Systems and methods for pulsed field ablation with increased pulse period

Abstract

An electroporation system is provided. The electroporation system includes a catheter comprising a plurality of electrodes; and a pulse generator coupled to the catheter, the pulse generator being configured to generate a waveform delivered using at least one of the plurality of electrodes. The waveform includes a first pulse pattern and a second pulse pattern consecutive to the first pulse pattern, wherein the pulse period defined between the start point of the first pulse pattern and the start point of the second pulse pattern is in the range of 1 millisecond (ms) to 100 ms, such that the waveform contributes to increasing the depth of lesion.

Description

[0001] Cross-references to related applications

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 608568, filed December 11, 2023, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This disclosure generally relates to tissue ablation systems. In particular, this disclosure relates to systems and methods for pulsed field ablation using increased pulse cycles. Background Technology

[0004] As is well known, ablation therapy can be used to treat a variety of conditions that cause pain to the 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 by an ablation catheter. Electrodes mounted on or within the ablation catheter are used to induce tissue destruction in the heart tissue to correct conditions such as ventricular and atrial arrhythmias, including but not limited to ectopic atrial tachycardia, atrial fibrillation, and atrial flutter.

[0005] Cardiac arrhythmias (i.e., irregular heart rhythms) can cause a variety of dangerous conditions, including loss of synchronized atrioventricular contractions and blood stasis, which can lead to various ailments and even death. It is believed that the primary cause of atrial arrhythmias is stray electrical signals within the left or right atrium of the heart. Ablation catheters apply ablation energy (e.g., radiofrequency energy, cryoablation, laser, chemicals, high-intensity focused ultrasound, etc.) to the heart tissue to cause damage. This damage disrupts unwanted electrical pathways, thereby limiting or blocking stray electrical signals that lead to arrhythmias.

[0006] Electroporation is a fundamental non-thermal ablation technique involving the application of a strong electric field that induces the formation of pores in cell membranes. The electric field can be induced by applying pulses of relatively short duration, such as those lasting from nanoseconds to milliseconds, and generating a moderate amount of heat. These pulses can be repeated to form a pulse train. When this electric field is applied to a tissue in the in vivo environment, the cells in the tissue experience an increased transmembrane potential, which opens pores in the cytoplasmic membrane. Electroporation can be reversible (i.e., the temporarily opened pores will reseal) 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, a suitably configured pulse train can itself be used to induce cell destruction, for example, by inducing irreversible electroporation.

[0007] 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 50 volts to about 10,000 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).

[0008] In PFA, different waveforms can be used to achieve different goals. For example, some waveforms may result in larger or smaller lesions than others. Furthermore, some waveforms result in higher or lower overall energy delivery than others (lower overall energy delivery generally corresponds to less heating of the target tissue). Another example is that 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 within a relatively short timeframe. Additionally, it is generally desirable to minimize tissue thermal heating 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 persistent atrial arrhythmias. Summary of the Invention

[0009] In one aspect, an electroporation system is provided. The electroporation system includes a catheter comprising a plurality of electrodes; and a pulse generator coupled to the catheter, the pulse generator being configured to generate a waveform to be delivered through at least one of the plurality of electrodes. The waveform includes a first pulse pattern and a second pulse pattern consecutive to the first pulse pattern, wherein the pulse period defined between the start point of the first pulse pattern and the start point of the second pulse pattern is in the range of 1 ms to 100 ms, such that the waveform contributes to increasing the depth of lesion.

[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 delivered through at least one of the plurality of electrodes. The waveform includes a first pulse pattern and a second pulse pattern successive to the first pulse pattern, wherein the pulse period defined between the start point of the first pulse pattern and the start point of the second pulse pattern is in the range of 1 millisecond (ms) to 100 ms, such that the waveform contributes to increasing the depth of lesion.

[0011] In another aspect, a method for electroporation therapy is provided. The method includes: generating a waveform using a pulse generator, the waveform including a first pulse pattern and a second pulse pattern continuous with the first pulse pattern, wherein the pulse period defined between the start point of the first pulse pattern and the start point of the second pulse pattern is in the range of 1 millisecond (ms) to 100 ms. The method further includes delivering the waveform using at least one of a plurality of electrodes on a catheter, wherein the pulse period of the waveform contributes to increasing the depth of lesion.

[0012] The waveform can be single-phase, two-phase (i.e., having positive and negative pulses), or multi-phase. At least one of the first pulse mode and the second pulse mode can be a two-phase pulse mode. At least one of the first pulse mode and the second pulse mode can be a single-phase pulse mode. Furthermore, the waveform may include one or more pulse bursts (each burst comprising multiple pulses). The waveform is defined by multiple parameters (e.g., pulse width, pulse amplitude, frequency, etc.).

[0013] The pulse period can be in the range of 1 ms to 3.5 ms, 3.5 ms to 100 ms, 5 ms to 100 ms, or 10 ms to 100 ms. The first pulse mode and the second pulse mode can be included within the pulse train. Those skilled in the art will understand that, depending on the length of the pulse train period, any suitable number of pulses can be included using the pulse period disclosed herein. A pulse train can include a total of 150 or fewer pulse modes. A pulse train can include 70 pulse modes, 1 to 9 pulse modes, or 3, 4, or up to 9 pulse modes.

[0014] The second pulse mode can be the last pulse mode in the pulse train. The second pulse mode can have a larger applied voltage and / or a longer pulse width than the first pulse mode.

[0015] The first pulse mode and the second pulse mode may be delivered between at least one first electrode and at least one second electrode. Between the delivery of the first pulse mode and the second pulse mode, at least one additional pulse may be delivered between at least one third electrode and at least one fourth electrode.

[0016] The electroporation system may include a fixed current delivery system configured to i) measure current during the delivery of at least one pulse, and ii) adjust the voltage of at least one subsequent pulse based on the measured current.

[0017] The foregoing and other aspects, features, details, utility, and advantages of this disclosure will become apparent from reading the following description and claims, as well as from examining the accompanying drawings. Attached Figure Description

[0018] Figure 1These are schematic and block diagram views of a system used for electroporation therapy.

