Electroporation system

Abstract

Provided herein are systems, devices, and methods for releasing electroporation energy to treat target tissue. The system includes a generator for providing an electroporation waveform. The generator includes a signal generator for generating an electroporation waveform and a controller for providing a signaling that causes the signal generator to generate the electroporation waveform. The system also includes a catheter including at least one catheter electrode. A signal generator provides an electroporation waveform to at least one catheter electrode. The electroporation waveform includes a plurality of energy pulses, each energy pulse being separated by an inter-pulse delay period.

Description

[0001] Cross - reference to related applications

[0002] This patent application claims priority to U.S. Provisional Patent Application No. 63 / 410,391, filed on September 27, 2022, entitled “A Controller for an Electroporation Apparatus”, the entire content of which is incorporated herein by reference.

[0003] Although this application does not claim priority to the following patent applications, it may be related to the following patent applications: U.S. Patent Application No. 17 / 686,001, filed on March 3, 2022, entitled "Ablation Equipment to Treat Target Regions of Tissue in Organs"; U.S. Patent Application No. 17 / 686,027, filed on March 3, 2022, entitled "Ablation Equipment to Treat Target Regions of Tissue in Organs"; U.S. Patent Application No. 17 / 939,465, filed on September 7, 2022, entitled "Systems, Methods and Devices for Non-Thermal Ablation of Target Tissue"; U.S. Patent Application No. 18 / 001,041, filed on December 7, 2022, entitled "Ablation Equipment to Treat Target Regions of Tissue in Organs"; U.S. Patent Application No. 18 / 258,466, filed on June 20, 2023, entitled "Electronic Apparatus for Delivering Coherent Sine Burst Irreversible Electroporation Energy to a Biological Tissue"; and U.S. Patent Application No. 18 / 338,135, filed on June 20, 2023, entitled "Power Unit for Delivering Coherent Sine Burst Irreversible Electroporation Energy to a Biological Tissue"; each of these patent applications is incorporated herein by reference. TECHNICAL FIELD

[0004] The present disclosure relates to an electroporation system, an electroporation controller, a method of controlling an electroporation system, and a computer program product including computer program code configured to cause the controller to execute the method. Background Art

[0005] Tissue ablation is used to treat patients in many medical procedures. Ablation can be performed to remove unwanted tissue (e.g., cardiac cells) or to denature it. Ablation can be performed by passing energy (e.g., electrical energy) through one or more electrodes and causing tissue necrosis where the electrodes contact the tissue. Ablation procedures can be performed on patients suffering from any arrhythmia (e.g., atrial fibrillation (AF)) by ablating cardiac tissue. Summary of the Invention

[0006] According to one aspect of the inventive concept, a system for delivering electroporation energy to a target tissue to be treated includes a generator configured to provide an electroporation waveform, and the generator includes: a signal generator configured to generate the electroporation waveform; and a controller configured to provide a signal notification configured to cause the signal generator to generate the electroporation waveform. The system further includes a catheter including at least one catheter electrode. The signal generator is configured to provide the electroporation waveform to the at least one catheter electrode. The electroporation waveform includes a plurality of energy pulses, and each energy pulse is separated by an inter-pulse delay period.

[0007] In some embodiments, the inter-pulse delay period includes a first delay period and a second delay period, the first delay period including a fixed duration between each of the plurality of energy pulses, and the second delay period including a variable duration between each of the plurality of energy pulses. Each variable duration can include a positive duration, a negative duration, or both a positive duration and a negative duration. The inter-pulse delay period can include a first inter-pulse delay period between a first energy pulse of the plurality of energy pulses and a second energy pulse of the plurality of energy pulses, and a second inter-pulse delay period between the second energy pulse of the plurality of energy pulses and a third energy pulse of the plurality of energy pulses, and the first inter-pulse delay period can include a first variable duration, and the second inter-pulse delay period can include a second variable duration. The first variable delay period can include a positive duration, and the second variable delay period can include a negative duration. The duration of the first variable duration can be equal to the absolute value of the duration of the second variable duration. The variable duration can include a duration based on a pseudo-random number.

[0008] In some embodiments, the inter-pulse delay period includes a variable duration between each energy pulse. The variable duration can include a duration based on a pseudo-random number. The variable duration can be configured to reduce harmonics generated due to the release of the energy pulses. The variable duration can be configured to reduce the harmonics by at least 10 dB.

[0009] In some embodiments, the electroporation waveform further includes a cycle length, and the cycle length includes the duration from the start of the first energy pulse among the plurality of energy pulses to the start of a subsequent energy pulse among the plurality of energy pulses. The cycle length can be configured to minimize the formation of microbubbles. The cycle length can include a duration of at least 30 ms.

[0010] In some embodiments, the inter-pulse delay period includes a duration of at least 1 ms.

[0011] In some embodiments, the inter-pulse delay period includes a duration of no more than 2000 ms.

[0012] In some embodiments, the controller includes a processor and a memory storage component coupled to the processor, and the memory storage component stores instructions for causing the processor to execute an algorithm. The algorithm can be configured to determine one or more parameters of the electroporation waveform. The algorithm can include one or more biases. The one or more biases can be configured to determine one or more parameters of the electroporation waveform such that the electroporation waveform tends to: a specific frequency range; a specific bipolar to unipolar energy release ratio; a specific phase difference between the included sine waves; a specific voltage or voltage range; a specific delay between energy releases, such as a specific inter-pulse delay; and combinations thereof.

[0013] In some embodiments, at least one catheter electrode includes a first set of non-adjacent catheter electrodes and a second set of non-adjacent catheter electrodes. The first catheter electrode in the second set of non-adjacent catheter electrodes can be located between the first catheter electrode and the second catheter electrode in the first set of non-adjacent catheter electrodes. The first energy pulse among the plurality of energy pulses can be provided to the first set of non-adjacent catheter electrodes, while the second energy pulse among the plurality of energy pulses can be provided to the second set of non-adjacent catheter electrodes. The third energy pulse among the plurality of energy pulses can be provided to the first set of non-adjacent catheter electrodes. The generator can be configured to provide the electroporation waveform in a bipolar arrangement.

[0014] In some embodiments, at least one catheter electrode includes a plurality of electrodes, and the plurality of electrodes includes a first catheter electrode and a group of at least two additional catheter electrodes. The signal generator can be configured to provide an electroporation waveform to the first catheter electrode and the group of at least two additional catheter electrodes. The generator can be configured to provide the electroporation waveform to the first catheter electrode and the at least two additional catheter electrodes in a bipolar arrangement. Each electrode of the plurality of electrodes can include a similar surface area. Each electrode of the plurality of electrodes can be equidistantly spaced apart from each adjacent electrode.

[0015] In some embodiments, the system further includes one or more external electrodes, and the signal generator is configured to provide an electroporation waveform to at least one catheter electrode and the one or more external electrodes. The one or more external electrodes can include at least two external electrodes, and each of the at least two external electrodes can be individually selected such that the electroporation waveform can be provided to any one of the at least two external electrodes and the at least one catheter electrode. The controller can also be configured to select one or more of the at least two external electrodes to provide the electroporation waveform such that the target tissue to be treated by the application of the electroporation waveform can be relatively positioned between the at least one catheter electrode and the one or more selected external electrodes.

