Systems and methods for reducing microbubbles in electroporation applications

Abstract

An electroporation system is provided. The electroporation system includes a catheter including a plurality of electrodes, and a pulse generator coupled to the catheter, the pulse generator configured to generate a waveform to be transmitted using at least one of the plurality of electrodes. The waveform includes a plurality of pulse trains, each pulse train including a plurality of loops, and each loop including a plurality of pulses, where each of the plurality of pulses has a pulse width of 3 microseconds (s) or less, where each pulse train includes no more than ten loops, where the plurality of pulse trains includes at least ten pulse trains, where each pulse train includes at least one loop, and where each loop includes at least one loop. And wherein the pulse width, the number of loops per pulse train, and the number of pulse trains help reduce microbubble formation.

Description

Cross-references to related applications

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 545,657, filed October 25, 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0002] This disclosure generally relates to tissue ablation systems. Specifically, this disclosure relates to applying electroporation therapy using waveforms that help reduce microbubble formation. Background Technology

[0003] As is well known, ablation therapy can be used to treat a variety of symptoms affecting human anatomy. For example, ablation therapy can be used to treat atrial arrhythmias. Damage is created in tissue when it is ablated or at least subjected to ablation energy generated by an ablation generator and delivered through an ablation catheter. Electrodes placed on or within the ablation catheter are used to induce tissue destruction in the heart to correct symptoms such as ventricular and atrial arrhythmias, including but not limited to ectopic atrial tachycardia, atrial fibrillation, and atrial flutter.

[0004] Cardiac arrhythmias (i.e., irregular heartbeats) can cause a variety of dangerous symptoms, including asynchronous atrioventricular contractions and blood flow stagnation, which can lead to various illnesses and even death. It is believed that the primary cause of atrial arrhythmias lies in stray electrical signals within the left or right atrium of the heart. Ablation catheters deliver ablation energy (e.g., radiofrequency energy, cryoablation, laser, chemicals, high-intensity focused ultrasound, etc.) to the heart tissue to create damage. This damage blocks unwanted electrical pathways, thereby limiting or preventing stray electrical signals that lead to arrhythmias.

[0005] Electroporation is a fundamental non-thermal ablation technique involving the application of a strong electric field to induce pore formation in cell membranes. This electric field can be induced by applying pulses of relatively short duration, lasting, for example, from 1 ns to several milliseconds. Such pulses can be repeated to form pulse trains. When such an electric field is applied to tissues in the in vivo environment, cells within the tissue experience an increased transmembrane potential, thereby opening pores on the cell membrane. Electroporation can be reversible (i.e., the temporarily opened pores will reclose) or irreversible (i.e., the pores will remain open). For example, in the field of gene therapy, reversible electroporation (i.e., temporarily opening pores) is used to transfect high molecular weight therapeutic vectors into cells. In other therapeutic applications, appropriately configured pulse trains can be used alone to induce cell destruction, for example, by inducing irreversible electroporation.

[0006] For example, pulsed field ablation (PFA) can be used to perform transient pulmonary vein isolation (PVI). PFA typically involves delivering high-voltage pulses from electrodes positioned on a catheter. For example, the voltage pulses can range from less than about 500 volts to about 2400 volts or higher. These fields can be applied between electrode pairs (bipolar therapy) or between one or more electrodes and a return patch (monopolar therapy).

[0007] In PFA, different waveforms can be used to achieve different objectives. For example, some waveforms may produce larger or smaller lesions compared to others. Furthermore, some waveforms produce higher or lower total energy transfer compared to others (lower total energy transfer typically corresponds to less heating of the target tissue). As another example, some waveforms are more likely to induce muscle contraction in the patient. Generally, it is desirable to deliver electroporation therapy with a relatively small number of therapeutic applications over a relatively short timeframe. Additionally, it is generally desirable to avoid thermal heating of the tissue and to have little or no skeletal muscle recruitment (i.e., to avoid muscle contraction). Furthermore, it is generally desirable to reduce the likelihood of waveforms generating sustained atrial arrhythmias.

[0008] Because PFA used in PVI (or other applications) involves the application of electrical pulses in a blood pool, it may induce microbubble formation in some instances. Microbubble formation can be attributed to, for example, the combined effects of electrolysis and gas displacement due to shock waves. Microbubbles are generally undesirable. Therefore, it is desirable to reduce or eliminate microbubble formation in PFA applications. Summary of the Invention

[0009] In one aspect, an electroporation system is provided. The electroporation system includes: a conduit comprising a plurality of electrodes, and a pulse generator coupled to the conduit, the pulse generator being configured to generate a waveform to be transmitted using at least one of the plurality of electrodes. The waveform includes a plurality of pulse groups, each pulse group comprising a plurality of loops, and each loop comprising a plurality of pulses, wherein each of the plurality of pulses has a pulse width of 3 microseconds (µs) or less, wherein each pulse group comprises no more than ten loops, wherein the plurality of pulse groups comprises at least ten pulse groups, and wherein the pulse width, the number of loops in each pulse group, and the number of pulse groups contribute to reducing microbubble formation.

[0010] On the other hand, a pulse generator for an electroporation system is provided. The pulse generator is configured to be coupled to a conduit comprising a plurality of electrodes and configured to generate a waveform to be transmitted using at least one of the plurality of electrodes. The waveform comprises a plurality of pulse groups, each pulse group comprising a plurality of loops, and each loop comprising a plurality of pulses, wherein each of the plurality of pulses has a pulse width of 3 microseconds (µs) or less, wherein each pulse group comprises no more than ten loops, wherein the plurality of pulse groups comprises at least ten pulse groups, and wherein the pulse width, the number of loops in each pulse group, and the number of pulse groups contribute to reducing microbubble formation.

[0011] In another aspect, an electroporation system is provided. The electroporation system includes: a conduit comprising a plurality of electrodes, and a pulse generator coupled to the conduit, the pulse generator being configured to generate a waveform to be transmitted using at least one of the plurality of electrodes. The waveform includes a first pulse transmitted between a first electrode and a second electrode of the plurality of electrodes. The system further includes a grounding electrode arrangement configured to release charge accumulated on the first and second electrodes during the transmission of the first pulse.

[0012] In another aspect, an electroporation system is provided. The electroporation system includes: a conduit comprising a plurality of electrodes, and a pulse generator coupled to the conduit, the pulse generator being configured to generate a waveform to be transmitted using at least one of the plurality of electrodes. The waveform includes a plurality of consecutive pulses transmitted between a first effective electrode and a second electrode of the plurality of electrodes, wherein each of the plurality of pulses is a negative pulse, wherein the first effective electrode has a larger surface area than the second electrode, and wherein the first effective electrode is set to positive polarity.

[0013] The plurality of pulses may include both positive and negative pulses. Specifically, the plurality of pulses may include: a first pulse transmitted between a first electrode and a second electrode among the plurality of electrodes, wherein the first electrode is configured with a positive voltage for transmitting the first pulse; and a second pulse transmitted between the first electrode and a third electrode among the plurality of electrodes, wherein the first electrode is configured with a negative voltage for transmitting the second pulse.

[0014] Each of the plurality of pulses may have a pulse width of 10µs or less, or 3µs or less, or 2µs or less, or 1µs or less (e.g., pulse widths of 500ns or less, 100ns or less, 10ns or less, or 1ns or less). In some embodiments, the pulses have pulse widths in the range of 1µs to 3µs. The plurality of pulse groups may include at least one pulse group, at least five pulse groups, at least ten pulse groups, at least fifteen pulse groups, or at least twenty pulse groups. Furthermore, each pulse group may include no more than twenty loops, no more than ten loops, no more than five loops, or no more than three loops.