[0019] Figure 2A and Figure 2B Is with Figure 1 The diagram shows a view of the conduit assembly used by the system.

[0020] Figures 3A to 3C Is with Figure 1 The diagram shows a view of the conduit assembly used by the system.

[0021] Figure 4 It can be used Figure 1 The system shown delivers a waveform.

[0022] Figure 5A This is a graph showing the change of transmembrane potential over time during a waveform with a 1ms pulse period.

[0023] Figure 5B This is a graph showing the change of transmembrane potential over time during a waveform with a pulse period of 100 μs. Detailed Implementation

[0024] This disclosure provides systems and methods for electroporation. An electroporation system includes a catheter comprising a plurality of electrodes; and a pulse generator coupled to the catheter, configured to generate a waveform to be delivered through at least one of the plurality of electrodes. The waveform includes a first pulse pattern and a second pulse pattern consecutive to the first pulse pattern, wherein the pulse period defined between the start point of the first pulse pattern and the start point of the second pulse pattern is in the range of 1 millisecond (ms) to 100 ms, such that the waveform contributes to increasing the depth of lesion.

[0025] Figure 1 This is a schematic and block diagram view 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 closer to the clinician, while “distal” refers to the direction away from the clinician and (typically) within the patient's body. The electrode assembly includes one or more individual, electrically insulated electrode elements. Each electrode element, also referred to herein as a catheter electrode, is individually wired such that it can be selectively paired or combined with any other electrode element to act as a bipolar or multipolar electrode.

[0026] System 10 can be used for irreversible electroporation (IRE) to destroy tissue. Specifically, System 10 can be used for electroporation-induced therapies involving the delivery of electrical pulses in a manner that directly leads to the irreversible loss of plasma membrane integrity, resulting in plasma membrane breakdown and cell destruction. This cell destruction mechanism can be viewed as an "outside-in" process, meaning that disturbance of the extracellular plasma membrane has a detrimental effect on the intracellular interior. Sometimes these electrical pulses can 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 pulsed electric fields 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 delivering 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 procedures. Furthermore, System 10 can be used with, for example, Figure 2A and Figure 2B The annular conduit depicted, and / or with, for example Figures 3A to 3C The basket-shaped catheters depicted are used together. In some systems, system 10 is used for reversible electroporation in place of or to supplement irreversible electroporation.

[0027] In one system, stimulation is selectively delivered on catheter 14 (e.g., between electrode pairs). Furthermore, the electrodes on catheter 14 can be switched between being connected to a 3D mapping system and being connected to an electroporation generator.

[0028] Irreversible electroporation via multi-electrode catheters allows for pulmonary vein isolation with a single shock per vein, resulting in significantly shorter procedure times compared to sequentially positioning radiofrequency (RF) ablation tips around the vein. Furthermore, irreversible electroporation can be used in focal ablation procedures. Notably, the system described herein can be used with any suitable irreversible electroporation application.

[0029] It should be understood that although the excitation strategy is described as involving square wave pulses, the system can use variations and remain within the spirit and scope of this disclosure. For example, exponentially decaying pulses, exponentially increasing pulses, and combinations thereof can be used.

[0030] Furthermore, it should be understood that the mechanism of cell damage in electroporation is primarily due not to heating effects, but rather to cell membrane disturbances caused by the application of 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 “cryotherapy” thus possesses the desired characteristics.

[0031] Against this backdrop, let's refer to it again now. Figure 1System 10 includes a catheter electrode assembly 12, which includes at least one catheter electrode. The electrode assembly 12 is incorporated as part of a medical device, such as a catheter 14 for electroporation therapy of tissue 16 in a patient's body 17. Figure 1 In this context, tissue 16 includes the heart or cardiac tissue. However, it should be understood that the system can be used for electroporation therapy on a variety of other body tissues, such as kidney tissue, tumors, etc.

[0032] Figure 1 Further illustrations show multiple return electrodes labeled 18, 20, and 21, schematically illustrating the body connections that various subsystems included in the overall system 10 (e.g., electroporation generator 26, electrophysiological (EP) monitors such as electrocardiogram monitor 28, and positioning and navigation systems 30 for visualization, mapping, and navigation of internal body structures) can utilize. In the illustrated system, return electrodes 18, 20, and 21 are patch electrodes. It should be understood that the example of a single patch electrode is merely illustrative (for clarity), and the subsystems to which these patch electrodes are connected may, and typically will, include more than one patch (body surface) electrode, and may include split patch electrodes (as described herein). Furthermore, in some systems, in multiplexing arrangements, therapy can be repeatedly switched between using different return electrodes 18, 20, and 21. In other systems, return electrodes 18, 20, and 21 can 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 can be part of electrode assembly 12 or part of a separate catheter or device (not shown). System 10 may also include a main computer system 32 (including an electronic control unit 50 and a data storage-memory 52), which may be integrated with the positioning and navigation system 30 in some systems. The computer system 32 may also include conventional interface components, such as various user input / output mechanisms 34A and a display 34B, as well as other components.

[0033] Electroporation generator 26 is configured to excite one or more electrode elements according to an electroporation excitation strategy (which may be predetermined or user-selectable). For electroporation therapy, generator 26 can be configured to generate electrical energy delivered via electrode assembly 12 as a pulsed electric field in the form of short-duration square wave pulses (e.g., durations from nanoseconds to milliseconds, or any duration suitable for electroporation), between closely spaced electrodes, capable of delivering (i.e., at the tissue site) an electric field strength of approximately 0.05 to 100.0 kV / cm. The amplitude and pulse width required for irreversible electroporation are inversely proportional. That is, as the pulse width decreases, the amplitude can generally be increased to achieve the desired value. Electrical energy can be delivered, for example, using a fixed voltage delivery system (in which a fixed voltage is applied, independent of patient impedance) or a fixed current delivery system (in which a fixed current is achieved by adjusting the voltage based on patient impedance). In a fixed current delivery system, patient impedance can be determined, for example, by delivering a relatively small voltage pulse and measuring the current to calculate the impedance, or by delivering an alternating current waveform and measuring the voltage to calculate the impedance. Fixed-current systems may also involve measuring current and adjusting voltage accordingly, for example, before or during therapy delivery. For instance, current can be measured during the delivery of the first therapy pulse (or a pre-therapy pulse with a relatively low voltage), impedance can be calculated from the measured current, and the voltage can be adjusted (and then kept constant) to obtain the desired current during therapy. In another example, current can be measured during one or more pulses delivered during therapy, impedance can be calculated for each pulse in which current is measured, and the voltage for each subsequent pulse can be actively adjusted.