[0016] In some embodiments, at least one catheter electrode includes a plurality of catheter electrodes, and the generator is configured to provide the electroporation waveform in a bipolar arrangement between two or more of the plurality of catheter electrodes.

[0017] In some embodiments, the system further includes one or more external electrodes, and the electroporation waveform is configured to be applied to at least one catheter electrode and the one or more external electrodes in a monopolar arrangement. The electroporation waveform can be configured to be applied in both a monopolar arrangement and a bipolar arrangement. The electroporation waveform can include: a first signal that includes a first sine wave; a second signal that includes a second sine wave; and a third signal that includes a combination reference of the first sine wave and the second sine wave, the first sine wave and the second sine wave can include a phase shift, the first signal can be configured to be provided to a first electrode of the at least one catheter electrode, the second signal can be configured to be provided to a second electrode of the at least one catheter electrode, and the third signal can be configured to be provided to at least one of the one or more external electrodes. When the phase shift between the first signal and the second signal is 0°, the electroporation waveform can be provided in a monopolar arrangement. When the phase shift between the first signal and the second signal is greater than 0° and not greater than 180°, the electroporation waveform can be provided in both a monopolar arrangement and a bipolar arrangement. The relative intensity of the monopolar energy release can be configured to vary relative to the intensity of the bipolar energy release based on the phase angle.

[0018] The techniques described herein, its attributes and attendant advantages will be best appreciated and understood from the following detailed description in conjunction with the accompanying drawings, in which representative embodiments are described by way of example.

[0019] Incorporated by reference

[0020] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. The content of all publications, patents, and patent applications mentioned in this specification is incorporated herein by reference in its entirety for all purposes. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 Schematic examples of systems including a catheter and a generator for providing electroporation consistent with the inventive concept are shown.

[0022] Figure 2 Examples of a portion of an electroporation waveform consistent with the inventive concept are shown.

[0023] Figure 3 Examples of a portion of an electroporation waveform consistent with the inventive concept are shown.

[0024] Figures 3A to 3D Charts of harmonics of various frequencies under different conditions consistent with the inventive concept are shown.

[0025] Figure 4 and Figure 4A Charts of a portion of an electroporation waveform and experimental results consistent with the inventive concept are shown, respectively.

[0026] Figure 5 A graph of stimulus intensity versus duration consistent with the inventive concept is shown.

[0027] Figure 6 Examples of electroporation waveforms including compensation signals consistent with the inventive concept are shown.

[0028] Figure 7 Examples of electroporation waveforms including compensation signals consistent with the inventive concept are shown.

[0029] Figure 8 Examples of electroporation waveforms including concurrent compensation signals consistent with the inventive concept are shown.

[0030] Figure 9A and Figure 9B Anatomical side views of a catheter including multiple electrodes located near tissue and representations of the effective electric fields generated by the electrodes consistent with the inventive concept are shown, respectively.

[0031] Figures 10A to 10C Anatomical side views of a catheter including a plurality of electrodes located near tissue and a representation of the effective electric field generated by the electrodes are shown, respectively, in accordance with the inventive concept.

[0032] Figure 11A and Figure 11B A representation of tissue damage caused by various forms of electroporation is shown in accordance with the inventive concept.

[0033] Figure 12 A side view of a catheter including a plurality of electrodes is shown in accordance with the inventive concept.

[0034] Figure 13 A perspective view of a catheter including a curved array of electrodes is shown in accordance with the inventive concept.

[0035] Figure 14 A perspective view of a catheter including an expandable array of electrodes is shown in accordance with the inventive concept.

[0036] Figure 15 A visual representation of a method for providing electroporation therapy is shown in accordance with the inventive concept.

[0037] Figures 16A to 16G Two anatomical representations and a damage depth chart, and two tissue damage representations and an ablation parameter chart are shown, respectively, in accordance with the inventive concept.

[0038] Figure 17 A schematic view of a system for performing monopolar and / or phase-combined energy release through a plurality of external patch electrodes is shown in accordance with the inventive concept.

[0039] Figures 17A to 17E A cross-sectional view and analysis results of a finite element analysis device are shown in accordance with the inventive concept.

[0040] Figures 18A to 18C A chart of the cell membrane potential during an action potential and examples of various pulse timing methods are shown, respectively, in accordance with the inventive concept.

[0041] Figures 19A to 19C Schematic diagrams of various energy release modes are shown in accordance with the inventive concept. Detailed Description

[0042] Reference will now be made in detail to embodiments of the present technology, examples of which are illustrated in the accompanying drawings. Like reference numerals may be used to refer to like components. However, the description is not intended to limit the present disclosure to particular embodiments, but should be understood to include various modifications, equivalents, and / or alternatives of the embodiments described herein.

[0043] It will be understood that, as used herein, the term “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”), or “containing” (and any form of containing, such as “contains” and “contain”) specify the presence of the stated feature, integer, step, operation, element, and / or component, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof.

[0044] It will also be understood that, although the terms first, second, third, etc. may be used herein to describe various limitations, elements, components, regions, layers, and / or sections, these limitations, elements, components, regions, layers, and / or sections should not be limited by these terms. These terms are only used to distinguish one limitation, element, component, region, layer, or section from another. Thus, a first limitation, element, component, region, layer, or section discussed below may be referred to as a second limitation, element, component, region, layer, or section without departing from the teachings of this application.

[0045] It will also be understood that when an element is referred to as being “on,” “attached to,” “connected to,” or “coupled to” another element, the element can be directly on or above the other element, or directly connected or coupled to the other element, or there can be one or more intervening elements. In contrast, when an element is referred to as being directly “on,” “directly attached to,” “directly connected to,” or “directly coupled to” another element, there are no intervening elements. Other words used to describe the relationship between elements should be interpreted in a similar manner (e.g., “between” versus “directly between,” “adjacent” versus “directly adjacent,” etc.).

[0046] It will also be understood that when a first element is referred to as being “in,” “on,” and / or “within” a second element, the first element can be located within the interior space of the second element, within a portion of the second element (e.g., within the wall of the second element); on the exterior surface and / or interior surface of the second element; and combinations of one or more of these.

[0047] As used herein, when used to describe the proximity of a first component or location to a second component or location, the term "proximal" shall be understood to include one or more locations near the second component or location, as well as locations within, on, and / or inside the second component or location. For example, a component positioned proximal to an anatomical site (e.g., a target tissue location) shall include a component positioned near the anatomical site, as well as a component positioned within, on, and / or inside the anatomical site.

[0048] Spatial relative terms such as "below", "beneath", "lower", "above", "upper", etc. may be used to describe the relationship of one element and / or feature to (one or more) other elements and / or features, for example, as shown in the figures. It will also be understood that spatial relative terms are intended to encompass different orientations of the device in use and / or operation, in addition to the orientation depicted in the figures. For example, if the device in the figures is flipped, an element described as "below" and / or "beneath" other elements or features will be oriented "above" the other elements or features. The device may be otherwise oriented (e.g., rotated 90 degrees or in other orientations), and the spatial relative descriptors used herein should be interpreted accordingly.

