be integrated with the location 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 strategy. For electroporation therapy, the generator 26 may be configured to generate current delivered through the electrode assembly 12 as a pulsed electric field in the form of brief square-wave pulses (e.g., nanosecond to millisecond durations, or any duration suitable for electroporation) between closely spaced electrodes capable of delivering a field strength (at the tissue site) of approximately 0.1 to 1.0 kV / cm. The amplitude and pulse width required for irreversible electroporation are inversely related; that is, the smaller the pulse width, the greater the amplitude, generally, to form pores.

[0022] The electroporation generator 26, sometimes referred to herein as a DC energy source, is configured to generate a series of DC energy pulses (i.e., square wave pulses) that produce bidirectional current flow (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. Other embodiments may have more or fewer energy settings, and the available settings may be the same or different. For successful electroporation, in some embodiments, a power level of 200 joules is utilized. For example, the electroporation generator 26 may output DC pulses having a peak magnitude of about 300 volts (V) to about 3,200 V at a power level of 200 joules. In other embodiments, any other suitable positive or negative voltage may be output.

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

[0024] 1, as noted above, catheter 14 may have electroporation capabilities and, in certain embodiments, may also have ablation capabilities (e.g., RF ablation). However, it should be understood that in those embodiments, the type of ablation energy provided (e.g., cryoablation, ultrasound, etc.) may be varied.

[0025] In the illustrated embodiment, the catheter 14 includes 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 include other conventional components not shown, such as a temperature sensor, additional electrodes, and corresponding electrical conductors or leads. The connector 40 provides a mechanical and electrical connection 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 illustrated.

[0026] The handle 42 provides a place for the clinician to hold the catheter 14 and may further provide a means for steering or guiding the shaft 44 within the body 17. For example, the handle 42 may include a means for varying the length of a guidewire that extends through the catheter 14 to the distal end 48 of the shaft 44, as well as a means for steering 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 configuration of the handle 42 may vary. In another embodiment, the catheter 14 may be robotically driven or controlled. Thus, rather than a clinician manipulating the handle to advance / retract and / or steer or guide the catheter 14 (and particularly its shaft 44), a robot is used to manipulate the catheter 14. The shaft 44 is an elongated, tubular, flexible member configured to move within the body 17. The shaft 44 is configured to support the electrode assembly 12 and contain associated conductors and, in some cases, additional electronics used for signal processing or conditioning. Shaft 44 may also allow for the movement, delivery, and / or removal of fluids (including irrigation fluids and bodily fluids), medications, and / or surgical tools or instruments. Shaft 44 may be made of conventional materials, such as polyurethane, and defines one or more lumens configured to accommodate and / or move electrical conductors, fluids, or surgical tools, as described herein. Shaft 44 may be introduced into a blood vessel or other structure within body 17 using a conventional introducer. Shaft 44 may then be advanced / retracted and / or guided or guided within body 17 to a desired location, such as a site at tissue 16, such as by use of a guidewire or other means known in the art.

[0027] A localization and navigation system 30 may be provided for visualizing, mapping, and navigating internal body structures. The localization and navigation system 30 may include conventional devices generally 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 shown in commonly assigned U.S. Patent No. 7,263,397, entitled "Method and Apparatus for Catheter Navigation and Location and Mapping in the Heart," the entire disclosure of which is incorporated herein by reference. In another example, the localization and navigation system 30 may be substantially similar to the EnSite X™ system shown in U.S. Patent Application No. 2020 / 0138334, entitled "Method for Medical Device Localization Based on Magnetic and Impedance Sensors," the entire disclosure of which is incorporated herein by reference. However, it should be understood that the localization and navigation system 30 is merely exemplary and not limiting in nature. Other techniques for localizing / navigating (and visualizing) catheters in space are known, such as Biosense Webster's CARTO navigation and localization system, Boston Scientific Scimed's Rhythmia® system, Koninklijke Philips NV's KODEX® system, Northern Digital's AURORA® system, commercially available fluoroscopic systems, or magnetic localization systems such as Mediguide's gMPS system.

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

[0029] Pulsed 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 the system 10, one or more impedance measurements may be made between electrodes on the catheter 14 and / or between the return electrodes 18, 20, and 21. For example, impedance measurements may be made for the system 10 as described in U.S. Patent Application Publication No. 2019 / 0117113, filed October 23, 2018; U.S. Patent Application Publication No. 2019 / 0183378, filed December 19, 2018; and U.S. Patent Application No. 63 / 027,660, filed May 20, 2020. All of the above US publications and applications are incorporated herein by reference in their entirety.