[0034] Electroporation generator 26, sometimes referred to herein as a DC power source, is a two-phase electroporation generator 26 configured to generate a series of energy pulses, each producing a current in two directions (i.e., positive and negative pulses). In other systems, the electroporation generator is a single-phase or multi-phase electroporation generator. In some systems, electroporation generator 26 is configured to output pulses in the form of energy at selectable energy levels, such as 50 joules, 100 joules, 200 joules, etc. Other systems may have more or fewer energy settings (settings may include, for example, waveform parameters, voltage, current, number of applications, etc.), and the values ​​of the available settings may be the same or different. For successful electroporation, some systems utilize an output level of 200 joules. For example, electroporation generator 26 can output pulses with peak values ​​ranging from approximately 10 volts (V) to 20,000 volts. Other systems can output any other suitable positive or negative voltage.

[0035] In some systems, the variable impedance 27 allows for impedance variations in system 10 to limit the arc. Furthermore, the variable impedance 27 can be used to alter one or more characteristics of the output of the electroporation generator 26, such as amplitude, duration, pulse shape, etc. Although exemplified as a separate component, the variable impedance 27 can be incorporated into either the conduit 14 or the generator 26.

[0036] Continue to refer to Figure 1 As mentioned above, catheter 14 may include functionality for electroporation and, in some systems, additional ablation functionality (e.g., RF ablation). However, it should be understood that variations may exist in the type of ablation energy provided (e.g., cryoablation, ultrasound, etc.) in these systems.

[0037] In the exemplary system, 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 shown herein, such as temperature sensors, additional electrodes, and corresponding conductors or leads. Connector 40 provides mechanical and electrical connection to cable 56 extending from generator 26. Connector 40 may include conventional components known in the art and is positioned at the proximal end of conduit 14 as shown.

[0038] Handle 42 provides a position for the clinician to hold catheter 14 and may further provide means for guiding or directing 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 means for guiding shaft 44. Furthermore, in some systems, handle 42 may be configured to change the shape, size, and / or orientation of a portion of the catheter, and it should be understood that the construction of handle 42 can vary. In alternative systems, catheter 14 may be robotically driven or controlled. Therefore, instead of the clinician manipulating the handle to advance / retract and / or guide or direct catheter 14 (and particularly 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 includes associated conductors, and may include additional electronics for signal processing or modulation. Axis 44 may also allow the transport, delivery, and / or removal of fluids (including flushing fluids and bodily fluids), drugs, biological agents, and / or surgical instruments or devices. Axis 44 may be made of conventional materials such as polyurethane and defines one or more lumens configured to accommodate and / or transport electrical conductors, fluids, or surgical instruments as described herein. Axis 44 may be guided into a blood vessel or other structure within body 17 using a conventional guide. Axis 44 may then be advanced / retracted and / or guided or directed through 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.

[0039] A positioning and navigation system 30 may be provided for visualization, mapping, and navigation of internal body structures. The positioning and navigation system 30 may include conventional instruments 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 generally illustrated as in commonly assigned U.S. Patent No. 7,263,339 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 generally illustrated as 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 restrictive in nature. Other technologies for positioning / navigating conduits in space (and for visualization) are known, including, 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 available fluorescence imaging systems, or magnetic positioning systems such as the gMPS system from Mediguide Ltd.

[0040] In this regard, some positioning, navigation, and / or visualization systems may include sensors for generating signals indicative of catheter position information, and may include, for example, one or more electrodes in the case of an impedance-based positioning system, or alternatively, one or more coils (i.e., wire windings) configured to detect one or more characteristics of a magnetic field, for example, in the case of a magnetic field-based positioning system. As yet another example, system 10 may utilize a combination of electric field-based and magnetic field-based systems, typically as shown in 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.

[0041] Pulsed field ablation (PFA), a method for achieving irreversible electroporation and cell death, can be implemented 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 to perform focal ablation. In PFA, the electric field can be applied between adjacent electrodes (in a bipolar approach) or between one or more electrodes and a return patch (in a unipolar approach). Each of these methods has its advantages and disadvantages.

[0042] Both methods, using appropriate electrode geometry, can provide continuous damage. For damage size and proximity, the monopolar method can potentially create deeper damage with the same applied voltage. Furthermore, the monopolar method can create damage from a distance (e.g., roughly adjacent but not necessarily in contact with tissue). The bipolar method may create smaller damage, requiring 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 between catheter electrodes 144 and / or return electrodes 18, 20, and 21 can be measured. 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, all of which are incorporated herein by reference in their entirety.

[0043] Figure 2A and Figure 2B This is a view 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.

[0044] Those skilled in the art will understand that any suitable catheter can be used in other systems. 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 several splines arranged in a plane, each spline including one or more electrodes), and / or focal ablation catheters (e.g., such as Abbott TactiFlex and TactiCath catheters).

[0045] Specifically, Figure 2A This is a side view of the catheter assembly 146 having 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 loop catheter, linear catheter, basket catheter, etc.). Figure 2A and Figure 2B As shown, the variable diameter ring 150 is coupled to the distal portion 151 of the shaft 44.

[0046] The variable diameter ring 150 can selectively expand (also known as "open") to a diameter of 160 ( Figure 2A The diameter can be varied between an expanded diameter (shown) and a retracted (also called "closed") diameter of 160 (not shown). In this example, the expanded diameter 160 is 28 mm, and the retracted diameter 160 is 15 mm. In other systems, the diameter 160 can vary between any suitable open and closed diameter 160.

[0047] In the illustrated system, the variable diameter ring 150 includes 14 conduit electrodes 144, which are spaced substantially uniformly around the circumference of the variable diameter ring 150 in an expanded configuration. In a retracted configuration, one or more electrodes 144 may overlap. Other arrangements of the conduit electrodes 144 can be implemented in other systems. For example, in one system, the variable diameter ring 150 includes 12 conduit electrodes 144.