[0049] As used herein, the terms "reduce", "decrease", "lower", etc. are used to include a decrease in quantity, including a decrease to zero. Reducing the likelihood of an event occurring shall include preventing the event from occurring. Correspondingly, the terms "prevent", "prevent from", and "in case of" shall respectively include the acts of "reduce", "decrease", "lower".

[0050] As used herein, the term "and / or" shall be understood to specifically disclose each of two designated features or components, whether or not the other is included. For example, "A and / or B" shall be understood to specifically disclose (i) A, (ii) B, and (iii) each of A and B, as if each were listed separately herein.

[0051] As used herein, the term "one or more" may refer to one, two, three, four, five, six, seven, eight, nine, ten or more, up to any number.

[0052] The terms "and combinations thereof" and "and combinations of these" may be used herein respectively after a list of items included individually or collectively. For example, a component, process, and / or other item selected from the group consisting of A; B; C; and combinations thereof shall include one or more of the components of the group, which components include: one, two, three or more items of A; one, two, three or more items of B; and / or one, two, three or more items of C.

[0053] In this specification, unless otherwise expressly stated, "and" may mean "or", and "or" may mean "and". For example, if a feature is described as having A, B, or C, the feature may have A, B, and C, or any combination of A, B, and C. Similarly, if a feature is described as having A, B, and C, the feature may have only one or two of A, B, or C.

[0054] As used herein, when a quantifiable parameter is described as having a value "between" a first value X and a second value Y, it shall include a parameter having the following values: at least X, not greater than Y, and / or at least X and not greater than Y. For example, a length between 1 and 10 shall include lengths that are at least 1 (including values greater than 10), less than 10 (including values less than 1), and / or greater than 1 and less than 10.

[0055] The expression "configured (or set) to" used in this disclosure may be interchangeably used with, for example, the expressions "adapted to", "capable of", "designed to", "adapted for", "configured to", and "able to" depending on the context. The expression "configured (or set) to" does not solely refer to "specially designed in hardware". Alternatively, in some cases, the expression "the device is configured to" may mean that the device "is able to" operate with other devices or components.

[0056] As used herein, the term "threshold" refers to a maximum value, a minimum value, and / or a range of values associated with a desired state or an undesired state. In some embodiments, a system parameter is maintained above a minimum threshold, below a maximum threshold, within a threshold range, and / or outside a threshold range to cause a desired effect (e.g., an effective therapy) and / or prevent or otherwise reduce (hereinafter referred to as "prevent") an undesired event (e.g., a device and / or a clinical adverse event). In some embodiments, a system parameter is maintained above a first threshold (e.g., above a first temperature threshold to cause a desired therapeutic effect on tissue) and below a second threshold (e.g., below a second temperature threshold to prevent undesired tissue damage). In some embodiments, the threshold is determined to include a safety margin to account for patient variability, system variability, tolerances, etc. As used herein, "exceeding a threshold" refers to a parameter being above a maximum threshold, below a minimum threshold, within a threshold range, and / or outside a threshold range.

[0057] The term "diameter" as used herein when describing a non-circular geometry shall be understood to be the diameter of an imaginary circle approximating the described geometry. For example, when describing a cross-section (e.g., the cross-section of a component), the term "diameter" shall be understood to represent the diameter of an imaginary circle having the same cross-sectional area as the described cross-section of the component.

[0058] As used herein, the terms "long axis" and "short axis" of a component are the length and diameter, respectively, of the smallest volume imaginary cylinder that can completely enclose the component.

[0059] As used herein, the term "functional element" should be understood to include one or more elements that are constructed and arranged to perform a function. Functional elements can include sensors and / or transducers. In some embodiments, the functional element is configured to release energy and / or otherwise treat tissue (e.g., a functional element configured as a treatment element). Alternatively or additionally, the functional element (e.g., a functional element including a sensor) can be configured to record one or more parameters, such as patient physiological parameters; patient anatomical parameters (e.g., tissue geometry parameters); patient environmental parameters; and / or system parameters. In some embodiments, a sensor or other functional element is configured to perform a diagnostic function (e.g., collect data for making a diagnosis). In some embodiments, the functional element is configured to perform a treatment function (e.g., release treatment energy and / or a therapeutic agent). In some embodiments, the functional element includes one or more elements that are constructed and arranged to perform a function selected from the group consisting of: releasing energy; extracting energy (e.g., cooling a component); applying a drug or other agent; manipulating a system component or patient tissue; recording or otherwise sensing a parameter, such as a patient physiological parameter or a system parameter; and combinations of one or more of these. Functional elements can include fluids and / or fluid delivery systems. Functional elements can include reservoirs, such as expandable balloons or other fluid-holding reservoirs. A "functional assembly" can include an assembly that is constructed and arranged to perform a function (e.g., a diagnostic and / or treatment function). A functional assembly can include an expandable assembly. A functional assembly can include one or more functional elements.

[0060] As used herein, the term "transducer" should be understood to include any component or combination of components that receives energy or any input and produces an output. For example, a transducer can include an electrode that receives electrical energy and distributes the electrical energy to tissue (e.g., based on the size of the electrode). In some configurations, the transducer converts an electrical signal into any output, such as: light (e.g., a transducer including a light-emitting diode or a light bulb); sound (e.g., a transducer including a piezoelectric crystal configured to release ultrasonic energy); pressure (e.g., an applied pressure or force); thermal energy; cryogenic energy; chemical energy; mechanical energy (e.g., a transducer including a motor or a solenoid); magnetic energy; and / or a different electrical signal (e.g., different from the input signal of the transducer). Alternatively or additionally, the transducer can convert a physical quantity (e.g., a change in a physical quantity) into an electrical signal. The transducer can include any component that releases energy and / or applies an agent to tissue, e.g., a transducer configured to release one or more of the following to tissue: electrical energy (e.g., a transducer including one or more electrodes); light energy (e.g., a transducer including a laser, a light-emitting diode, and / or optical components such as lenses or prisms); mechanical energy (e.g., a transducer including a tissue manipulation element); sound energy (e.g., a transducer including a piezoelectric crystal); chemical energy; electromagnetic energy; magnetic energy; and combinations of one or more of these.

[0061] As used herein, the term "fluid" can refer to a liquid, a gas, a gel, or any flowable material, e.g., a material that can be propelled through a lumen and / or an opening.

[0062] As used herein, the term "material" can refer to a single material, or a combination of two, three, four, or more materials.

[0063] It should be understood that certain features that are described in the context of separate embodiments for clarity in the present inventive concept can also be provided in combination in a single embodiment. Conversely, the various features that are described in the context of a single embodiment for clarity in the present inventive concept can also be provided separately or in any suitable sub-combination. For example, it will be understood that all features listed in any claim (whether an independent claim or a dependent claim) can be combined in any given manner.