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

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

[0032] The systems and methods described herein use waveforms with 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 with various frequencies, amplitudes, pulse shapes, initial pulse polarities, etc. Additionally, the embodiments described herein may be implemented using current sources, voltage sources, or intermediate output impedance sources to generate the waveforms.

[0033] The description herein assumes an ideal amplifier with no start-up effects (i.e., the first cycle is identical to all subsequent cycles), no close-down effects (i.e., the last cycle is identical to all previous cycles and there is no output after the last cycle), and infinite bandwidth. However, the waveforms described herein may be adapted for use with amplifiers that do not, and circuits for implementing these waveforms may be used to improve charge balance.

[0034] In the exemplary waveforms described below, the horizontal axis represents time and the vertical axis represents amplitude (e.g., amperes). Note that the time scales, amplitudes, and pulse shapes shown are merely examples, and any suitable parameters may be used. Furthermore, amplitude may be expressed in terms of current values, electric field values, etc. For each exemplary waveform, the waveform signal itself and the integral of the waveform signal (to indicate the charge delivered by the waveform) are shown. The integral 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 a positive pulse and a negative pulse. In some embodiments (e.g., electroporation applications), the voltage amplitude of each pulse may be in the range of about 300 V to about 3,200 V, and more particularly, in the range of about 1,000 V to about 2,000 V. Furthermore, the pulse width of an individual pulse (i.e., one positive pulse or one negative pulse) may be in the range of about 500 ns to 20 μs, more particularly, in the range of about 1.0 μs to about 10.0 μs, and even more particularly, in the range of about 2.0 μs to about 5.0 μs. Of course, one skilled in the art will recognize that any suitable pulse parameters may be used.

[0036] For relatively low frequency signals, neurons may become excited by the first pulse of the burst. The neutralizing effect of a subsequent opposite polarity pulse (which returns the net charge to zero) may come too late to suppress the excitation. For such signals, the embodiments described herein address this issue by halving the maximum absolute value of the charge in the pulse burst, thereby achieving twice the current without excitation.

[0037] For high frequency signals, excitable tissue experiences an approximate average charge and becomes excited if the approximate average charge is above a certain level over a certain period of time. Thus, in many of the embodiments described herein (as described in more detail below), the average charge is zero, making muscles and nerves less susceptible to stimulation by high frequency bursts.

[0038] 2A is one embodiment of a waveform 200 that may be generated using system 10 (shown in FIG. 1). Waveform 200 includes a pulse train 202 having alternating positive and negative pulses 204. Pulse train 202 includes a first pulse 210, a last pulse 212, and multiple intermediate pulses 214. All pulses 204 have the same amplitude and pulse length. This is also referred to as a symmetric pulse pattern.

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

[0040] 2B is another embodiment waveform 250 that can be generated using system 10 (shown in FIG. 1). Waveform 250 includes a pulse train 252 having alternating positive and negative pulses 254. Pulse train 252 includes a first pulse 260, a last pulse 262, and multiple intermediate pulses 264.

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

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

[0043] Note that the maximum magnitude of integrated signal 270 (corresponding to the maximum absolute charge value) is smaller than the maximum magnitude of integrated signal 220. This smaller magnitude is less likely to induce muscle contraction and / or nerve stimulation. This smaller magnitude may facilitate the use of electrodes with smaller surfaces in some applications.

[0044] 2C is another embodiment waveform 280 that can be generated using system 10 (shown in FIG. 1). Waveform 280 includes a pulse train 282 having alternating positive and negative pulses 284. Pulse train 282 includes a first pulse 290, a last pulse 292, and multiple intermediate pulses 294.

[0045] In this embodiment, all of the intermediate pulses 294 have the same amplitude and the same 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 from the intermediate pulse 294. 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 the 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 the waveform 280 is zero. That is, the average value of the integrated signal 296 is zero throughout the burst, and also at regular intervals throughout the burst. Furthermore, the overall charge delivered by the waveform 280 is zero, as indicated by the integrated signal 296 being zero at the end of the waveform 280.

[0047] Again, the maximum magnitude of integrated signal 296 (corresponding to the maximum absolute charge value) is less than the maximum magnitude of integrated signal 220. This small magnitude is less likely to induce muscle contraction and / or nerve stimulation, and may facilitate the use of electrodes with small surfaces in some applications.