[0048] The conduit electrode 144 is a platinum ring electrode configured to conduct and / or release current in the range of 1000 volts and / or 10 amperes. In other systems, 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 1000 volts and / or 10 amperes). Each conduit electrode 144 is separated from each other by an insulating gap 152. In the example system, each conduit electrode 144 has the same length 164 (… Figure 2B(As shown), and each insulating gap 152 has the same length 166 as every other gap 152. In the example system, both lengths 164 and 166 are approximately 2.5 mm. In other systems, lengths 164 and 166 may differ from each other. Furthermore, in some systems, not all conduit electrodes 144 have the same length 164, and / or not all insulating gaps 152 have the same length 166. In some systems, the conduit electrodes 144 are not uniformly spaced around the circumference of the variable diameter ring 150.

[0049] The diameter 160 and the spacing between the catheter electrodes 144 can be developed to provide a target energy density range for the tissue, as well as sufficient electroporation coverage for different human anatomical geometries. Typically, a sufficient number of electrodes 144 of appropriate length 164 are desired to provide substantially uniform and continuous coverage around the circumference of the variable diameter ring 150, while still allowing sufficient flexibility to allow the variable diameter ring 150 to expand and retract to vary the diameter 160 to the desired limits.

[0050] As described above, the length 164 of the catheter electrode 144 can be varied. Increasing the length 164 of the catheter electrode 144 increases the coverage of the electrode 144 around 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 reduce 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 long 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 by the power source is below the minimum current density required for successful therapy. 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 described above, a higher current density may lead to an increased risk of arcing and heating during electroporation and may require the addition of a larger additional system resistance to prevent arcing. Furthermore, to achieve the desired uniform coverage around the circumference of the variable diameter ring 150, more conduit electrodes 144 may be required if the length 164 is reduced. 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.

[0051] 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. Here, 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. It is noteworthy that the balloon 208 acts as an insulator and generally reduces energy loss, which can potentially lead to an increase in lesion size. In some systems, the balloon 208 may be filled with a cold medium (e.g., cold fluid or cold saline). Furthermore, in some systems, the balloon 208 may be a double-layered balloon.

[0052] 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.

[0053] In this system, each spline 204 includes multiple individual electrodes 220. For example, each spline 204 may include an elastic material (e.g., nitinol) covering a polymer tube 222, with the individual electrodes 220 attached to the exterior of the polymer tube 222. In the illustrated system, 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 to correspond to the portion of the spline 204 that will come into contact with the pulmonary vein.

[0054] Alternatively, each spline 204 may include any suitable number and arrangement of electrodes 220. For example, in some systems, each spline 204 includes four electrodes 220.

[0055] In this system, the alternating splines 204 have alternating polarities. That is, the electrodes 220 on a particular spline 204 have the same polarity, but the electrodes 220 on a particular spline 204 have a different polarity than the electrodes 220 on adjacent splines 204. Alternatively, any suitable polarization scheme can be used. During delivery, the spline 204 may collapse toward the axis 202. Subsequently, in order to perform ablation, the spline 204 is deployed to extend radially outward.

[0056] All splines 204 may have the same length, or at least some of the splines 204 may have different lengths. Furthermore, the insulating material on each spline 204 may have the same length, or at least some splines 204 may have insulating material of different lengths. Additionally, in some systems, the catheter assembly 200 includes a distal electrode (not shown) located at the distal end of the spline 204. The distal electrode may be used to perform point ablation (e.g., by creating a bipolar effect between the distal electrode and one of the splines 204), and / or may be used for visualization / mapping purposes (e.g., using the distal electrode in combination with electrodes on shaft 202).

[0057] Figure 3B This is a perspective view of an alternative catheter assembly 250 that can be used with catheter 14. 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 may be referred to as a basket assembly.

[0058] 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 system, 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.

[0059] Each spline 254 includes a proximal end 260 coupled to the shaft 252 and a distal end 262 coupled to the shaft 252. The spline 1004 extends radially outward from the proximal end 260 to an inflection point 264 and then radially inward to the distal end 262. Figure 3C The catheter assembly 250 located within the pulmonary vein 266 is shown.

[0060] Each spline 254 is primarily made of an elastic material (e.g., nitinol) and functions as a relatively large electrode. In this system, the alternating splines 254 have alternating polarities. That is, each positive spline 254 is located between two negative splines 254, and vice versa. Alternatively, any suitable polarization scheme can be used.

[0061] 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 with polyimide or PEBAX), and the exposed portion of the spline 254 serves as an electrode. Figure 3B and Figure 3CIn the system shown, 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 results in the portion of spline 254 that contacts the pulmonary vein 266 being exposed (see...). Figure 3C Alternatively, any suitable insulation configuration can be used.

[0062] During delivery, the spline 254 and balloon 258 may collapse. To perform ablation, the spline 254 is deployed with radially outward-extending inflection points 264, and the balloon 258 is selectively inflated to occupy the space between the spline 254.

[0063] 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, can help reduce the cost of catheter assembly 250 and improve its reliability.

[0064] All splines 254 may have the same length, or at least some of the splines 254 may have different lengths. Furthermore, the insulating material 270 on each spline 254 may have the same length, or at least some splines 254 may have insulating material 270 of different lengths. Additionally, in some systems, the catheter assembly 250 includes a distal electrode (not shown) located at the distal end of the spline 254. The distal electrode may be used to perform point ablation (e.g., by creating a bipolar effect between the distal electrode and one of the splines 254), and / or may be used for visualization / mapping purposes (e.g., using the distal electrode in combination with electrodes on shaft 252).

[0065] Those skilled in the art will understand that catheter assembly 146 ( Figure 2A and Figure 2B As shown), catheter assembly 200 ( Figure 3A (as shown) and catheter assembly 250 ( Figure 3B and Figure 3C (As shown) is merely an example. It is worth noting that the systems and methods described in this article can be implemented using any suitable conduit components.