[0064] It should be understood that at least some of the drawings and descriptions of the present inventive concept have been simplified to focus on elements relevant to a clear understanding of the present inventive concept, while omitting other elements that would be understood by a person of ordinary skill in the art for the sake of clarity, and these elements can also be part of the present inventive concept. However, since such elements are well known in the art and because they do not necessarily contribute to a better understanding of the present inventive concept, a description of such elements is not provided herein.

[0065] The terms defined in this disclosure are only used to describe specific embodiments of this disclosure and are not intended to limit the scope of this disclosure. Unless the context clearly indicates otherwise, terms provided in the singular form are also intended to include the plural form. Unless otherwise defined herein, all terms used herein (including technical or scientific terms) have the same meaning as commonly understood by one of ordinary skill in the art. Terms defined in a general dictionary should be interpreted to have a meaning that is the same as or similar to the context of the relevant art, and should not be interpreted to have an idealized or exaggerated meaning, unless clearly defined otherwise herein. In some cases, the terms defined in this disclosure should not be interpreted as excluding embodiments of this disclosure.

[0066] Tissue ablation is used in many medical procedures to treat one or more medical conditions of a patient. Ablation can be performed to remove unwanted tissue (e.g., heart cells associated with arrhythmia) or to denature it. Ablation can be carried out by passing energy (e.g., electrical energy) through one or more electrodes and causing tissue necrosis at a location near the electrodes (e.g., where the heat generated by applying the energy is sufficient to cause cell death, and / or where the electric field generated is sufficient to irreversibly electroporate the tissue). Ablation procedures can be performed on the heart tissue of patients suffering from any form of arrhythmia (e.g., atrial fibrillation (AF)).

[0067] Radiofrequency ablation (RFA) is a medical procedure that uses heat generated from the application of alternating current to ablate tissue that is part of the electrical conduction system of the heart, tumor tissue, and / or other dysfunctional tissue. In this context, the typical frequency of the alternating current can be considered to be from 350 kHz to 500 kHz.

[0068] In particular, in these types of ablation procedures, an energy release device (e.g., a catheter or other probe having one or more electrodes) is inserted near the target tissue to cause destruction of the target area of the heart tissue by applying heat energy. In fact, when the energy release device is placed on the tissue surface, electro-induced thermal ablation (e.g., radiofrequency ablation (RFA)) can be used to effectively and continuously ablate a tissue site locally. Although RFA can effectively ablate a large amount of target tissue, this thermal technique has limitations. One frequently mentioned problem in using this procedure during cardiac ablation involves heat dissipation, which on the one hand can include blood flow, and the heat generated on the ablation element will be carried away / dissipated by the cooler blood flow on the element. This heat dissipation effect can change (e.g., undesirably reduce) both the shape and the maximum volume of the tissue being ablated.

[0069] In recent years, pulsed electric fields (PEF) have been used as an alternative to the aforementioned RFA for ablating cardiac and / or other organ tissues. Pulsed electric fields (PEF) refer to the application of intermittent high-intensity electric fields over short time periods (e.g., several microseconds or nanoseconds), which causes electroporation of the cells in the tissue. Electroporation is the process by which the applied electric field (i.e., PEF) causes the formation of pores in the cell membrane. The formation of pores leads to permeability, which can be reversible or irreversible, depending on the parameters of the applied PEF.

[0070] In reversible electroporation, the electroporated cells remain viable. This method is the basis for electrochemotherapy and gene electrotransfer. In contrast, in the case of irreversible electroporation (IRE), the cells and tissues become non-viable since the technique induces the activation of a programmed cell death cascade.

[0071] IRE is a mature treatment for solid tumors, but IRE can also be used in cardiology, particularly for cardiac ablation, especially considering the limitations of current heat-based methods.

[0072] When used for ablating cardiac tissue, irreversible electroporation (IRE) involves applying electrical pulses to the target tissue for a duration in the range of microseconds to nanoseconds, which results in non-thermal defects at the nanoscale on the cell membrane. These defects cause disruption of the cell membrane homeostasis, leading to irreversible cell membrane permeability that causes cell death without significantly increasing the temperature of the tissue ablation zone. In some embodiments, the systems, devices, and methods of the present inventive concept are configured to avoid increasing the temperature of the tissue near the tissue ablation zone by a maximum increment of no more than 13 °C (e.g., no more than 10 °C, 7 °C, or 4 °C), and / or avoid increasing the temperature of the tissue near the tissue ablation zone to a maximum of no more than 50 °C (e.g., a maximum of no more than 47 °C or 44 °C).

[0073] This application relates to providing an electroporation waveform including a plurality of energy pulses, each energy pulse including a sine wave signal, wherein the respective energy pulses are separated by inter-pulse delay periods. By setting the inter-pulse delay periods and other delay periods described herein, it is possible to successfully cause target cell death while avoiding undesired heating at the target treatment site, while avoiding or at least reducing the formation of microbubbles, or both.

[0074] Now refer to Figure 1, showing a schematic example of a system consistent with the inventive concept, including a catheter and a generator for providing electroporation. As shown, system 10 may include a generator 100, which includes a controller 110 configured to control one or more signal generators (e.g., signal generator 120). System 10 may include one or more power supply components, such as a power supply 130 of generator 100. Power supply 130 may be configured to supply power to signal generator 120. Generator 100 may be configured to apply electrical energy including one or more waveforms (e.g., electroporation waveform 200 described in detail herein). System 10 may include one or more patient treatment devices, such as the catheter 300 shown. Catheter 300 may include an array of one or more electrodes, such as electrode array 310 including electrode 311, as shown. Catheter 300 may be operably attached to generator 100 such that electroporation waveform 200 may be provided by generator 100 and electroporation waveform 200 may be applied to a patient via catheter 300, as described herein. Applying electroporation waveform 200 to one or more electrodes 311 may generate one or more electric fields (single or combined electric field 290) that are generated in the tissue near electrodes 311 of catheter 300. As described herein, the parameters and methods of application of electroporation waveform 200 may be configured such that tissue within a portion of field 290 sufficient to electroporate the tissue is effectively electroporated, as described herein. In some embodiments, one or more components may not form part of generator 100. For example, an external power supply may be used, so power supply 130 may not form part of generator 100. In other examples, signal generator 120 itself may also include a power supply 130 instead of providing two separate components. In some examples, controller 110 may be powered by power supply 130, while in other examples, controller 110 may be powered by other means.

[0075] In some embodiments, electroporation waveform 200 is configured to provide Coherent Sinusoidal Pulse Electroporation (CSE) when applied to tissue. CSE includes applying a phase sinusoidal wave of high voltage (e.g., at least 100V or 1500V) to ablate (e.g., irreversibly electroporate) tissue, as described herein.