[0048] FIG. 3A illustrates another embodiment of a waveform 300 that can be generated using system 10 (shown in FIG. 1). Waveform 300 includes a pulse train 302 having alternating positive and negative pulses 304. Pulse train 302 includes a first pulse 310, a last pulse 312, and multiple intermediate pulses 314. In one example, first pulse 310, last pulse 312, and intermediate pulses 314 each have a voltage amplitude ranging from about 200 V to about 2000 V and a pulse width ranging from about 1.0 μs to about 5.0 μs. Alternatively, any suitable 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 referred to as an asymmetric pulse pattern.

[0049] The integrated signal 320 represents the charge delivered by the waveform 300 over time. As shown in FIG. 3A, the overall charge delivered by the waveform 300 is zero due to the equal areas of the positive and negative pulses. However, the average charge delivered by the waveform 300 is not zero at any point within the burst. Thus, the waveform 300 provides the "average charge" experienced by the tissue over the entire burst.

[0050] 3B is another embodiment waveform 350 that can be generated using system 10 (shown in FIG. 1). Waveform 350 includes a pulse train 352 having alternating positive and negative pulses 354. Pulse train 352 includes a first pulse 360, a last pulse 362, and multiple intermediate pulses 364. In one example, first pulse 360, last pulse 362, and intermediate pulses 364 each have a voltage amplitude in the range of about 200 V to about 2000 V and a pulse width in the range of about 1.0 μs to about 5.0 μs. Alternatively, any suitable 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 a 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 have different pulse widths. 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] Integrated signal 370 represents the charge delivered by waveform 350 over time. By halving the pulse width of first pulse 360 ​​and last pulse 362 (relative to waveform 300), the average charge delivered by waveform 350 becomes zero. That is, the average value of integrated signal 370 is zero throughout the burst, and also at regular intervals throughout the burst. Furthermore, the overall charge delivered by waveform 350 is zero, as indicated by the integrated signal 370 being zero at the end of waveform 350.

[0053] Note that the maximum magnitude of integrated signal 370 (corresponding to the maximum absolute charge value) is smaller than the maximum magnitude of integrated signal 320. This smaller magnitude is less likely to induce muscle contraction and / or nerve stimulation. This smaller magnitude may also facilitate the use of electrodes with smaller surfaces in some applications.

[0054] By using a long pulse width polarity (ie, negative pulses in this embodiment) for the first pulse 360 ​​and the last pulse 362, the requirements for amplifier bandwidth and switching speed are reduced.

[0055] 4 is another embodiment of a waveform 400 that can be generated using system 10 (shown in FIG. 1). Waveform 400 includes a pulse train 402 having alternating positive and negative pulses 404. Pulse train 402 includes a first pulse 410, a last pulse 412, and multiple intermediate pulses 414. In one example, first pulse 410, last pulse 412, and intermediate pulses 414 each have a voltage amplitude in the range of about 200 V to about 2000 V and a pulse width in the range of about 1.0 μs to about 5.0 μs. Alternatively, any suitable voltage and pulse width values ​​may be used.

[0056] In this embodiment, all of the intermediate pulses 414 have the same amplitude and the same 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 from the intermediate pulses 414. Specifically, the pulse amplitudes of the first pulse 410 and the last pulse 412 are half the amplitude of the intermediate pulses 414. Thus, waveform 400 is somewhat similar to waveform 280 (shown in FIG. 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 the waveform 400 over time. For the waveform 400, the average charge delivered is not zero throughout the burst, but is still zero at regular intervals throughout the burst. Furthermore, the overall charge delivered by the waveform 400 is zero, as indicated by the integrated signal 416 being zero at the end of the waveform 400.

[0058] For waveform 400, although the average charge delivered is not zero, the maximum magnitude of integrated signal 416 (corresponding to the maximum absolute charge value) is less than the maximum magnitude of integrated signal 220. This smaller magnitude reduces the likelihood of muscle contraction and / or nerve stimulation. This smaller magnitude may also facilitate the use of electrodes with smaller surfaces in some applications.

[0059] As will be appreciated by those skilled in the art, instead of the first pulse 410 and the last pulse 412 having half the amplitude of the middle pulse 414, the first pulse 410 and the last pulse 412 may have the same amplitude as the middle pulse 414 but half the pulse width of the middle pulse 414 to achieve similar results.

[0060] 2B, 2C, and 3B show waveforms that comprise 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 average charge across a waveform) can also be implemented with fewer pulses. For example, a subset of pulses within a burst may comprise a zero average charge waveform, but the burst itself may not have zero average charge.

[0061] In the embodiments disclosed herein, short periods between the positive and negative pulses allow for timing imprecision in the switching components and reduce the bandwidth of the output signal. These periods do not affect the overall average charge (i.e., zero) or reduce 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 circuitry used to implement the first and last pulses can be used to correct for amplifier imperfections (e.g., turn-on effects at the beginning of the burst or amplitude reduction toward the end of the burst).