[0066] For electroporation therapy, the waveform uses a pulse generator (e.g., Figure 1The electroporation generator 26 shown generates and applies the waveform 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 single-phase, bi-phase (i.e., having both positive and negative pulses), or multi-phase. Furthermore, the waveform can include one or more pulse trains (each pulse train comprising multiple pulses). Additionally, the waveform is defined by multiple parameters (e.g., pulse width, pulse amplitude, frequency, etc.).

[0067] Different waveforms can be used to achieve different goals. For example, some waveforms may result in larger or smaller lesions than others. Furthermore, some waveforms result in higher or lower overall energy delivery than others (lower overall energy delivery generally corresponds to less heating of the target tissue). Another example is that 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 within 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).

[0068] Figure 4 It is possible to use, for example, system 10 ( Figure 1 The waveform 400 delivered (as shown) includes a first pulse pattern 401, which includes a positive pulse 402 followed by a negative pulse 404. Furthermore, there is an intra-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 first pulse pattern 401 can be symmetrical (i.e., 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., 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 first pulse amplitude 412 and the second pulse amplitude 416 are non-zero, the first pulse mode 401 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 the first pulse pattern 401 is a single-phase waveform with a single negative pulse 404. If the second pulse amplitude 416 is zero, then the first pulse pattern 401 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 each be 3 microseconds (3 μs) and have an intra-pulse delay of 1 μs. This can be referred to as a 3-1-3 waveform (i.e., a first pulse width of 3 μs — an intra-pulse delay of 1 μs — a second pulse width of 3 μs). The first pulse amplitude 412 and the second pulse amplitude 416 can each be on the order of, for example, 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 there is an intra-pulse delay of 1 μs. This can be referred to as a 0-1-3 waveform (i.e., a first pulse width of 0 μs — an intra-pulse delay of 1 μs — a second pulse width of 3 μs). The second pulse amplitude 416 can be on the order of, for example, 1800V. In another example, the intra-pulse delay can be 0 μs.

[0073] In this system, waveform 400 also includes a second pulse pattern 420 following the first pulse pattern 401. The second pulse pattern 420 may be substantially similar to the first pulse pattern 401 (e.g., the second pulse pattern 420 may be a biphasic pulse pair having a positive pulse 422 followed by a negative pulse 424). Alternatively, the second pulse pattern 420 may have different parameters than the first pulse pattern 401 (e.g., a different number of pulses, a different pulse amplitude, a different pulse length, and / or a different pulse shape).

[0074] An inter-pulse delay 430 is defined between the end of the first pulse pattern 401 (e.g., the end of the negative pulse 404 of the first pulse pattern 401) and the start of the second pulse pattern 420 (e.g., the start of the positive pulse 422 of the second pulse pattern 420). Furthermore, a pulse period 432 is defined between the start of the first pulse pattern 401 (e.g., the start of the positive pulse 402 of the first pulse pattern 401) and the start of the second pulse pattern 420 (e.g., the start of the positive pulse 422 of the second pulse pattern 420).

[0075] It is noteworthy that the length of the pulse cycle (such as pulse cycle 432) has been observed to significantly affect both lesion formation and patient movement. Specifically, an increased pulse cycle can improve lesion formation (e.g., by increasing lesion depth). This should be balanced with maintaining tip stability and maintaining a low or moderate level of patient movement. For example, pulse cycles greater than 100 μs or greater than 200 μs (e.g., pulse cycles in the range of 100 μs to 1 millisecond (ms)) generally improve lesion formation. As an additional example, in some systems, pulse cycles in the range of 1 ms to 100 ms, or more particularly in the range of 1 ms to 3.5 ms, or more particularly in the range of 3.5 ms to 100 ms, or more particularly in the range of 5 ms to 100 ms, or even more particularly in the range of 10 ms to 100 ms, generally improve lesion formation.

[0076] The effect of increased pulse period has been demonstrated for both single-phase and two-phase waveforms. Specifically, experiments have shown that damage formation is significantly reduced with pulse periods below 5 ms (damage depth improves rapidly with pulse periods greater than 1 ms). In contrast, relatively consistent and improved damage formation has been demonstrated with pulse periods of 5 ms or more.

[0077] Increased pulse cycles can reduce patient movement in some scenarios (e.g., due to skeletal muscle recruitment (SMR)). This is important for catheter stability, patient comfort, physician perception, and treatment efficiency, and is particularly important for monopolar methods as well as bipolar methods with a significant distance between bipolar electrodes.

[0078] Longer pulse cycles result in fewer pulses within a given time period, which helps reduce microbubble formation and heat generation while maintaining or increasing the depth of damage.

[0079] Longer pulse cycles also lead to reduced dielectric stress on the catheter insulation (because longer pulse cycles allow for increased charge decay), simplifying catheter insulation constraints and enabling the delivery of higher therapeutic voltages and currents, further enhancing lesion generation. Longer pulse cycles also allow for additional cooling between pulses, reducing heat distribution during electroporation.

[0080] exist Figure 4In this system, the first pulse mode 401 and the second pulse mode 420 are delivered between the same set of electrodes. That is, the first pulse mode 401 is delivered between one or more first electrodes and one or more second electrodes (e.g., in a unipolar, bipolar, or multipolar manner), and the second pulse mode 420 is delivered between the same one or more first electrodes and one or more second electrodes. In this system, although the first pulse mode 401 and the second pulse mode 420 are delivered continuously relative to one or more first electrodes and one or more second electrodes, additional pulses can be delivered between different electrodes (e.g., between one or more third electrodes and one or more fourth electrodes) during the interval between the first pulse mode 401 and the second pulse mode 420.

[0081] During the electrode channel window, one or more pulses (e.g., single-phase and / or bi-phase waveforms) are delivered by selected electrodes. For example, waveform 400 is an example set of pulses delivered between specific electrodes. Those skilled in the art will understand that many different electrode excitation schemes are possible.