[0015] The grounding electrode arrangement may include grounding electrodes positioned near the first and second electrodes. The grounding electrode arrangement may include a switching circuit configured to periodically switch the first and second electrodes to ground.

[0016] The waveform can be a two-phase waveform. The waveform can also be a single-phase waveform.

[0017] The first effective electrode may include a single electrode. The first effective electrode may include two or more electrodes. The first effective electrode and the second electrode may include splines on a basket-shaped catheter. The first effective electrode may include two splines on the basket-shaped catheter. The first effective electrode and the second electrode may include electrodes on a linear catheter.

[0018] The foregoing and other aspects, features, details, utility, and advantages of this disclosure will become apparent from reading the following description and claims and from viewing the accompanying drawings. Attached Figure Description

[0019] Figure 1 This is a schematic block diagram of a system used for electroporation therapy.

[0020] Figure 2A and 2B It is possible to be with Figure 1 A view of the conduit components used in the system shown.

[0021] Figures 3A-3C It is possible to be with Figure 1 A view of the alternative conduit components used in the system shown.

[0022] Figure 4 It can be used Figure 1 The waveform transmitted by the system is shown. Detailed Implementation

[0023] This disclosure provides systems and methods for electroporation. An electroporation system includes: a conduit comprising a plurality of electrodes, and a pulse generator coupled to the conduit, the pulse generator being configured to generate a waveform to be transmitted using at least one of the plurality of electrodes. The waveform includes a plurality of pulse groups, each pulse group comprising a plurality of loops, and each loop comprising a plurality of pulses, wherein each of the plurality of pulses has a pulse width of 3 microseconds (µs) or less, wherein each pulse group comprises no more than ten loops, wherein the plurality of pulse groups comprises at least ten pulse groups, and wherein the pulse width, the number of loops in each pulse group, and the number of pulse groups contribute to reducing microbubble formation.

[0024] Figure 1 This is a schematic block diagram of a system 10 for electroporation therapy. Typically, system 10 includes a catheter electrode assembly 12 disposed at the distal end 48 of catheter 14. As used herein, "proximal" refers to the direction toward the catheter tip near the clinician, and "distal" refers to the direction away from the clinician and (typically) within the patient's body. The electrode assembly includes one or more separate, electrically isolated electrode elements. Each electrode element (also referred to herein as a catheter electrode) is individually wired, allowing it to be selectively paired or combined with any other electrode element to function as a bipolar or multipolar electrode.

[0025] System 10 can be used for irreversible electroporation (IRE) to destroy tissue. Specifically, System 10 can be used for electroporation-induced therapy involving the delivery of electrical pulses in a manner that directly causes irreversible loss of plasma membrane integrity, resulting in plasma membrane rupture and cell destruction. This cell destruction mechanism can be viewed as an "outside-in" process, meaning that damage to the cell's outer plasma membrane adversely affects the cell interior. Sometimes, these electrical pulses may directly manipulate and damage intracellular organelles to induce cell death without causing significant damage to the cell membrane. Typically, for classic plasma membrane electroporation, electrical energy can be delivered as a pulsed electric field in the form of short-duration pulses (e.g., with a duration of 10 nanoseconds (ns) to 100 milliseconds (ms)) between closely spaced electrodes capable of transmitting an electric field strength of approximately 0.05 to 100.0 kV / cm. System 10 can be used for high-output (e.g., high-voltage and / or high-current) electroporation operations. Furthermore, System 10 can be used with, for example, Figure 2A and 2B The annular duct shown and / or with such Figures 3A-3C The basket-shaped catheter shown is used together. In some embodiments, system 10 is used for reversible electroporation as an alternative to or supplement to irreversible electroporation.

[0026] In one embodiment, stimulation is selectively delivered on catheter 14 (e.g., between electrode pairs). Furthermore, the electrodes on catheter 14 can be switched between connection to a 3D mapping system and connection to an electroporation generator.

[0027] Irreversible electroporation via multi-electrode catheters allows for pulmonary vein isolation with a single shock per vein, resulting in shorter operation times compared to sequentially positioning radiofrequency (RF) ablation tips around the veins. Furthermore, irreversible electroporation can be used for focal ablation procedures. It is worth noting that the embodiments described herein can be used for any suitable irreversible electroporation application.

[0028] It should be understood that although the excitation strategy is described as involving square wave pulses, variations may be used in the embodiments and are still within the spirit and scope of this disclosure. For example, exponentially decaying pulses, exponentially increasing pulses, and combinations thereof may be used.

[0029] Furthermore, it should be understood that the mechanism of cell damage in electroporation is not primarily due to thermal effects, but rather to disruption of the cell membrane by applying a high-voltage electric field (e.g., through pore formation and / or other cell damage). Therefore, electroporation can avoid some of the potential thermal effects that may occur when using radio frequency (RF) energy. This “cooler therapy” thus possesses the desired characteristics.

[0030] Against this backdrop, let's refer to it again now. Figure 1 System 10 includes a catheter electrode assembly 12, which includes at least one catheter electrode (e.g., multiple electrodes). Electrode assembly 12 is incorporated as part of a medical device such as catheter 14 for electroporation treatment of tissue 16 in a patient's body 17. In the illustrative embodiment, tissue 16 includes the heart or cardiac tissue. However, it should be understood that the embodiments can be used for electroporation treatment of a variety of other body tissues, such as kidney tissue, tumors, etc.

[0031] Figure 1Further illustrations show multiple return electrodes, labeled 18, 20, and 21, representing bodily connections usable by various subsystems included in the overall system 10, such as an electroporation generator 26, an electrophysiological (EP) monitor like an electrocardiogram monitor 28, and a positioning and navigation system 30 for visualization, mapping, and navigation of internal body structures. In the illustrated embodiment, return electrodes 18, 20, and 21 are patch electrodes. It should be understood that the illustration of a single patch electrode is merely illustrative (for clarity), and such subsystems to which these patch electrodes are connected may and will typically include more than one patch (surface) electrode, and may include segmented patch electrodes (as described herein). Furthermore, in some embodiments, in a multiplexing arrangement, treatment may be repeatedly switched between using different return electrodes 18, 20, and 21. In other embodiments, return electrodes 18, 20, and 21 may be any other type of electrode suitable for use as return electrodes, including, for example, one or more catheter electrodes. Return electrodes as catheter electrodes may be part of electrode assembly 12 or part of a separate catheter or device (not shown). System 10 may further include a main computer system 32 (including an electronic control unit 50 and a data storage memory 52), which in some embodiments may be integrated with the positioning and navigation system 30. System 32 may further include conventional interface components, such as various user input / output mechanisms 34A and displays 34B, as well as other components.

[0032] Electroporation generator 26 is configured to excite electrode elements according to an electroporation excitation strategy, which may be predetermined or user-selectable. For electroporation treatment, generator 26 can be configured to generate electrical energy as a pulsed electric field transmitted via electrode assembly 12 in the form of short-duration square-wave pulses (e.g., duration from 1 nanosecond to several milliseconds, or any duration suitable for electroporation) between closely spaced electrodes (i.e., at the tissue site) capable of transmitting an electric field strength of approximately 0.05 to 100.0 kV / cm. The amplitude required for irreversible electroporation is inversely proportional to the pulse width. That is, as the pulse width decreases, the amplitude can typically be increased to achieve the desired duration. Electrical energy can be transmitted, for example, using a fixed voltage transmission system (in which a fixed voltage is applied, independent of patient impedance) or a fixed current transmission system (in which a fixed current is achieved by adjusting the voltage based on patient impedance). In a fixed current transmission system, patient impedance can be determined, for example, by transmitting a relatively small voltage pulse and measuring the current, or by transmitting an alternating current waveform and measuring the voltage. Fixed-current systems may also involve measuring current during treatment delivery and actively adjusting voltage between pulses.