[0076] Generator 100 may include one or more isolation transformers. Compared with square waves, sine waves are more compatible with isolation transformers because the energy of sine waves can be concentrated at a single frequency within the passband of the isolation transformer. Isolation transformers are considered the "gold standard" for patient safety because these types of transformers allow the patient potential to "float" relative to the potential within generator 100, and all pulsed field ablation (PFA) energy must be coupled through the magnetic field of the transformer to reach the patient. Thus, due to the isolation created by the magnetic field of the transformer, any electrical faults in generator 100 on the primary side of the transformer will not propagate to the secondary side attached to catheter 300. By providing a sine wave through generator 100 and leveraging the voltage gain that may be achieved with an appropriately selected isolation transformer, generator 100 is capable of generating a higher voltage in a sine-wave-based generator configuration, thereby creating a higher electric field, which will cause a deeper propagation of irreversible PFA.

[0077] In addition, as described herein, by varying the relative phase between multiple sine waves applied to adjacent activation electrodes, generator 100 can easily combine pure sine waves, resulting in constructive interference. If an external electrode 60 is connected and there is no phase shift in the sine waves of a given frequency applied to adjacent activation electrodes 311 (e.g., electrodes located on the endocardial surface), a monopolar field will be generated between electrode 311 and external electrode 60 (e.g., including one or more patch electrodes). If the sine waves applied to adjacent activation electrodes 311 are at the same frequency but have a 180-degree phase difference, the two waves will undergo constructive interference and combine, resulting in a bipolar sine wave whose amplitude is twice the amplitude of the sine waves applied to each individual electrode 311. In this configuration, there is no need for an external electrode 60 (e.g., no loop patch electrode).

[0078] System 10 can use a monopolar field to create a deeper lesion at a given peak voltage than a bipolar lesion. This increased depth is due to the field being directed from the endocardial tissue surface contacted by electrode 311 outward through the heart thickness and through other parts of the body (e.g., toward one or more external electrodes 60), but tends to produce a greater degree of neuromuscular stimulation due to the larger number of muscle groups between electrode 311 and external electrode 60. Depending on the spacing of electrodes 311 and other factors, monopolar lesions also result in less uniform "filling" between adjacent electrodes 311 and can include gaps. The bipolar field maintains its field locally because the electrodes 311 placed on the endocardium act as both sources and receivers simultaneously, resulting in negligible neuromuscular stimulation and higher filling uniformity with no gaps between the electrodes. Although the more local nature of the bipolar field results in less tissue penetration at a given peak voltage, this can be compensated for by doubling the voltage through out-of-phase driving, and thus in applications such as atrial fibrillation (AF), the bipolar field is generally preferred, where the thickness of the tissue to be ablated to the epicardial surface is typically less than 5 mm.

[0079] Finally, another advantage of the sine-wave-based system is that sine-wave-based PFA is more efficient than PFA based on biphasic or monophasic square waves. Different from standard RF ablation that relies on the root mean square (RMS) of alternating current (AC) to cause resistive heating, electroporation is a field effect that depends on the peak amplitude of the generated field. For any given amplitude, a sine wave has less power and thus generates less heat compared to a square wave of the same amplitude. In addition, the part of the spectral energy in the square wave that causes heat is contained in the odd harmonics. These harmonics are multiples of the fundamental frequency, and in this case, due to the low-pass characteristics of biological tissue, the effectiveness of electroporation is lower. In short, to generate a field of the same amplitude as the sine-wave-based system, the square-wave system requires more heating energy at frequencies that have the least impact on lesion formation.

[0080] System 10 can be configured to deliver electroporation at a treatment site of a patient via catheter 300. Specifically, the electroporation technique can include high-frequency irreversible electroporation. However, in some embodiments, system 10 can be configured to deliver different types of electroporation, such as, for example, low-frequency non-thermal irreversible electroporation or reversible electroporation, and / or electrolytic electroporation (e.g., electrolytic electroporation including a combination of low-frequency and high-frequency electroporation).

[0081] In some embodiments, when applying the electroporation waveform 200, energy can be released in a bipolar arrangement between two or more adjacent electrodes and / or other endocardial electrodes (e.g., electrode 311 of catheter 300) as described herein. Additionally or alternatively, energy can be released between an endocardial electrode 311 and one or more external patient return patches (e.g., the shown external electrode 60). The release of energy between an endocardial electrode (e.g., electrode 311) and one or more external patch electrodes (e.g., external electrode 60) can be described as releasing energy in a monopolar arrangement. In some embodiments, such as when the system 10 uses a pure sine wave, the electroporation waveform 200 can be applied by the generator 100 in a phase-combined arrangement (i.e., a combination of bipolar application and monopolar application), where these pure sine waves can be combined to produce constructive interference by changing the relative phase between the sine waves applied to adjacent active electrodes (e.g., electrode 311), and the generator 100 can provide a reference voltage to the external electrode 60 (e.g., one or more patch electrodes located on the patient's skin) as described herein.

[0082] Compared to the lesions produced using a bipolar method, which utilizes two or more endocardial electrodes (e.g., electrode 311), the monopolar energy release method can be used to produce deeper lesions at a given peak voltage because the direction of the synthetic field (e.g., field 290) can be oriented from the contacting endocardial tissue outward through the thickness of the heart wall tissue and through other parts of the body, toward one or more patch electrodes on the patient's skin. This monopolar energy release tends to produce a greater degree of neuromuscular stimulation due to the larger number of muscle groups along the path to the associated patient return electrode (e.g., external electrode 60). In some embodiments, such as depending on the spacing of the catheter 300 and the electrode 311 and other factors, the lesions produced using monopolar energy release may result in less uniform 'filling' between adjacent electrodes 311 and may include gaps. The bipolar field keeps its field local because the endocardial electrode 311 serves as both a source and a receiver, thereby producing negligible neuromuscular stimulation and higher filling uniformity, and there are no gaps between the electrodes.

[0083] In some embodiments, by pulling the field in a given direction towards one or more activated patch electrodes, the placement and / or selection of one or more external patch electrodes (e.g., external electrode 60) can enhance and / or reduce the magnitude of the resulting monopolar component. For example, if the external electrode 60 includes patch electrodes placed on the patient's skin such that the substrate to be ablated is the tissue between the endocardial electrode 311 and the external electrode 60, the size of the resulting lesion will increase (e.g., to a deeper depth and produce a transmural lesion). The system 10 can be configured to ablate one or more locations in any chamber of the heart, e.g., when configured to allow a clinician to ablate any location in the left atrium and / or other heart chambers. In some embodiments, the electrode 60 includes a plurality of patch electrodes located at different positions on the patient's skin, where each electrode can be independently activated (e.g., configured to be selected as a return electrode), such as activating a particular patch electrode to direct the field in one or more directions of the anterior, posterior, superior, and / or inferior directions, e.g., resulting in a transmural lesion in the heart wall at the location of the associated electrode 311. The monopolar energy release using the external electrode 60 including a plurality of patch electrodes can be similar to the monopolar energy release and / or phase combination energy release described below herein with reference to Figure 17 and / or the phase combination energy release described below.