[0082] For example, consider catheter assembly 250 ( Figure 3B and Figure 3C As shown, it includes eight electrodes (each spline 254 acts as an electrode). These eight electrodes can be numbered E1, E2, ... E8 in sequence around the circumference of the conduit assembly 250. In one example excitation scheme, during the first electrode channel window, a first waveform is delivered between E1 (set to a positive voltage) and E2 (set to a negative voltage), and a second waveform is delivered simultaneously between E5 (set to a positive voltage) and E6 (set to a negative voltage). During the second electrode channel window, the first waveform is delivered between E3 (set to a positive voltage) and E4 (set to a negative voltage), and the second waveform is delivered simultaneously between E7 (set to a positive voltage) and E8 (set to a negative voltage). Again, those skilled in the art will understand that many different electrode excitation schemes are possible.

[0083] 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 and second electrode channel windows described above. Once this loop is complete, a subsequent loop will begin, again starting from the first electrode channel window. Multiple loops form a pulse train, and a treatment session may include one or more pulse trains. Typically, the time interval between subsequent pulse trains is longer than the time interval between loops within a pulse train. That is, i) the time between the end of the last pulse of the last loop in the first pulse train and the start of the first pulse of the first loop in the subsequent second pulse train is greater than ii) the time between the end of the last pulse of the second-to-last loop in the first pulse train and the start of the first pulse of the last loop in the first pulse train.

[0084] It is worth noting that as the pulse period increases (e.g., above 5 ms as mentioned above), the number of pulse patterns that can be delivered within a given time period decreases. For example, an 80 ms R-wave gating window may correspond to a treatment delivery window of 69 ms for a pulse train (due to switching and response time). This allows for 1 to 9 pulse patterns per pulse train (e.g., a single pulse pattern, or two pulse patterns with a pulse period of approximately 69 ms, or three pulse patterns with a pulse period of approximately 34.5 ms, or four pulse patterns with a pulse period of approximately 23 ms, and so on, up to nine pulse patterns with a pulse period of approximately 8.625 ms). In some systems, the pulse period can vary between pulse patterns, resulting in non-uniform intervals between pulse patterns. Alternatively, the pulse patterns are evenly spaced within the pulse train.

[0085] It is worth noting that for longer pulse train periods, a higher number of pulses per pulse train can be included while still maintaining an increasing pulse period. For example, for a pulse train period of approximately 150 ms, 150 pulse patterns with a pulse period of 1 ms can be included within the pulse train. Those skilled in the art will understand that, depending on the length of the pulse train period, any suitable number of pulses can be included using the pulse periods disclosed herein.

[0086] Those skilled in the art will also understand that a lower pulse period typically allows for additional pulses per pulse train. For example, with a pulse period of 1 ms, 70 pulses can be delivered within a pulse train (e.g., with a pulse train period of approximately 69 ms). With a pulse period of 100 μs, 700 pulses with relatively small pulse widths (e.g., on the order of nanoseconds) can be delivered within a pulse train (e.g., with a pulse train period of approximately 69 ms).

[0087] Generally, it has been shown that for a relatively small total number of pulse modes, it is more efficient to spread the pulse modes across multiple pulse trains (i.e., with larger pulse periods) than to squeeze multiple pulse modes into fewer pulse trains (i.e., with smaller pulse periods).

[0088] As stated above, longer pulse periods have been shown to improve damage formation. For example, in one experiment, for a 3-1-3 waveform, an 8 ms pulse period resulted in a significant improvement in damage depth compared to a 330 μs pulse period. Similarly, in another experiment, for a 2-1-2 waveform, a 5 ms pulse period resulted in a significant improvement in damage depth compared to a 100 μs pulse period. Those skilled in the art will understand that other waveforms (e.g., 5-1-5 waveform, 1-1-1 waveform, etc.) should produce similar improvements.

[0089] The following provides a brief explanation of why longer pulse cycles may lead to improved lesion depth. As those skilled in the art will understand, in electroporation applications, when cells are subjected to high-voltage electrical pulses of relatively short duration, the transmembrane potential of the cells increases. When the transmembrane potential increases beyond a certain electroporation threshold (e.g., 0.5 V), for relatively thin membranes (e.g., ~5 nanometers (ns)), the electric field is amplified several times (e.g., 100 MV / cm), resulting in pore formation. This phenomenon is called electroporation, and the pores formed can be resealed (reversible electroporation) or remain permanently open (irreversible electroporation). In addition to the electric field strength, the duration of electric field exposure also determines the outcome of electroporation.

[0090] Once the transmembrane potential increases above the electroporation threshold, it must remain above the threshold for a certain period of time to induce electroporation. Longer pulse widths, higher voltages, and an increased number of pulses all help to keep the transmembrane potential above the electroporation threshold.

[0091] For a single-phase pulse, the membrane spontaneously discharges, allowing the transmembrane potential to remain above the electroporation threshold for a relatively long period, resulting in effective electroporation. Depending on the time between pulses (i.e., the pulse period), waveforms can be generated that help maximize the time above the electroporation threshold while still applying relatively few pulses. The pulse length of such waveforms can also be controlled to help maximize the time above the threshold (e.g., a nanosecond pulse will increase the transmembrane potential less than a microsecond pulse).

[0092] In contrast, with biphasic pulses, there is a reversal of the electric field when switching between pulses of different polarities. This reversal causes the membrane to discharge (or charges the membrane to the opposite polarity), a phenomenon known as "auxiliary discharge." Auxiliary discharge reduces the amount of time the transmembrane potential remains above the electroporation threshold. Typically, the opposite polarity phases of a biphasic pulse counteract each other by charging the membrane in opposite directions. In asymmetric biphasic pulse pairs, the stronger second phase usually results in more efficient electroporation.

[0093] When multiple biphasic pulse pairs are applied, subsequent pulse pairs introduce auxiliary discharge on top of the previous pulse pairs. For example, consider a waveform consisting of a first biphasic pulse pair (with a first positive pulse followed by a first negative pulse) followed by a second biphasic pulse pair (with a second positive pulse followed by a second negative pulse). The above discussion... Figure 4 An example of this waveform is shown. In this waveform, the second positive pulse will cause an auxiliary discharge of the charge caused by the first negative pulse, reducing the time above the electroporation threshold and resulting in fewer effective electroporations (e.g., shallower lesions).