[0033] Electroporation generator 26, sometimes referred to herein as a DC power source, is a biphase electroporation generator 26 configured to generate a series of energy pulses that produce current in both directions (i.e., positive and negative pulses). In other embodiments, the electroporation generator is a single-phase or multiphase electroporation generator. In some embodiments, electroporation generator 26 is configured to output energy in pulses at selectable energy levels (such as fifty joules, one hundred joules, two hundred joules, etc.). Other embodiments may have more or fewer energy settings, and the available setting values ​​may be the same or different (settings may include, for example, waveform parameters, voltage, current, number of applications, etc.). For successful electroporation, some embodiments utilize an output level of two hundred joules. For example, electroporation generator 26 may output pulses with peak amplitudes from about 10 volts (V) to about 20,000 V. Other embodiments may output any other suitable positive or negative voltage.

[0034] In some embodiments, the variable impedance 27 allows for alteration of the impedance of system 10 to limit arc discharge. Furthermore, the variable impedance 27 can be used to change one or more characteristics of the output of the electroporation generator 26, such as amplitude, duration, pulse shape, etc. Although illustrated as a separate component, the variable impedance 27 may be incorporated into the conduit 14 or the generator 26.

[0035] Continue to refer to Figure 1 As described above, catheter 14 may include electroporation functionality, and in some embodiments may also include additional ablation functionality (e.g., RF ablation). However, it should be understood that in these embodiments, the type of ablation energy provided may vary (e.g., cryoablation, ultrasound, etc.).

[0036] In an illustrative embodiment, conduit 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. Conduit 14 may also include other conventional components not illustrated herein, such as temperature sensors, additional electrodes, and corresponding conductors or leads. Connector 40 provides mechanical and electrical connection to a cable 56 extending from generator 26. Connector 40 may include conventional components known in the art, as shown in the figure, positioned at the proximal end of conduit 14.

[0037] Handle 42 provides a position for a clinician to hold catheter 14 and may further provide means for manipulating or guiding shaft 44 within body 17. For example, handle 42 may include means for changing the length of a guidewire extending through catheter 14 to the distal end 48 of shaft 44 or for manipulating shaft 44. Furthermore, in some embodiments, handle 42 may be configured to change the shape, size, and / or orientation of a portion of the catheter, and it is understood that the configuration of handle 42 may vary. In alternative embodiments, catheter 14 may be robot-driven or controlled. Therefore, instead of a clinician manipulating the handle to advance / retract and / or manipulate or guide catheter 14 (and particularly its shaft 44), a robot is used to manipulate catheter 14. Shaft 44 is an elongated, tubular, flexible member configured to move within body 17. Shaft 44 is configured to support electrode assembly 12 and house associated conductors, and possibly additional electronics for signal processing or modulation. Shaft 44 may also allow the transport, transfer, and / or removal of fluids (including flushing fluids and bodily fluids), drugs, biological agents, and / or surgical instruments or devices. The shaft 44 may be made of conventional materials such as polyurethane and defines one or more cavities configured to receive and / or transport electrical conductors, fluids, or surgical instruments, as described herein. The shaft 44 may be introduced into a blood vessel or other structure within the body 17 via a conventional guide. The shaft 44 may then be advanced / retracted and / or manipulated or guided through the body 17 to a desired location, such as a site of tissue 16, including by using a guidewire or other means known in the art.

[0038] The positioning and navigation system 30 can be used for visualization, mapping, and navigation of internal body structures. The positioning and navigation system 30 may include conventional devices known in the art. For example, the positioning and navigation system 30 may be substantially similar to the EnSite Precision™ system, commercially available from Abbott Laboratories, and is substantially as illustrated 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 positioning and navigation system 30 may be substantially similar to the EnSite X™ system, and is substantially as illustrated in U.S. Patent Application Publication 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 positioning and navigation system 30 is merely an example and is not inherently limiting. Other techniques known for locating / navigating catheters in space (and for visualization) include, for example, the CARTO navigation and positioning system from Biosense Webster, Inc., the Rhythmia® system from Boston Scientific Scimed, Inc., the KODEX® system from Koninklijke Philips NV, the AURORA® system from Northern Digital, Inc., commonly used fluorescence imaging systems, or magnetic positioning systems such as the gMPS system from Mediguide.

[0039] In this regard, some positioning, navigation, and / or visualization systems may include sensors for generating signals indicating catheter position information, and may include one or more electrodes, for example, in the case of an impedance-based positioning system, or alternatively, for example, in the case of a magnetic field-based positioning system, may include 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 based on a combination of electric and magnetic fields, substantially as shown in U.S. Patent No. 7,536,218 entitled “Hybrid Magnetic-Based and Impedance Based Position Sensing,” the entire disclosure of which is incorporated herein by reference.

[0040] Pulsed field ablation (PFA) is a method for achieving irreversible electroporation and cell death, which can be performed using the systems and methods described herein. In certain cases, PFA can be used on specific cardiac tissue sites, such as the pulmonary veins, to perform pulmonary vein isolation (PVI) or focal ablation. In PFA, an electric field can be applied between adjacent electrodes (in the bipolar method) or between one or more electrodes and a return patch (in the unipolar method). Each of these methods has its own advantages and disadvantages.

[0041] With appropriate electrode geometry, both methods can provide continuous damage. For damage size and proximity, the monopolar method can create deeper damage with the same applied voltage. Furthermore, the monopolar method can create damage from a distance (e.g., typically close to but not necessarily in contact with tissue). The bipolar method can create smaller damage and requires closer proximity or contact with tissue to create transmural damage (depending on, for example, tissue thickness). To monitor the operation of system 10, one or more impedances can be measured between the catheter electrodes 144 and / or between the return electrodes 18, 20, and 21. For example, for system 10, impedances can be measured 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 Publication No. 63 / 027,660, filed May 20, 2020, the entire contents of which are incorporated herein by reference.

[0042] Figure 2A and 2B This is a view of one embodiment of a catheter assembly 146 that can be used with catheter 14 in system 10. Catheter assembly 146 may be referred to as an annular catheter.

[0043] Those skilled in the art will understand that any suitable catheter can be used in other embodiments. That is, the systems and methods described herein are not limited to use with the specific catheter assemblies shown. For example, the systems and methods described herein can be implemented in linear catheters, mesh catheters (e.g., catheters comprising multiple splines arranged in a plane, each spline including one or more electrodes), and / or focal ablation catheters (e.g., such as Abbott's TactiFlex and TactiCath catheters).

[0044] Specifically, Figure 2A This is a side view of the catheter assembly 146 with a variable diameter ring 150 at the distal end 142. Figure 2B This is an end view of the variable diameter ring 150 of the catheter assembly 146. Those skilled in the art will understand that the methods and systems described herein can be implemented using any suitable catheter (e.g., fixed ring catheter, linear catheter, basket catheter, etc.). Figure 2A and 2B As shown, the variable diameter ring 150 is coupled to the distal portion 151 of the shaft 44.

[0045] The variable diameter ring 150 can selectively expand (also known as "open") to a diameter of 160 ( Figure 2A The diameter 160 (shown) is converted between an expansion diameter 160 (not shown) and a contraction (also referred to as "closure") diameter 160. In an exemplary embodiment, the expansion diameter 160 is 28 mm and the contraction diameter 160 is 15 mm. In other embodiments, the diameter 160 can vary between any suitable opening diameter 160 and closing diameter 160.