[0084] The controller 110 may include modules (e.g., electronic modules) that may be configured to perform and / or facilitate one or more functions of the system 10, such as one or more processes; energy release, such as the application of an electroporation waveform; data analysis; data transmission; signal processing; and / or other functions of the system 10 (referred to herein as "functions of the system 10" or "system functions"). The controller 110 may include one or more electronic components, electronic assemblies, and / or other electronic parts, such as parts selected from the group consisting of: microprocessors; microcontrollers; state machines; memory storage components; analog-to-digital converters; rectifier circuits; filters and other signal regulators; sensor interface circuits; transducer interface circuits; and combinations of one, two, or more of these. For example, the controller 110 may include at least one processor and at least one memory storage component, such as processor 111 and memory 112, each as shown. The memory 112 may be coupled to the processor 111, and the memory 112 may store instructions used by the processor 111 to execute one or more algorithms of the system 10. For example, the system 10 may include one or more algorithms (algorithm 25 as shown), which are executed by the processor 111 and / or another similar processor device and instructions stored in the memory. Algorithm 25 may include one or more machine learning, neural network, and / or other artificial intelligence algorithms (referred to herein as "AI algorithms"). All or part of algorithm 25 may be integrated into one, two, or more of the various components of the system 10 (e.g., devices or other components of the system 10 that include the console and / or processor of the system 10) (e.g., stored in the memory of the system 10). The controller 110 may include a microprocessor or other processing unit that enables the controller 110 to receive input data and provide an output signal based on the input data. In some embodiments, the controller 110 is configured to receive input from a user input device and / or from an automated computing device. Input from the user input device may reach the controller 110 directly, and / or may be provided via one or more other electronic devices. The input received by the controller 110 may be related to specific parameters that define an electroporation waveform. For example, the received parameters may include the desired frequency, intensity, duration, phase, period length, or other parameters of the waveform. As an output, the controller 110 may be configured to provide a signal notification that is configured to interact with the signal generator 120, in which the signal notification is configured to cause the signal generator 120 to generate a desired electroporation waveform.

[0085] In some embodiments, the generator 100 of system 10 and / or another component may include a user interface, such as the user interface 150 of the illustrated generator 100, e.g., a user interface configured to provide information to and / or receive information from an operator of the system 10. As shown, the user interface 150 may be integrated into the generator 100. Alternatively or additionally, the user interface 150 may include components separated from the generator 100, e.g., a display separated from but operably attached to the generator 100. The user interface 150 may include one, two, or more user input and / or user output components. For example, the user interface 150 may include a joystick, keyboard, mouse, touch screen, speaker, light, transducer, and / or other human-machine interface devices, the illustrated user interface device 151. In some embodiments, the user interface 150 includes a display (e.g., a touch screen display), such as the illustrated display 152. In some embodiments, the processor 111 may provide a graphical user interface (GUI) 153 that is presented on and / or provided by the display 152. The algorithm 25 may be configured to execute one or more software routines to enable a user to control one or more functions of the system 10. One or more software routines executed by the algorithm 25 may include a graphical user interface, e.g., the GUI 153. The user interface device 151 may include input and / or output devices selected from the group consisting of: speakers; indicator lights, such as LED indicator lights; haptic feedback devices, such as devices including a vibration alert component; foot pedals; switches, such as momentary switches; microphones; cameras, e.g., when the processor 111 enables eye tracking and / or other inputs via image processing; and combinations thereof. In some embodiments, the catheter 300 includes at least a portion of the user interface 150, such as the user input device 151, e.g., when the functional element 399 of the catheter 300 includes a button or other interface device 151 of the user interface 150. Additionally or alternatively, the catheter 300 may include a user interface device 151 that includes a user output device, such as a light or a speaker, e.g., a light configured to indicate the readiness state of the system 10 (e.g., a light configured to indicate that the system 10 is ready and / or not ready to provide the electroporation waveform 200).

[0086] In some embodiments, system 10 includes data storage and processing means, server 400. Server 400 may include an "off-site" server (e.g., located outside the clinical site where patient image data is recorded), such as a server owned, maintained, and / or otherwise provided by the manufacturer of system 10. Alternatively or additionally, server 400 may include a cloud-based server. Server 400 may include the illustrated processing unit 410, which may be configured to perform one or more functions of system 10, such as one or more of the functions described herein. Processing unit 410 may include one or more algorithms, such as algorithm 25 described herein. Processing unit 410 may include a memory (not shown), which may store instructions for executing algorithm 25. Server 400 may be configured to receive and store various forms of data, such as: treatment data, diagnostic data, planning data, and / or program result data collected by system 10, data 420. In some embodiments, data 420 may include data collected from multiple patients (e.g., multiple patients treated using system 10), such as data collected during and / or after a clinical procedure in which electroporation waveform 200 is applied to a patient via system 10. In some embodiments, generator 100 and server 400 may communicate via a network (e.g., a wide area network such as the Internet). Alternatively or additionally, system 10 may include a virtual private network (VPN) through which various devices of system 10 transmit data.

[0087] As described herein, one or more functions of system 10 performed by controller 110 and / or processing unit 410 may be performed by either device or both. For example, in some embodiments, treatment data may be collected by controller 110 of generator 100. The treatment data may then be transmitted to server 400, where the data is processed, such as to identify one or more trends, such as one or more trends in the effectiveness of various parameters of electroporation waveform 200 described herein. Insights obtained from the data processing at server 400 may then be transmitted back to generator 100, for example, to inform a decision-making process regarding one or more parameters of electroporation waveform 200 to be provided to treat a patient (e.g., a decision made by algorithm 25 and / or an operator of system 10).

[0088] In some embodiments, algorithm 25 is configured to adjust (e.g., automatically and / or semi-automatically adjust, e.g., adjust based on one or more biases included in algorithm 25 described herein) one or more operating parameters of system 10, such as one or more of the parameters of the electroporation waveform 200 described herein. In some embodiments, algorithm 25 is configured to adjust the operating parameters based on one or more sensor signals, such as sensor signals provided by a sensor-based functional element of the present inventive concept described herein. Algorithm 25 may be configured to adjust (e.g., automatically adjust and / or recommend an adjustment) operating parameters selected from the group consisting of: which or which electrodes of a group of electrodes to provide the electroporation waveform 200 to (e.g., one or more electrodes 311 and / or one or more external electrodes 60); which energy mode to use to release energy; the phase angle between two or more signals of the electroporation waveform 200; which tissue locations to release energy to, such as locations determined by analyzing cardiac mapping data; which external electrode 60 to provide the electroporation waveform 200 to in order to direct the resulting electric field towards the target tissue; and combinations of two or more of these.

[0089] In some embodiments, algorithm 25 is configured to determine one or more parameters of a stimulation waveform. In these embodiments, algorithm 25 may include one or more biases, such as biases for generating a stimulation waveform that tends towards: a specific frequency range; a specific ratio of bipolar to monopolar energy release; a specific phase difference between included sine waves; a specific voltage or voltage range; a specific delay between energy releases, such as a specific inter-pulse delay; and combinations of one or more of these.

[0090] It will be understood that the term "signaling" as used herein refers to one or more signals provided by controller 110 that include information for interpretation by signal generator 120 or (optionally) another component of system 10. Signaling may be provided via one or more wired connections and / or wireless data communication modes. As mentioned above, signaling may be provided to signal generator 120 in accordance with Figure 1 the embodiments described, and / or may be provided to the power supply itself, which is configured to generate an electroporation waveform as described herein.