[0094] This phenomenon can be reduced by increasing the pulse period (e.g., increasing the time between the end of the first negative pulse and the start of the second negative pulse in the example above). Therefore, increasing the pulse period increases the time the transmembrane potential remains above the electroporation threshold, resulting in more efficient electroporation (e.g., deeper lesions). Consequently, with shorter periods, additional pulses (or higher voltages and / or pulse widths) would be required to achieve the same electroporation efficiency as with longer pulse periods.

[0095] Cell size, tissue type, and conductivity all affect the membrane's natural discharge time (and the amount of electroporation achieved). Therefore, different pulse cycles can be used for different cell and tissue types. Furthermore, different pulse cycles can be used to apply different voltages and pulse widths. In some systems, the conductivity of the cellular microenvironment can be manipulated (e.g., using flushing) to help control the depth of damage.

[0096] Figure 5A Figure 502 shows the change of transmembrane potential over time during a waveform with a 1 ms pulse period. In contrast, Figure 5B Figure 504 shows the change of transmembrane potential over time during a waveform with a pulse period of 100 µs. From Figure 5B It can be seen that the shorter pulse period causes a sudden interruption of the natural voltage decay caused by the auxiliary discharge, thereby reducing the depth of damage. Conversely, from Figure 5A It can be seen that a longer pulse period allows the voltage to decay naturally.

[0097] For similar reasons, the last pulse in a pulse train is likely to be the most effective, as there will be a relatively long time before the next pulse begins. Therefore, in some systems, the last pulse in a pulse train (whether it has two polarity phases or only the second polarity phase) has a higher voltage and / or a longer pulse width than the previous pulses in the pulse train.

[0098] As mentioned above, in addition to improving lesion depth, increased pulse cycles can also help reduce skeletal muscle recruitment (SMR) and phrenic nerve stimulation, both of which affect patient mobility. For electrodes that are relatively close together, the effect of increasing the pulse cycle may be relatively small. However, for electrodes that are relatively far apart, increasing the pulse cycle has been shown to reduce patient mobility.

[0099] Similarly, as mentioned above, spreading a given number of pulses across more pulse trains generally produces a better depth of injury than delivering the same number of pulses across fewer pulse trains. For example, it has been shown that delivering two therapeutic applications, each consisting of 10 pulse loops within a single pulse train, results in a shallower depth of injury than delivering two therapeutic applications (each consisting of 10 pulse trains, each with only one loop).

[0100] The systems and methods described herein are for electroporation waveforms. An electroporation system includes a catheter comprising a plurality of electrodes; and a pulse generator coupled to the catheter, configured to generate a waveform delivered using at least one of the plurality of electrodes. The waveform includes a first pulse pattern and a second pulse pattern consecutive to the first pulse pattern, wherein the pulse period defined between the start point of the first pulse pattern and the start point of the second pulse pattern is in the range of 1 millisecond (ms) to 100 ms, such that the waveform contributes to increasing lesion depth.

[0101] Although certain systems of this disclosure have been described with a degree of specificity above, those skilled in the art can make various modifications to the disclosed systems without departing from the scope of this disclosure. All directional references (e.g., up, down, upward, downward, left, right, leftward, rightward, 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 are not intended to be limiting, particularly regarding the location, orientation, or use of this disclosure. Coordination references (e.g., attachment, coupling, connection, etc.) should be interpreted broadly and may include intermediate members between element connections and relative movement between elements. Therefore, coordinating references do not necessarily imply that two elements are directly connected and in a fixed relationship with each other. All content contained in the foregoing description or in the accompanying drawings is intended to be illustrative and not restrictive only. Changes in detail or structure may be made without departing from the spirit of this disclosure as defined by the appended claims.

[0102] When elements of this disclosure or its preferred systems are introduced, the articles “a,” “an,” “the,” and “the” are intended to indicate the presence of one or more of the stated elements. The terms “comprising,” “including,” and “having” are intended to be inclusive and indicate that there may be additional elements besides those listed.

[0103] 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.

[0104] The invention is defined in the appended claims. A non-exhaustive list of aspects of the invention set forth in the numbered clauses is helpful for understanding the invention:

[0105] 1. An electroporation system, comprising:

[0106] The catheter, comprising a plurality of electrodes; and

[0107] A pulse generator coupled to the conduit, the pulse generator being configured to generate a waveform to be delivered through at least one of the plurality of electrodes, the waveform comprising:

[0108] First pulse mode; and

[0109] A second pulse pattern that is continuous with the first pulse pattern, wherein the pulse period defined between the start point of the first pulse pattern and the start point of the second pulse pattern is in the range of 1 millisecond (ms) to 100 ms, such that the waveform helps to increase the depth of damage.

[0110] 2. The electroporation system according to Clause 1, wherein the pulse period is in the range of 5 ms to 100 ms.

[0111] 3. The electroporation system according to clause 1 or 2, wherein the pulse period is in the range of 10 ms to 100 ms.

[0112] 4. The electroporation system according to any one of clauses 1 to 3, wherein the first pulse mode and the second pulse mode are included in a pulse train, and wherein the pulse train includes a total of 150 or fewer pulse modes.

[0113] 5. The electroporation system according to any of the preceding clauses, wherein the second pulse mode is the last pulse mode in the pulse train, and wherein the second pulse mode has a larger applied voltage and / or a longer pulse width than the first pulse mode.

[0114] 6. The electroporation system according to any of the preceding clauses, wherein the first pulse mode and the second pulse mode are delivered between at least one first electrode and at least one second electrode, and wherein, between the delivery of the first pulse mode and the second pulse mode, at least one additional pulse is delivered between at least one third electrode and at least one fourth electrode.

[0115] 7. The electroporation system according to any of the preceding clauses, wherein the electroporation system includes a fixed current delivery system configured to i) measure current during the delivery of at least one pulse, and ii) adjust the voltage of at least one subsequent pulse based on the measured current.

[0116] 8. 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 delivered through at least one of the plurality of electrodes, the waveform comprising:

[0117] First pulse mode; and

[0118] A second pulse pattern that is continuous with the first pulse pattern, wherein the pulse period defined between the start point of the first pulse pattern and the start point of the second pulse pattern is in the range of 1 millisecond (ms) to 100 ms, such that the waveform helps to increase the depth of damage.