[0062] Those skilled in the art will appreciate that the specific waveforms disclosed herein are exemplary. In general, any combination of pulse duration, pulse amplitude, or pulse shape may be used such that the first and last pulses achieve half the charge level of the intermediate pulses, resulting in a waveform with zero average charge. That is, a waveform with zero average charge may be contained within a longer burst waveform and may have a shorter duration than the longer burst waveform.

[0063] Systems and methods described herein relate to a pulse generator for use with an electroporation system, the pulse generator configured to be coupled to a catheter including a plurality of electrodes and configured to generate a waveform delivered using at least one of the plurality of electrodes, the waveform including a pulse train having positive and negative pulses, the pulse train having at least one of a reduced maximum absolute charge and zero average charge across the pulse train.

[0064] While specific embodiments of the present 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 the present disclosure. All directional references (e.g., up, down, upper, lower, left, right, left-handed, right-handed, upper, lower, upper, lower, vertical, horizontal, clockwise, and counterclockwise) are used for identification purposes only to aid the reader in understanding the present disclosure and are not intended to limit the location, orientation, or use of the present disclosure in particular. References to connections (e.g., attached, coupled, connected, etc.) should be interpreted broadly and may include intermediate members between element connections and relative movement between elements. As such, references to connections do not necessarily indicate that two elements are directly connected and in a fixed relationship to each other. All matter in the above description or shown in the accompanying drawings should be interpreted as illustrative only and not limiting. Changes in detail or structure may be made without departing from the spirit of the present disclosure, as defined by the appended claims.

[0065] When introducing elements of the present disclosure or preferred embodiments thereof, the articles "a," "an," "the," and "said" are intended to mean that there are one or more of the elements. The terms "comprising," "including," and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements.

[0066] Since various changes may be made to the above configurations without departing from the scope of the present disclosure, it is intended that all matter in the above description or shown in the accompanying drawings should be interpreted as illustrative and not in a limiting sense. The following items are elements that are claimed in the international application: (Item 1) 1. A pulse generator for use with an electroporation system, comprising: the pulse generator is configured to be coupled to a catheter including a plurality of electrodes and configured to generate a waveform that is delivered using at least one of the plurality of electrodes; the waveform includes a pulse train having positive and negative pulses; A pulse generator wherein the pulse train has an average charge of zero. (Item 2) the pulse train includes a first pulse, a last pulse, and at least one intermediate pulse between the first and last pulses; Item 10. The pulse generator of item 1, wherein the polarity of the first pulse is the same as the polarity of the last pulse. (Item 3) the at least one intermediate pulse has a first pulse width; 3. The pulse generator of claim 2, wherein the first pulse and the last pulse have a second pulse width different from the first pulse width. (Item 4) Item 4. The pulse generator of item 3, wherein the second pulse width is half the first pulse width. (Item 5) 3. The pulse generator of claim 2, wherein a positive pulse of the at least one intermediate pulse has a different pulse width and a different amplitude than a negative pulse of the at least one intermediate pulse. (Item 6) the at least one intermediate pulse has a first pulse amplitude; 3. The pulse generator of claim 2, wherein the first pulse and the last pulse have a second pulse amplitude different from the first pulse amplitude. (Item 7) 7. The pulse generator of claim 6, wherein the second pulse amplitude is half the first pulse amplitude. (Item 8) the pulse train is a subset of pulses within a longer burst waveform; Item 10. The pulse generator of item 1, wherein the average charge of the burst waveform is non-zero. (Item 9) 1. A pulse generator for use with an electroporation system, comprising: the pulse generator is configured to be coupled to a catheter including a plurality of electrodes and configured to generate a waveform that is delivered using at least one of the plurality of electrodes; the waveform comprises a pulse train having positive and negative pulses; the pulse train includes a first pulse, a last pulse, and at least one intermediate pulse between the first and last pulses; The pulse generator, wherein the first pulse and the last pulse have at least one of a different amplitude and a different pulse width than the at least one intermediate pulse to facilitate reducing the maximum absolute charge of the pulse train. (Item 10) 10. The pulse generator of claim 9, wherein the first pulse and the last pulse have different polarities. (Item 11) the first pulse and the last pulse have the same polarity; 10. The pulse generator of claim 9, wherein the average charge of the pulse train is zero. (Item 12) the at least one intermediate pulse has a first pulse width; 10. The pulse generator of claim 9, wherein the first pulse and the last pulse have a second pulse width that is half the first pulse width. (Item 13) the at least one intermediate pulse has a first pulse amplitude; 10. The pulse generator of claim 9, wherein the first pulse and the last pulse have a second pulse amplitude that is half the first pulse amplitude. (Item 14) 1. A method of controlling an electroporation system, comprising: generating a waveform with a pulse generator comprising a pulse train having positive and negative pulses, the pulse train having an average charge of zero; delivering the generated waveform to a target tissue using one or more electrodes on a catheter coupled to the pulse generator; A method comprising: (Item 15) the pulse train includes a first pulse, a last pulse, and at least one intermediate pulse between the first and last pulses; Item 15. The method of item 14, wherein the polarity of the first pulse is the same as the polarity of the last pulse. (Item 16) the at least one intermediate pulse has a first pulse width; Item 16. The method of item 15, wherein the first pulse and the last pulse have a second pulse width different from the first pulse width. (Item 17) Item 17. The method of item 16, wherein the second pulse width is half the first pulse width. (Item 18) Item 16. The method of item 15, wherein a positive pulse of the at least one intermediate pulse has a different pulse width and a different amplitude than a negative pulse of the at least one intermediate pulse. (Item 19) the at least one intermediate pulse has a first pulse amplitude; Item 16. The method of item 15, wherein the first pulse and the last pulse have a second pulse amplitude different from the first pulse amplitude. (Item 20) 20. The method of claim 19, wherein the second pulse amplitude is half the first pulse amplitude.