[0046] In the illustrated embodiment, the variable diameter ring 150 includes fourteen catheter electrodes 144, which are distributed substantially evenly spaced around the circumference of the variable diameter ring 150 in an expansion configuration. In a contraction configuration, one or more electrodes 144 may overlap. In other embodiments, other arrangements of the catheter electrodes 144 may be implemented. For example, in one embodiment, the variable diameter ring 150 includes twelve catheter electrodes 144.

[0047] The conduit electrode 144 is a platinum ring electrode configured to conduct and / or release current in the range of one kilovolt and / or ten amperes. In other embodiments, the variable diameter ring 150 may include any suitable number of conduit electrodes 144 made of any suitable material. The conduit electrodes 144 may include any conduit electrode suitable for conducting high voltage and / or high current (e.g., in the range of one kilovolt and / or ten amperes). The individual conduit electrodes 144 are separated from each other by an insulating gap 152. In an exemplary embodiment, each conduit electrode 144 has the same length 164 (… Figure 2BAs shown), each insulation gap 152 has the same length 166 as the others. In an exemplary embodiment, both lengths 164 and 166 are approximately 2.5 mm. In other embodiments, lengths 164 and 166 may be different from each other. Furthermore, in some embodiments, the conduit electrodes 144 may not all have the same length 164, and / or the insulation gaps 152 may not all have the same length 166. In some embodiments, the conduit electrodes 144 are not uniformly spaced on the circumference of the variable diameter ring 150.

[0048] The spacing between the diameter 160 and the catheter electrodes 144 can be designed to provide energy density within a target range to the tissue and sufficient electroporation coverage for different human anatomical geometries. Typically, it is desirable that a sufficient number of electrodes 144 of appropriate length 164 provide substantially uniform and continuous coverage on the circumference of the variable diameter ring 150, while still allowing sufficient flexibility to allow the variable diameter ring 150 to expand and contract to vary the diameter 160 to the desired limit.

[0049] As described above, the length 164 of the catheter electrode 144 can be varied. Increasing the length 164 of the catheter electrode 144 can increase the coverage of the electrode 144 on the circumference of the variable diameter ring 150, while also reducing the current density on the electrode 144 (by increasing the surface area), which can help prevent arcing and thermal effects during electroporation. However, excessively increasing the length 164 may prevent the variable diameter ring 150 from forming a smooth circular shape and may limit the closed diameter 160 of the variable diameter ring 150. Furthermore, an excessively large length 164 may increase the surface area of ​​the catheter electrode 144 to the point that the current density applied to the catheter electrode 144 is below the minimum current density required for successful treatment. Conversely, decreasing the length 164 reduces the surface area, thereby increasing the current density on the catheter electrode 144 (assuming no other system changes). As discussed above, a larger current density may lead to an increased risk of arcing and heating during electroporation and may require a larger additional system resistance to prevent arcing. Furthermore, in order to achieve the desired uniform coverage on the circumference of the variable diameter ring 150, more conduit electrodes 144 may be required as the length 164 decreases. Increasing the number of conduit electrodes 144 on the variable diameter ring 150 may prevent the variable diameter ring 150 from shrinking to the desired minimum diameter 160.

[0050] Figure 3AThis is a perspective view of an alternative catheter assembly 200 that can be used with catheter 14. Catheter assembly 200 may be referred to as a basket catheter. Catheter assembly 200 includes a shaft 202 and a plurality of splines 204 surrounding a distal portion 206 of the shaft 202. In this embodiment, catheter assembly 200 also includes a balloon 208 surrounded by the splines 204. The balloon 208 can be selectively inflated to fill the space between the splines 204. Notably, the balloon 208 acts as an insulator and generally reduces energy loss, which could potentially increase the size of lesions. In some embodiments, the balloon 208 may be filled with a cold medium (e.g., a cryogenic fluid or cold saline). Furthermore, in some embodiments, the balloon 208 may be a double-layered balloon.

[0051] Each spline 204 includes a proximal end 210 coupled to the shaft 202 and a distal end 212 coupled to the shaft 202. From the proximal end 210 to the distal end 212, the spline 204 has a radially outwardly extending arcuate shape.

[0052] In this embodiment, each spline 204 includes a plurality of individual electrodes 220. For example, each spline 204 may include an elastic material (e.g., nitinol) covering a polymer tube 222, wherein the individual electrodes 220 are attached to the outer surface of the polymer tube 222. In the illustrated embodiment, each spline 204 includes two electrodes 220. Furthermore, as shown in FIG2, the electrodes 220 are typically positioned closer to the distal end 212 than the proximal end 210, corresponding to the portion of the spline 204 that will contact the pulmonary vein.

[0053] Alternatively, each spline 204 may include any suitable number and arrangement of electrodes 220. For example, in some embodiments, each spline 204 includes four electrodes 220.

[0054] In this embodiment, the polarities of the alternating splines 204 are alternated. That is, the electrodes 220 on a particular spline 204 have the same polarity, but the electrodes 220 on a particular spline 204 have different polarities than the electrodes 220 on adjacent splines 204. Alternatively, any suitable polarization scheme can be used. During transport, the spline 204 may collapse toward the shaft 202. Subsequently, in order to perform ablation, the spline 204 is unfolded to extend radially outward.

[0055] The spline 204 may have the same length, or at least some spline 204 may have different lengths. Furthermore, the insulating material on each spline 204 may have the same length, or at least some spline 204 may have insulating material of different lengths. Additionally, in some embodiments, the catheter assembly 200 includes a distal electrode (not shown) positioned distal to the spline 204. This distal electrode can be used to perform point ablation (e.g., by forming a bipolar between the distal electrode and a spline 204), and / or can be used for visualization / mapping purposes (e.g., in combination with an electrode on the shaft 202).

[0056] Figure 3B This is a perspective view of an alternative catheter assembly 250 that can be used with catheter 14, and Figure 3C This is a side view of catheter assembly 250. It is similar to catheter assembly 200. Figure 3A As shown), the conduit assembly 250 can be referred to as a basket assembly.

[0057] The catheter assembly 250 includes a shaft 252 and a plurality of splines 254 surrounding a distal portion 256 of the shaft 252. In this embodiment, the catheter assembly 250 includes a balloon 258 surrounded by the splines 254. The balloon 258 can be selectively inflated to occupy the space between the splines 254. Notably, the balloon 258 acts as an insulator and typically reduces energy, which could potentially lead to an increase in lesion size.

[0058] Each spline 254 includes a proximal end 260 coupled to the shaft 252 and a distal end 262 coupled to the shaft 252. Starting from the proximal end 260, the spline 1004 extends radially outward to the inflection point 264 and then radially inward to the distal end 262. Figure 3C The catheter assembly 250 is shown positioned within the pulmonary vein 266.

[0059] The body of each spline 254 is made of an elastic material (e.g., nitinol) and serves as a relatively large electrode. In this embodiment, the polarities of the alternating splines 254 are alternate. That is, each positive electrode spline 254 is positioned between two negative electrode splines 254, or vice versa. Alternatively, any suitable polarization scheme can be used.

[0060] To control the ablation area of ​​each spline 254, a portion of each spline 254 may be covered with an insulating material 270 (e.g., heat-shrink tubing or polymer tubing, or sprayed or dip-coated polyimide or PEBAX), and the exposed portion of the spline 254 serves as an electrode. Figure 3B and 3CIn the illustrated embodiment, inflection point 264 and the portion of spline 254 between inflection point 264 and distal end 262 are typically exposed, while the portion of spline 254 between inflection point 264 and proximal end 260 is typically insulated. This exposes the portion of spline 254 that contacts the pulmonary vein 266 (see...). Figure 3C Alternatively, any suitable insulation configuration can be used.