[0119] 9. The pulse generator according to Clause 8, wherein the pulse period is in the range of 5 ms to 100 ms.

[0120] 10. The pulse generator according to clause 8 or 9, wherein the pulse period is in the range of 10 ms to 100 ms.

[0121] 11. The pulse generator according to any one of clauses 8 to 10, wherein the first pulse mode and the second pulse mode are included in a pulse train, and wherein the pulse train includes a total of 150 or fewer pulse modes.

[0122] 12. The pulse generator according to any one of clauses 8 to 11, wherein the second pulse mode is the last pulse mode in the pulse train, and wherein the second pulse mode has a larger applied voltage and / or a longer pulse width than the first pulse mode.

[0123] 13. The pulse generator according to any one of clauses 8 to 12, wherein at least one of the first pulse mode and the second pulse mode is a biphase pulse mode.

[0124] 14. The pulse generator according to any one of clauses 8 to 12, wherein at least one of the first pulse mode and the second pulse mode is a single-phase pulse mode.

[0125] 15. A method for electroporation therapy, the method comprising:

[0126] A waveform is generated using a pulse generator, the waveform including a first pulse pattern and a second pulse pattern continuous with the first pulse pattern, wherein the pulse period defined between the start point of the first pulse pattern and the start point of the second pulse pattern is in the range of 1 millisecond (ms) to 100 ms; and

[0127] The waveform is delivered using at least one of a plurality of electrodes on the catheter, wherein the pulse period of the waveform helps to increase the depth of the injury.

[0128] 16. The method according to Clause 15, wherein the pulse period is in the range of 5 ms to 100 ms.

[0129] 17. The method according to clause 15 or 16, wherein the pulse period is in the range of 10 ms to 100 ms.

[0130] 18. The method according to any one of clauses 15 to 17, wherein the first pulse pattern and the second pulse pattern are included in a pulse train, and wherein the pulse train includes a total of 150 or fewer pulse patterns.

[0131] 19. The method according to any one of clauses 15 to 18, wherein the second pulse mode is the last pulse mode in the pulse train, and wherein the second pulse mode has a larger applied voltage and / or a longer pulse width than the first pulse mode.

[0132] 20. The method according to any one of clauses 15 to 19, wherein at least one of the first pulse mode and the second pulse mode is a biphasic pulse mode.

Claims

1. An electroporation system, comprising: The catheter includes multiple electrodes; as well as A pulse generator coupled to the conduit, the pulse generator being configured to generate a waveform to be delivered through at least one of the plurality of electrodes, the waveform comprising: First pulse mode; and A second pulse pattern that is continuous with the first pulse pattern, wherein the pulse period defined between the start point of the first pulse pattern and the start point of the second pulse pattern is in the range of 1 ms to 100 ms, such that the waveform helps to increase the depth of damage.

2. The electroporation system of claim 1, wherein, The pulse period is in the range of 5ms to 100ms.

3. The electroporation system of claim 1, wherein, The pulse period is in the range of 10ms to 100ms.

4. The electroporation system of claim 1, wherein, The first pulse pattern and the second pulse pattern are included in a pulse train, wherein the pulse train includes a total of 150 or fewer pulse patterns.

5. The electroporation system according to claim 1, wherein, The second pulse mode is the last pulse mode in the pulse train, and wherein the second pulse mode has a larger applied voltage and / or a longer pulse width than the first pulse mode.

6. The electroporation system according to claim 1, wherein, The first pulse mode and the second pulse mode are delivered between at least one first electrode and at least one second electrode, and wherein, between the delivery of the first pulse mode and the second pulse mode, at least one additional pulse is delivered between at least one third electrode and at least one fourth electrode.

7. The electroporation system according to claim 1, wherein, The electroporation system includes a fixed current delivery system configured to i) measure current during the delivery of at least one pulse, and ii) adjust the voltage of at least one subsequent pulse based on the measured current.

8. 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 delivered through at least one of the plurality of electrodes, the waveform comprising: First pulse mode; as well as A second pulse pattern that is continuous with the first pulse pattern, wherein the pulse period defined between the start point of the first pulse pattern and the start point of the second pulse pattern is in the range of 1 ms to 100 ms, such that the waveform helps to increase the depth of damage.

9. The pulse generator according to claim 8, wherein, The pulse period is in the range of 5ms to 100ms.

10. The pulse generator according to claim 8, wherein, The pulse period is in the range of 10ms to 100ms.

11. The pulse generator according to claim 8, wherein, The first pulse pattern and the second pulse pattern are included in a pulse train, wherein the pulse train includes a total of 150 or fewer pulse patterns.

12. The pulse generator according to claim 8, wherein, The second pulse mode is the last pulse mode in the pulse train, and wherein the second pulse mode has a larger applied voltage and / or a longer pulse width than the first pulse mode.

13. The pulse generator according to claim 8, wherein, At least one of the first pulse mode and the second pulse mode is a biphasic pulse mode.

14. The pulse generator according to claim 8, wherein, At least one of the first pulse mode and the second pulse mode is a single-phase pulse mode.

15. A method for electroporation therapy, the method comprising: A waveform is generated using a pulse generator, the waveform including a first pulse pattern and a second pulse pattern continuous with the first pulse pattern, wherein the pulse period defined between the start point of the first pulse pattern and the start point of the second pulse pattern is in the range of 1 ms to 100 ms; and The waveform is delivered using at least one of a plurality of electrodes on the catheter, wherein the pulse period of the waveform helps to increase the depth of the injury.

16. The method according to claim 15, wherein, The pulse period is in the range of 5ms to 100ms.

17. The method according to claim 15, wherein, The pulse period is in the range of 10ms to 100ms.

18. The method according to claim 15, wherein, The first pulse pattern and the second pulse pattern are included in a pulse train, wherein the pulse train includes a total of 150 or fewer pulse patterns.

19. The method according to claim 15, wherein, The second pulse mode is the last pulse mode in the pulse train, and wherein the second pulse mode has a larger applied voltage and / or a longer pulse width than the first pulse mode.

20. The method of claim 15, wherein, At least one of the first pulse mode and the second pulse mode is a biphasic pulse mode.

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