[0091] In some embodiments, algorithm 25 may be configured to cause system 10 to perform method 510, which provides an electroporation waveform (e.g., electroporation waveform 200 described herein) to an ablation device (e.g., catheter 300). Method 510 may include providing a signal notification from controller 110 to signal generator 120. The signal notification may be configured to cause signal generator 120 to generate electroporation waveform 200, and the electroporation waveform may include a plurality of pulses, where each energy pulse is separated by an inter-pulse delay period, e.g., as referenced Figure 2 and described elsewhere herein, energy pulses 210 are separated by inter-pulse delay periods 220. In some embodiments, each energy pulse may include one or more different sine wave signals, as described herein. Method 510 may also include generating an electroporation waveform based on the signal notification (e.g., signal generator 120 may generate electroporation waveform 200 based on the signal notification from controller 110). Method 510 may include providing electroporation waveform 200 from the signal generator to an electroporation catheter (e.g., catheter 300) to provide electroporation waveform 200 to a target region.

[0092] In some embodiments, algorithm 25 may be configured to cause system 10 to perform method 520, which provides an electroporation waveform and one or more compensation signals, e.g., as referenced below Figures 5 to 7 and described elsewhere herein. In some embodiments, method 520 includes providing a signal notification (e.g., a signal notification from controller 110) to provide electroporation waveform 200, where electroporation waveform 200 includes one or more sequentially provided energy pulses 210, where each energy pulse 210 is configured to induce electroporation. Method 520 may also include providing a signal notification from controller 110 to cause signal generator 120 to provide one or more compensation signals (e.g., compensation signal 2102 described herein), where the one or more compensation signals are configured to reduce charge accumulation at the treatment location of the patient, the accumulated charge being caused by one or more of a plurality of stimulation signals (e.g., a plurality of energy pulses 210). In some embodiments, controller 110 may be configured to provide the signal notification to signal generator 120 to cause signal generator 120 to provide electroporation waveform 200 that includes an energy pulse and a charge reduction compensation signal. In some embodiments, the compensation signal is added to electroporation waveform 200.

[0093] In some embodiments, algorithm 25 may be configured to cause system 10 to perform method 530. Method 530 may include providing a first signal notification that is configured to apply a first potential difference between a first electrode and a second electrode (e.g., first electrode 311 and second electrode 311 of catheter 300), where the second electrode is a non-adjacent electrode (e.g., non-proximate electrode) to the first electrode. Method 530 may further include providing a second signal notification that is configured to apply a second potential difference between a third electrode and a fourth electrode (e.g., third electrode 311 and fourth electrode 311 of catheter 300), where the third electrode is an adjacent electrode (e.g., proximate electrode) to the first electrode and the fourth electrode is a non-adjacent electrode to the third electrode. In some embodiments, applying the first potential difference between the first electrode and the second electrode and applying the second potential difference between the third electrode and the fourth electrode are asynchronous. Method 530 may be applied to multiple electrodes and electrode pairs to create a continuous cell ablation lesion.

[0094] Signal generator 120 may include any suitable signal generator for generating an electroporation waveform that includes an electrical signal for exciting one or more electrodes 311 of catheter 300. That is, the electroporation waveform is configured to apply a voltage electric field to biological tissue via electrodes 311 of catheter 300. Specifically, signal generator 120 may include a sine wave generator that is configured to generate a signal that includes one or more sine waves. Power supply 130 may include any suitable means for providing power to at least signal generator 120.

[0095] Catheter 300 may include multiple electrodes 311 (e.g., electrodes 311 of electrode array 310 described herein), and electrodes 311 are capable of being positioned on or near target tissue that is to be subjected to electroporation by system 10. Electrodes 311 may be configured such that a potential difference is created between the activated electrodes 311 in response to the electroporation waveform provided to the activated electrodes 311.

[0096] In some embodiments, system 10 and / or one or more components of system 10 further include one or more functional elements (referred to herein as "functional elements"), such as functional element 99 of generator 100, functional element 199, and / or functional element 399 of catheter 300, each as shown. Each functional element may include at least two functional elements. Each functional element may include one or more elements selected from the group consisting of: sensors; transducers; and combinations thereof. Each functional element of system 10 may include a sensor configured to generate a signal. Each functional element may include a sensor selected from the group consisting of: physiological sensors; pressure sensors; strain gauges; position sensors; GPS sensors; accelerometers; temperature sensors; magnetic sensors; chemical sensors; biochemical sensors; protein sensors; flow sensors (e.g., ultrasonic flow sensors); gas detection sensors (e.g., ultrasonic bubble detectors); sound sensors (e.g., ultrasonic sensors); impedance sensors; charge sensors; and combinations thereof. Each functional element may include a physiological sensor selected from the group consisting of: pressure sensors (e.g., blood pressure sensors); blood gas sensors; flow sensors (e.g., blood flow sensors); temperature sensors (e.g., blood or other tissue temperature sensors); and combinations thereof. In some embodiments, system 10 may further include one or more algorithms (e.g., algorithm 25 described herein), the one or more algorithms being configured to process signals generated by sensor-based functional elements. Each functional element may include one or more transducers. Each functional element may include one or more transducers selected from the group consisting of: heating elements, e.g., heating elements configured to release sufficient heat to ablate tissue; cooling elements, e.g., cooling elements configured to release cryogenic energy to ablate tissue; acoustic transducers, e.g., ultrasonic transducers; vibration transducers; and combinations thereof. In some embodiments, functional element 399 includes one or more vacuum ports that are fluidly connected (e.g., via the lumen of catheter 300) to functional element 199 that includes a vacuum source. In these embodiments, a vacuum may be applied to functional element 399 by element 199 such that one or more portions of catheter 300 (e.g., one or more portions including one or more electrodes 311) are held in contact with tissue via the applied vacuum.

[0097] Now referring to Figure 2 , an example of a portion of an electroporation waveform consistent with the inventive concept is shown. In some embodiments, Figure 2 's waveform includes a series of energy pulses having a fixed inter-pulse delay, e.g., as described herein. Figure 2FIG. 200 shows an exemplary electroporation waveform 200 that includes a plurality of energy pulses 210 and a plurality of inter-pulse delay periods 220, each period 220 being arranged between pairs of energy pulses 210 such that the energy pulses 210 are temporally spaced energy pulses. A single cycle 230 of the electroporation waveform 200 can be defined as from the start of the first energy pulse to the start of the next energy pulse. In some embodiments, the electroporation waveform 200 includes a series of a plurality of cycles 230, shown as a pulse train 240. It will be understood that this is merely an example, as the cycle 230 can also be defined as the portion between any two co-located points on consecutive energy pulses 210 or consecutive delay periods 220. In Figure 2 , voltage is provided along the y-axis and time is provided along the x-axis. In some embodiments, the inter-pulse delay period 220 includes two parts, such as a fixed inter-pulse delay period 2201 and a variable inter-pulse delay period 2202 (not shown, but such as referenced Figure 4A and elsewhere in this document).