[0061] During transport, spline 254 and balloon 258 can collapse. To perform ablation, spline 254 is deployed, inflection point 264 extends radially outward, and balloon 258 is selectively inflated to occupy the space between spline 254.

[0062] The combination of balloon 258 and spline 254 facilitates the direct delivery and deployment of catheter assembly 250. Furthermore, balloon 258 drives more energy into the ablated tissue and stabilizes spline 254 to prevent lateral movement. Additionally, using spline 254 as an electrode, rather than a separate, smaller electrode, helps reduce the cost of catheter assembly 250 and improves its reliability.

[0063] The spline 254 may have the same length, or at least some spline 254 may have different lengths. Furthermore, the insulating material 270 on each spline 254 may have the same length, or at least some spline 254 may have insulating material 270 of different lengths. Additionally, in some embodiments, the catheter assembly 250 includes a distal electrode (not shown) positioned distal to the spline 254. This distal electrode can be used to perform point ablation (e.g., by forming a bipolar between the distal electrode and a spline 254), and / or for visualization / mapping purposes (e.g., by combining the distal electrode with an electrode on the shaft 252).

[0064] Those skilled in the art will understand that catheter assembly 146 ( Figure 2A and 2B As shown), catheter assembly 200 ( Figure 3A (as shown) and catheter assembly 250 ( Figure 3B and 3C (As shown) is merely an example. It is worth noting that the systems and methods described herein can be implemented using any suitable conduit components.

[0065] For electroporation therapy, a pulse generator is used (e.g., electroporation generator 26). Figure 1The waveform is generated and applied between two or more catheter electrodes (i.e., a bipolar method) or between a single catheter electrode and a return patch (i.e., a unipolar method). The waveform can be monophasic, biphasic (i.e., having both positive and negative pulses), or multiphasic. Furthermore, the waveform can include one or more pulse groups (where each pulse group includes multiple pulses). Additionally, the waveform is defined by multiple parameters (e.g., pulse width, pulse amplitude, frequency, etc.).

[0066] Different waveforms can be used to achieve different goals. For example, some waveforms may produce larger or smaller lesions compared to others. Furthermore, some waveforms produce higher or lower total energy transfer compared to others (lower total energy transfer typically corresponds to less heating of the target tissue). As another example, some waveforms are more likely to induce muscle contraction in the patient. Generally, it is desirable to deliver electroporation therapy with a relatively small number of treatment applications over a relatively short timeframe. Additionally, it is generally desirable to avoid thermal heating of the tissue and to have little or no skeletal muscle recruitment (i.e., to avoid muscle contraction). Furthermore, as mentioned above, it is desirable to reduce or eliminate microbubble formation.

[0067] As explained in detail herein, many different techniques and strategies can be implemented to help reduce microbubble formation. For example, the polarity of the electrical pulses (e.g., monophasic versus biphasic pulses), pulse width, electrode polarity switching arrangements, electrode multiplexing, the number of pulses per pulse group, grounding electrode arrangements, and / or electrode surface area can be adjusted or implemented to help reduce microbubble formation. These methods can be used individually or in combination to achieve PFA therapeutic applications that reduce microbubble formation, increase lesion size, reduce heat output, reduce skeletal muscle recruitment, and reduce total treatment time.

[0068] Figure 4 This is one embodiment of waveform 400. Waveform 400 includes a positive pulse 402 and a subsequent negative pulse 404. Furthermore, there is an inter-pulse delay 406 between the positive pulse 402 and the negative pulse 404.

[0069] like Figure 4 As shown, the positive pulse 402 has a first pulse width 410 and a first pulse amplitude 412. Similarly, the negative pulse 404 has a second pulse width 414 and a second pulse amplitude 416. The waveform 400 can be symmetrical (i.e., where the first pulse width 410 and the first pulse amplitude 412 are substantially equal to the second pulse width 414 and the second pulse amplitude 416) or asymmetrical (i.e., where at least one of the first pulse width 410 and the first pulse amplitude 412 is different from the second pulse width 414 and the second pulse amplitude 416).

[0070] When both the amplitude of the first pulse 412 and the amplitude of the second pulse 416 are non-zero, waveform 400 is biphase (i.e., as shown in the image). Figure 4 (As shown). For a single-phase waveform, one of the first pulse amplitude 412 and the second pulse amplitude 416 is zero. For example, if the first pulse amplitude 412 is zero, then waveform 400 is a single-phase waveform with a single negative pulse 404. If the second pulse amplitude 416 is zero, then waveform 400 is a single-phase waveform with a single positive pulse 402.

[0071] In a biphase example, the first pulse width 410 and the second pulse width 414 can both be 3 microseconds (3µs), with an inter-pulse delay of 1µs. This can be referred to as a 3-1-3 waveform (i.e., first pulse width 3µs — inter-pulse delay 1µs — second pulse width 3µs). The first pulse amplitude 412 and the second pulse amplitude 416 can both be, for example, approximately 1800 volts (1800V).

[0072] In a single-phase example, the first pulse width 410 is 0 µs, the second pulse width 414 is 3 µs, and the inter-pulse delay is 1 µs. This can be referred to as a 0-1-3 waveform (i.e., first pulse width 0 µs — inter-pulse delay 1 µs — second pulse width 3 µs). The second pulse amplitude 416 can be, for example, approximately 1800 V. In another example, the inter-pulse delay can be 0 µs.

[0073] During the electrode channel window, one or more pulses (e.g., single-phase and / or bi-phase waveforms) are transmitted by the selected electrodes. Those skilled in the art will understand that many different electrode excitation schemes are possible.

[0074] For example, consider catheter assembly 250 ( Figure 3B and 3CAs shown, it includes eight electrodes (each spline 254 serving as one electrode). These eight electrodes can be sequentially numbered E1, E2, ... E8 on the circumference of the conduit assembly 250. In an exemplary excitation scheme, during a first electrode channel window, a first waveform is transmitted between E1 (set to a positive voltage) and E2 (set to a negative voltage), and a second waveform is transmitted simultaneously between E5 (set to a positive voltage) and E6 (set to a negative voltage). During a second electrode channel window, the first waveform is transmitted between E3 (set to a positive voltage) and E2 (set to a negative voltage), and a second waveform is transmitted simultaneously between E7 (set to a positive voltage) and E6 (set to a negative voltage). During a third electrode channel window, the first waveform is transmitted between E3 (set to a positive voltage) and E4 (set to a negative voltage), and a second waveform is transmitted simultaneously between E7 (set to a positive voltage) and E8 (set to a negative voltage). Furthermore, during the fourth electrode channel window, a first waveform is transmitted between E5 (set to a positive voltage) and E4 (set to a negative voltage), and a second waveform is transmitted simultaneously between E1 (set to a positive voltage) and E8 (set to a negative voltage). Similarly, those skilled in the art will understand that many different electrode excitation schemes are possible.

[0075] Multiple electrode channel windows form a loop. This loop completes when the electrode excitation pattern begins to repeat. For example, a single loop may include the first, second, third, and fourth electrode channel windows described above. Once this loop is complete, a subsequent loop will begin, again starting from the first electrode channel window.