Claims

1. 1. A pulse generator for use with an electroporation system, comprising: the pulse generator is configured to be coupled to a catheter including a plurality of electrodes and configured to generate a waveform that is delivered using at least one of the plurality of electrodes; the waveform includes a pulse train having positive and negative pulses; A pulse generator wherein the pulse train has an average charge of zero.

2. the pulse train includes a first pulse, a last pulse, and at least one intermediate pulse between the first and last pulses; 2. The pulse generator of 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; 3. The pulse generator of claim 2, wherein the first pulse and the last pulse have a second pulse width different from the first pulse width.

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

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

6. the at least one intermediate pulse has a first pulse amplitude; 3. The pulse generator of claim 2, wherein the first pulse and the last pulse have a second pulse amplitude different from the first pulse amplitude.

7. 7. The pulse generator of 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; 2. The pulse generator of claim 1, wherein the burst waveform has a non-zero average charge.

9. 1. A pulse generator for use with an electroporation system, comprising: the pulse generator is configured to be coupled to a catheter including a plurality of electrodes and configured to generate a waveform that is delivered using at least one of the plurality of electrodes; the waveform comprises a pulse train having positive and negative pulses; the pulse train includes a first pulse, a last pulse, and at least one intermediate pulse between the first and last pulses; the first pulse and the last pulse have the same polarity; the average charge of said pulse train is zero; The first pulse and the last pulse have at least one of a different amplitude and a different pulse width than the at least one intermediate pulse.

10. the at least one intermediate pulse has a first pulse width; 10. The pulse generator of claim 9, wherein the first pulse and the last pulse have a second pulse width that is half the first pulse width.

11. the at least one intermediate pulse has a first pulse amplitude; 10. The pulse generator of claim 9, wherein the first pulse and the last pulse have a second pulse amplitude that is half the first pulse amplitude.

12. 1. A method carried out by an electroporation system, comprising:

10. A method, wherein the electroporation system includes generating, using a pulse generator configured to be coupled to a catheter including one or more electrodes, a waveform having positive and negative pulses and including a pulse train delivered using the one or more electrodes, wherein the pulse train has an average charge of zero.

13. the pulse train includes a first pulse, a last pulse, and at least one intermediate pulse between the first and last pulses; The method of claim 12 , wherein the polarity of the first pulse is the same as the polarity of the last pulse.

14. the at least one intermediate pulse has a first pulse width; 14. The method of claim 13, wherein the first pulse and the last pulse have a second pulse width different from the first pulse width.

15. 15. The method of claim 14, wherein the second pulse width is half the first pulse width.

16. 14. The method of claim 13, wherein a positive pulse of the at least one intermediate pulse has a different pulse width and a different amplitude than a negative pulse of the at least one intermediate pulse.

17. the at least one intermediate pulse has a first pulse amplitude; 14. The method of claim 13, wherein the first pulse and the last pulse have a second pulse amplitude different from the first pulse amplitude.

18. 18. The method of claim 17, wherein the second pulse amplitude is half the first pulse amplitude.

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