[0076] Multiple loops constitute a pulse group, and a single treatment session may include one or more pulse groups. For example, each pulse group may include one to twenty loops, and a single treatment session may include ten to twenty pulse groups. Typically, the time interval between consecutive pulse groups is longer than the time interval between loops within a single pulse group. That is, i) the time between the end of the last pulse of the last loop in the first pulse group and the start of the first pulse of the first loop in the subsequent second pulse group is greater than ii) the time between the end of the last pulse of the second-to-last loop in the first pulse group and the start of the first pulse of the last loop in the first pulse group.

[0077] In one example, the length of each electrode channel window is 60µs (e.g., using a 3-1-3 waveform with a 53µs delay), the length of each loop (also known as the loop period) is 330µs (e.g., four 60µs electrode channel windows with a 90µs delay), and the length of each pulse group is 3.3 milliseconds (ms) (e.g., ten 330µs loops). Again, these values ​​are just examples and any suitable time period can be used.

[0078] Pulse polarity and pulse width

[0079] As mentioned above, the polarity of the electrical pulse (e.g., single-phase vs. bi-phase pulses) and the pulse width can affect microbubble formation. To evaluate this effect, microbubble formation was evaluated for various PFA waveforms, including 3-1-0, 0-1-3, 3-1-3, 1-1-1, and 2-2-2 waveforms. These waveforms were also evaluated at various voltage levels (e.g., 1800 volts and 2200 volts).

[0080] This analysis revealed that single-phase waveforms (compared to two-phase waveforms) typically produce significantly higher microbubble volumes and numbers across various pulse widths. For example, single-phase waveforms may generate five to ten times more microbubbles.

[0081] Regarding pulse width, similar total bubble volumes were observed for the 3-1-3 waveform at 1800V, the 1-1-1 waveform at 1800V, and the 2-1-2 waveform at 2200V. However, a reduced bubble volume was observed for the 1-1-1 waveform at 2200V. Furthermore, the total number of bubbles generally decreased with shorter pulse widths. Therefore, reducing the pulse width appears to significantly reduce microbubble formation. For example, to help reduce microbubble generation, in at least some embodiments, single-phase or biphase waveforms include pulse widths of 10µs or less, or more specifically 3µs or less, or more specifically 2µs or less, or more specifically 1µs or less (e.g., including pulse widths of 500ns or less, 100ns or less, 10ns or less, or 1ns or less). For example, in some embodiments, single-phase or biphase waveforms include pulses in the range of 1µs to 3µs.

[0082] In a single-phase waveform, the application of multiple pulses leads to the accumulation of negative charge on the cathode and positive charge on the electrode. This charge buildup results in the generation of microbubbles, which may be due to electrolysis. In contrast, the charge buildup is significantly reduced because the two-phase waveform reverses the pulse polarity.

[0083] Reducing the inter-pulse delay between the positive and negative pulses of the biphasic waveform also helps reduce charge buildup, thereby reducing microbubble formation. Furthermore, increasing the pulse frequency (or decreasing the pulse width) also reduces charge buildup, which may explain why reducing the pulse width appears to significantly reduce microbubble formation.

[0084] Number of pulses in each pulse group

[0085] As mentioned above, the number of pulses per pulse group can also affect microbubble formation. To assess this effect, microbubble formation was evaluated for various PFA pulse group modes. Notably, it was observed that reducing the number of pulses per pulse group (e.g., by reducing the number of loops per pulse group) while increasing the total number of pulse groups resulted in a decrease in microbubble formation. In other words, distributing the pulses across a larger number of pulse groups leads to a reduction in microbubble formation. This also helps to reduce thermal effects, as fewer pulses are applied within a given time period.

[0086] Dispersing the pulses over a longer time period allows any accumulated charge on the electrodes to decay and allows for reduced heating. As mentioned above, reducing charge buildup generally reduces microbubble formation. Furthermore, reducing heating also reduces microbubble formation.

[0087] As described above, a loop comprises an electrode excitation pattern (i.e., one or more pulses). When the electrode excitation pattern begins to repeat, a new loop begins. Furthermore, multiple loops constitute a pulse group.

[0088] To reduce microbubble formation, the loops can be distributed across multiple pulse groups. For example, to help reduce microbubble generation, in at least some embodiments, the pulse pattern includes at least one pulse group, or more specifically at least five pulse groups, or more specifically at least ten pulse groups, or more specifically at least fifteen pulse groups, or more specifically at least twenty pulse groups. Furthermore, in at least some embodiments, each pulse group includes no more than twenty loops, or more specifically no more than ten loops, or more specifically no more than five loops, or more specifically no more than three loops.

[0089] Electrode polarity switching arrangement

[0090] As mentioned above, the electrode polarity switching arrangement can also affect microbubble formation. To evaluate this effect, microbubble formation was evaluated for various PFA switching arrangements.

[0091] As described above, for catheter assembly 250 ( Figure 3B and 3C An excitation scheme (shown) involves transmitting pulses between individual electrode pairs E1-E8 across four electrode channel windows. In this excitation scheme, each electrode is set to the same polarity throughout the entire scheme. For example, E1 is set to a positive voltage when used in conjunction with E2 (in the first electrode channel window) and with E8 (in the fourth electrode channel window). In other words, odd-numbered electrodes (E1, E3, E5, and E7) are always set to a positive voltage, and even-numbered electrodes (E2, E4, E6, and E8) are always set to a negative voltage. This is referred to herein as the first excitation scheme.

[0092] In different second excitation schemes, each electrode switches between positive and negative voltage operation throughout the entire excitation scheme. For example, during the first electrode channel window, a first waveform is transmitted between E1 (set to positive voltage) and E2 (set to negative voltage), and a second waveform is transmitted simultaneously between E5 (set to positive voltage) and E6 (set to negative voltage). During the second electrode channel window, a first waveform is transmitted between E3 (set to negative voltage) and E2 (set to positive voltage), and a second waveform is transmitted simultaneously between E7 (set to negative voltage) and E6 (set to positive voltage). During the third electrode channel window, a first waveform is transmitted between E3 (set to positive voltage) and E4 (set to negative voltage), and a second waveform is transmitted simultaneously between E7 (set to negative voltage) and E8 (set to positive voltage). Furthermore, during the fourth electrode channel window, a first waveform is transmitted between E5 (set to negative voltage) and E4 (set to positive voltage), and a second waveform is transmitted simultaneously between E1 (set to negative voltage) and E8 (set to positive voltage). Therefore, in the second excitation scheme, each electrode switches between being set to a positive voltage and being set to a negative voltage.

[0093] The first and second excitation schemes were evaluated in terms of microbubble formation. Notably, switching the electrode polarity (i.e., as in the second excitation scheme) resulted in a reduction in microbubble formation. Furthermore, microbubble formation was further reduced (as described above) by dispersing the pulses across more pulse groups. Additionally, switching the electrode polarity of the single-phase waveform significantly reduced microbubble formation. This is likely because a single-phase waveform (without switching electrode polarity) typically results in significantly more charge accumulation on the designated electrode compared to a two-phase waveform. Therefore, switching the electrode polarity of the single-phase waveform significantly reduces this charge accumulation, thereby reducing microbubble formation. Thus, a single-phase waveform with electrode polarity switching advantageously reduces charge accumulation (similar to a two-phase waveform), and the longer time between polarity switches (relative to a two-phase waveform) improves damage formation.

[0094] Electrode multiplexing

[0095] As mentioned above, electrode multiplexing can also affect microbubble formation. To assess this effect, microbubble formation was evaluated for different excitation schemes.

[0096] Specifically, microbubble formation was evaluated for a first excitation scheme (as described above) and a third excitation scheme. In the first excitation scheme, multiplexing was implemented, with pulses transmitted across four different electrode channel windows, where two pairs of electrodes transmitted waveforms within each window. In the third excitation scheme, no multiplexing was implemented. For example, for catheter assembly 250 ( Figure 3B and 3CAs shown in the diagram, in the third excitation scheme, all eight electrodes are excited within a single electrode channel window (e.g., for 125 µs). Therefore, the third excitation scheme can be referred to as a simultaneous configuration.

[0097] Simultaneous configuration (i.e., no multiplexing) was observed to help reduce microbubble formation. Furthermore, as mentioned above, microbubble formation can be further reduced by dispersing the pulses over a longer time period.

[0098] Grounding electrode arrangement

[0099] As mentioned above, the arrangement of grounded electrodes can also affect microbubble formation. For example, as described above, the decay of charge accumulated on the electrodes can affect electrolysis and microbubble formation. Therefore, techniques can be implemented to remove accumulated charge more quickly after each pulse application.

[0100] For example, in one embodiment, the grounding electrode is positioned near the treatment site to reduce charge buildup. In another embodiment, the pulse-generating electrode uses a switching circuit to periodically switch to ground to reduce charge buildup (e.g., after each pulse, after a set of pulses, or after a pulse cluster). These techniques can reduce microbubble formation without spreading the pulses across a larger number of pulse clusters, which can reduce the total treatment time.

[0101] Electrode surface area and polarity

[0102] As mentioned above, electrode surface area (and associated polarity) can also affect microbubble formation. To assess this effect, microbubble formation was evaluated for various electrode surface areas and polarities.

[0103] Specifically, it was observed that transmitting a negative single-phase waveform (including one or more negative pulses) between a larger first electrode set to positive polarity and a smaller second electrode set to negative polarity helps reduce microbubble formation. It appears that the larger surface area of ​​the first electrode produces less electrolysis, thus reducing microbubble formation. This result can also be achieved by transmitting a positive single-phase waveform between the larger first electrode set to negative polarity and the smaller second electrode set to positive polarity.

[0104] It is noteworthy that the level of microbubble formation generated by transmitting a negative single-phase waveform between a larger first electrode set to positive polarity and a smaller second electrode set to negative polarity is similar to that observed with a two-phase waveform. Furthermore, the damage performance of the single-phase waveform appears unaffected. Therefore, this configuration combines the advantages of increasing damage size (e.g., due to the larger range of the electric field and because it is a single-phase waveform) and reducing microbubble formation (comparable to a two-phase waveform).

[0105] With this in mind, catheter designs can be modified accordingly to reduce microbubble formation. For example, consider catheter assembly 250 ( Figure 3B and 3C (As shown). In one embodiment, the electrodes set to negative voltage in the excitation scheme (e.g., E2, E4, E6, and E8 in the first excitation scheme) each have a smaller surface area than the electrodes set to positive voltage in the excitation scheme while transmitting negative single-phase pulses (e.g., E1, E3, E5, and E7 in the first excitation scheme). Of course, this concept can also be extended to any other suitable catheter embodiment (e.g., the catheter embodiment shown in Figures 2 and 3A).

[0106] In another embodiment, where all electrodes have the same surface area, multiple electrodes can be activated together to achieve a larger effective surface area. For example, in catheter assembly 250, electrodes E2 and E3 can both be set to positive voltage, and electrode E1 can be set to negative voltage while transmitting a negative monophasic pulse. When electrodes E2 and E3 are simultaneously (at positive voltage), they effectively act as a single cathode that transmits a negative monophasic pulse larger than the negative voltage E1. Those skilled in the art will understand that other similar techniques can be implemented in other catheter assemblies. For example, a first electrode and a second electrode (where the first electrode has a larger surface area than the second electrode) can both be included on a linear catheter. Similarly, this concept can be extended to any other suitable catheter embodiment (e.g., Figure 2 and...). Figure 3A (The catheter example shown).

[0107] The systems and methods described herein relate to electroporation devices. An electroporation system includes: a conduit comprising a plurality of electrodes, and a pulse generator coupled to the conduit, the pulse generator being configured to generate a waveform to be transmitted using at least one of the plurality of electrodes. The waveform includes a plurality of pulse groups, each pulse group comprising a plurality of loops, and each loop comprising a plurality of pulses, wherein each of the plurality of pulses has a pulse width of 3 microseconds (µs) or less, wherein each pulse group comprises no more than ten loops, wherein the plurality of pulse groups comprises at least ten pulse groups, and wherein the pulse width, the number of loops in each pulse group, and the number of pulse groups contribute to reducing microbubble formation.

[0108] While certain embodiments of this disclosure have been described above with a degree of specificity, those skilled in the art can make numerous modifications to the disclosed embodiments without departing from the spirit or scope of this disclosure. All directional references (e.g., up, down, upward, downward, left, right, left-right, top, bottom, above, below, vertical, horizontal, clockwise, and counterclockwise) are used for identification purposes only to aid the reader's understanding of this disclosure and do not impose limitations, particularly regarding the location, orientation, or use of this disclosure. Connections (e.g., attachment, coupling, connection, etc.) should be interpreted broadly and may include intermediate members between element connections and relative movement between elements. Therefore, a connection does not necessarily imply that two elements are directly connected and fixed to each other. It is intended that everything contained in the foregoing description or shown in the accompanying drawings should be interpreted as illustrative rather than restrictive. Changes in details or structure may be made without departing from the spirit of this disclosure as defined by the appended claims.

[0109] When elements of this disclosure or its preferred embodiments are introduced, the articles “a,” “an,” “the,” and “the” are intended to indicate the presence of one or more of that element. The terms “comprising,” “including,” and “having” are intended to be open-ended and mean that other elements may be present in addition to those listed.

[0110] Since various changes can be made to the above construction without departing from the scope of this disclosure, it is intended that all content contained in the above description or shown in the accompanying drawings should be interpreted as illustrative rather than restrictive.

[0111] The following is a list of numbered clauses of this invention:

[0112] 1. An electroporation system, comprising:

[0113] A conduit including multiple electrodes; and

[0114] A pulse generator coupled to the catheter, the pulse generator being configured to generate a waveform to be transmitted using at least one of the plurality of electrodes, the waveform including:

[0115] Multiple pulse groups, each pulse group comprising multiple loops, and each loop comprising multiple pulses, wherein each of the multiple pulses has a pulse width of 3 microseconds (µs) or less, wherein each pulse group comprises no more than ten loops, wherein the multiple pulse groups comprise at least ten pulse groups, and wherein the pulse width, the number of loops in each pulse group, and the number of pulse groups contribute to reducing microbubble formation.

[0116] 2. The electroporation system according to Clause 1, wherein the plurality of pulses includes both positive and negative pulses.

[0117] 3. The electroporation system according to clause 1 or 2, wherein said plurality of pulses comprises:

[0118] A first pulse is transmitted between a first electrode and a second electrode of the plurality of electrodes, wherein the first electrode is configured with a positive voltage for transmitting the first pulse; and

[0119] A second pulse is transmitted between the first electrode and the third electrode of the plurality of electrodes, wherein the first electrode is set to a negative voltage for transmitting the second pulse.

[0120] 4. The electroporation system according to any of the preceding clauses, wherein each of the plurality of pulses has a pulse width of 2µs or less or 1µs or less.

[0121] 5. The electroporation system according to any of the preceding clauses, wherein the plurality of pulse groups comprises at least fifteen pulse groups, and wherein each pulse group comprises no more than five loops, or wherein the plurality of pulse groups comprises at least twenty pulse groups, and wherein each pulse group comprises no more than three loops.

[0122] 6. A pulse generator for an electroporation system, the pulse generator being configured to be coupled to a conduit comprising a plurality of electrodes and configured to generate a waveform to be transmitted using at least one of the plurality of electrodes, the waveform comprising:

[0123] Multiple pulse groups, each pulse group comprising multiple loops, and each loop comprising multiple pulses, wherein each of the multiple pulses has a pulse width of 3µs or less, wherein each pulse group comprises no more than ten loops, wherein the multiple pulse groups comprise at least ten pulse groups, and wherein the pulse width, the number of loops in each pulse group, and the number of pulse groups contribute to reducing microbubble formation.

[0124] 7. The pulse generator according to Clause 6, wherein the plurality of pulses includes both positive pulses and negative pulses.

[0125] 8. The pulse generator according to clause 6 or 7, wherein said plurality of pulses comprises:

[0126] A first pulse is transmitted between a first electrode and a second electrode of the plurality of electrodes, wherein the first electrode is configured with a positive voltage for transmitting the first pulse; and

[0127] A second pulse is transmitted between the first electrode and the third electrode of the plurality of electrodes, wherein the first electrode is set to a negative voltage for transmitting the second pulse.

[0128] 9. An electroporation system, comprising:

[0129] A conduit including multiple electrodes; and

[0130] A pulse generator coupled to the catheter, the pulse generator being configured to generate a waveform to be transmitted using at least one of the plurality of electrodes, the waveform including at least a first pulse transmitted between a first electrode and a second electrode of the plurality of electrodes; and

[0131] The grounding electrode arrangement is configured to release the charge accumulated on the first and second electrodes during the transmission of the first pulse from the first and second electrodes.

[0132] 10. The electroporation system according to Clause 9, wherein the grounding electrode arrangement includes a grounding electrode positioned near the first electrode and the second electrode, or wherein the grounding electrode arrangement includes a switching circuit configured to periodically switch the first electrode and the second electrode to ground.

[0133] 11. The electroporation system according to Clause 9, wherein the waveform is a two-phase waveform or a single-phase waveform.

[0134] 12. An electroporation system, comprising:

[0135] A conduit including multiple electrodes; and

[0136] A pulse generator coupled to the catheter, the pulse generator being configured to generate a waveform to be transmitted using at least one of the plurality of electrodes, the waveform including:

[0137] Multiple consecutive pulses are transmitted between a first effective electrode and a second electrode among the plurality of electrodes, wherein each of the plurality of pulses is a negative pulse, wherein the first effective electrode has a larger surface area than the second electrode, and wherein the first effective electrode is set to positive polarity.

[0138] 13. The electroporation system according to Clause 12, wherein the first effective electrode comprises a single electrode.

[0139] 14. The electroporation system according to Clause 12, wherein the first effective electrode comprises two or more electrodes.

[0140] 15. The electroporation system according to Clause 12, wherein the first effective electrode and the second electrode comprise splines on a basket-shaped conduit.

[0141] 16. The electroporation system according to Clause 15, wherein the first effective electrode comprises two splines on the basket-shaped conduit.

[0142] 17. The electroporation system according to any one of clauses 12 to 14, wherein the first effective electrode and the second electrode comprise electrodes on a linear conduit.

Claims

1. An electroporation system, comprising: A conduit containing multiple electrodes; as well as A pulse generator coupled to the catheter, the pulse generator being configured to generate a waveform to be transmitted using at least one of the plurality of electrodes, the waveform including: Multiple pulse groups, each pulse group comprising multiple loops, and each loop comprising multiple pulses, wherein each of the multiple pulses has a pulse width of 3 microseconds (µs) or less, wherein each pulse group comprises no more than ten loops, wherein the multiple pulse groups comprise at least ten pulse groups, and wherein the pulse width, the number of loops in each pulse group, and the number of pulse groups contribute to reducing microbubble formation.

2. The electroporation system according to claim 1, wherein the plurality of pulses includes both positive pulses and negative pulses.

3. The electroporation system according to claim 1, wherein the plurality of pulses comprises: A first pulse is transmitted between a first electrode and a second electrode among the plurality of electrodes, wherein the first electrode is configured with a positive voltage to transmit the first pulse; as well as A second pulse is transmitted between the first electrode and the third electrode of the plurality of electrodes, wherein the first electrode is set to a negative voltage for transmitting the second pulse.

4. The electroporation system of claim 1, wherein each of the plurality of pulses has a pulse width of 1 µs or less.

5. The electroporation system of claim 1, wherein the plurality of pulse groups comprises at least fifteen pulse groups, and wherein each pulse group comprises no more than five loops.

6. The electroporation system of claim 1, wherein the plurality of pulse groups comprises at least twenty pulse groups, and wherein each pulse group comprises no more than three loops.

7. A pulse generator for an electroporation system, the pulse generator being configured to be coupled to a conduit comprising a plurality of electrodes and configured to generate a waveform to be transmitted using at least one of the plurality of electrodes, the waveform comprising: Multiple pulse groups, each pulse group comprising multiple loops, and each loop comprising multiple pulses, wherein each of the multiple pulses has a pulse width of 3 microseconds (µs) or less, wherein each pulse group comprises no more than ten loops, wherein the multiple pulse groups comprise at least ten pulse groups, and wherein the pulse width, the number of loops in each pulse group, and the number of pulse groups contribute to reducing microbubble formation.

8. The pulse generator according to claim 7, wherein the plurality of pulses includes both positive pulses and negative pulses.

9. The pulse generator according to claim 7, wherein the plurality of pulses comprises: A first pulse is transmitted between a first electrode and a second electrode among the plurality of electrodes, wherein the first electrode is configured with a positive voltage to transmit the first pulse; as well as A second pulse is transmitted between the first electrode and the third electrode of the plurality of electrodes, wherein the first electrode is set to a negative voltage for transmitting the second pulse.

10. An electroporation system, comprising: A conduit containing multiple electrodes; as well as A pulse generator coupled to the catheter, the pulse generator being configured to generate a waveform to be transmitted using at least one of the plurality of electrodes, the waveform including at least a first pulse transmitted between a first electrode and a second electrode of the plurality of electrodes; as well as The grounding electrode arrangement is configured to release the charge accumulated on the first and second electrodes during the transmission of the first pulse from the first and second electrodes.

11. The electroporation system of claim 10, wherein the grounding electrode arrangement includes a grounding electrode positioned near the first electrode and the second electrode.

12. The electroporation system of claim 10, wherein the grounding electrode arrangement includes a switching circuit configured to periodically switch the first electrode and the second electrode to ground.

13. The electroporation system of claim 10, wherein the waveform is a biphase waveform.

14. The electroporation system of claim 10, wherein the waveform is a single-phase waveform.

15. An electroporation system, comprising: A conduit containing multiple electrodes; as well as A pulse generator coupled to the catheter, the pulse generator being configured to generate a waveform to be transmitted using at least one of the plurality of electrodes, the waveform including: Multiple consecutive pulses are transmitted between a first effective electrode and a second electrode among the plurality of electrodes, wherein each of the plurality of pulses is a negative pulse, wherein the first effective electrode has a larger surface area than the second electrode, and wherein the first effective electrode is set to positive polarity.

16. The electroporation system of claim 15, wherein the first effective electrode comprises a single electrode.

17. The electroporation system of claim 15, wherein the first effective electrode comprises two or more electrodes.

18. The electroporation system of claim 15, wherein the first effective electrode and the second electrode comprise splines on a basket-shaped conduit.

19. The electroporation system of claim 18, wherein the first effective electrode comprises two splines on the basket-shaped conduit.

20. The electroporation system of claim 15, wherein the first effective electrode and the second electrode comprise electrodes on a linear conduit.

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