[0098] In some embodiments, system 10 is configured to provide a first portion of the electroporation waveform 200 from a first set of electrodes 311 and a second portion of the electroporation waveform 200 from a second set of electrodes 311, e.g., to apply the electroporation waveform 200 in a staggered pattern, such as referenced Figures 18A to 18C and elsewhere in this document. In some embodiments, the pulse train 240 can include a first set of energy pulses (energy pulses 210m) and a second set of energy pulses (energy pulses 210n), where the energy pulses 210m are applied from the first set of electrodes 311 (e.g., Figure 15 the electrodes 311a, 311c shown in Figure 15Applied to the electrodes 311b and 311d shown in []. In some embodiments, each period 230 may include an energy pulse 210m and an energy pulse 210n. The electrode 311b may be located between the electrodes 311a and 311c such that, as described below, the electroporation waveform 200 is provided from non-adjacent electrodes in a staggered pattern. In some embodiments, the inter-pulse delay period 220 includes the duration between the first set of energy pulses 210 (e.g., energy pulse 210m) applied from the first set of electrodes 311, wherein, in some embodiments, at least a second energy pulse 210 (e.g., energy pulse 210n) is applied from the second set of electrodes 311 during the inter-burst delay period 220 of the first set of energy pulses 210m. The inter-pulse delay period 220 may include a staggered offset period 2203, where the staggered offset period 2203 includes a time delay between the end of the first energy pulse 210m and the start of the second energy pulse 210n. In some embodiments, the staggered offset period 2203 includes a duration equal to half of the inter-pulse delay period 220 such that each energy pulse 210 (e.g., energy pulses 210m and 210n) is applied at the same frequency, e.g., as Figure 18B shown. Alternatively or additionally, the duration of the staggered offset period 2203 may be less than half of the duration of the inter-pulse delay period 220, e.g., such that the energy pulses 210m and 210n are applied within the first half of the period 230, e.g., as Figure 18C shown.

[0099] In some embodiments, system 10 is configured to provide portions of the electroporation waveform 200 to two, three, four, or more sets of electrodes 311 in a staggered pattern. For example, a first portion (energy pulse 210m) of the electroporation waveform 200 may be applied via every other electrode 311 (e.g., electrodes 311 in a linear array 310 of sequentially numbered electrodes 1 - 12, e.g., electrodes 311 - 1, 311 - 4, 311 - 7, and 311 - 10). A second portion (energy pulse 210n) may be applied from electrodes 311 - 2, 311 - 5, 311 - 8, and 311 - 11; a third portion (energy pulse 210o) may be applied from electrodes 311 - 3, 311 - 6, 311 - 9, and 311 - 12. The period 230 may include the application of one of each of the energy pulses 210m, 210n, 210o. In some embodiments, the offset periods 2203 staggered between energy pulses 210m, 210n and 210n, 210o may include similar and / or different durations. In some embodiments, the total offset period between the first energy pulse (e.g., energy pulse 210m) and the last energy pulse (e.g., energy pulse 210o) in the energy pulse period 230 may include a period less than the refractory period of the action potential (AP) induced by the first energy pulse 210m, e.g., as referenced Figure 18C and described elsewhere in this document.

[0100] As provided herein, the electroporation waveform 200 includes the total waveform provided for the application of reversible electroporation, irreversible electroporation, or both reversible and irreversible electroporation. In one or more embodiments, the electroporation waveform 200 may specifically be an ablation waveform that includes ablation pulses configured to cause cell death via irreversible electroporation.

[0101] The electroporation waveform 200 may include a plurality of energy pulses 210. In some embodiments, each energy pulse 210 includes one or more different sine wave signals. For example, the electroporation waveform 200 may include a plurality of energy pulses 210, where each energy pulse 210 includes a plurality of different sine wave signals. It will be understood that the phrase "different sine wave signals" as used herein is intended to define a plurality of sine wave signals that can be distinguished from one another. Such a signal configuration may involve sine waves that are completely discrete from one another, i.e., they start at a reference voltage, cross the reference voltage, and end at substantially the same reference voltage before the next sine wave begins. The reference voltage may be zero volts, but the reference voltage may also have a different value. Different sine waves may also refer to sine waves that partially overlap but whose sine wave forms are distinguishable from one another. Those sine waves that overlap in such a way that they undergo constructive interference to produce a sine wave with a greater total amplitude, or those that form a sine wave or other waveform with a wider line width than any of the original sine waves (e.g., when the component sine waves cannot be individually distinguished), are not necessarily considered different sine wave signals. In some embodiments, each energy pulse 210 may include a single different sine wave. It should be understood that "a single different sine wave" is defined as providing only one different sine wave in each energy pulse 210, without any other distinguishable sine waves. If the superposition of sine waves provides an effective, single different sine wave (as described above), such a configuration does not prohibit the superposition of multiple sine waves. In an example where a single different sine wave is used in each energy pulse 210, the frequency of the single different sine wave may be between 20 kHz and 200 kHz, and the amplitude may be between 500 V and 3 kV, which will provide a maximum and minimum amplitude difference of 1 kV to 6 kV. In particular, the frequency may be approximately 50 kHz. It will be understood that the sine wave may be applied to two electrodes (e.g., two adjacent or non-adjacent electrodes 311) and / or one or more electrodes of two sets, each for providing a potential difference therebetween. In the case where the phase difference between the sine wave applied to the first electrode (or the first set of electrodes) and the sine wave applied to the second electrode (or the second set of electrodes) is 0 degrees, the composite signal will be monopolar, as described herein, for example. In the case where the phase difference between the sine wave applied to the first electrode and the sine wave applied to the second electrode is 180 degrees, the composite signal will be bipolar (e.g., when no signal is applied to the external electrode 60), as described herein, for example. Alternatively, the phase difference may have another value, which will result in the signal having both a monopolar component and a bipolar component, such as when configured for phase-combined energy release as described herein.

[0102] The electroporation waveform 200 may include a pulsed waveform, and the signal between the start of the first pulse and the start of subsequent pulses may be defined as a single cycle 230 of the electroporation waveform 200. Applying an energy pulse 210 to the electrode 311 of the catheter 300 creates a potential difference, which in turn creates an electric field that causes the desired electroporation. It should be understood that causing electroporation may refer to causing reversible electroporation or irreversible electroporation. There may be an inter-pulse delay period 220 between the first energy pulse and subsequent energy pulses, during which no energy pulse 210 is applied. It will be understood that there may be some noise or other signals during the inter-pulse delay period 220, but no pulse with pulse characteristics suitable for stimulating electroporation is applied during the delay period 220. Applying a pulse that does not cause electroporation during the inter-pulse delay period 220 may allow, for example, the provision of an offset pulse, which is provided to counteract the accumulation of charge in the patient's body caused by the above-mentioned pulses. By providing an inter-pulse delay period 220 during which no pulse causing electroporation is applied, a reduction in microbubbles can be achieved compared to a system that does not provide such an inter-pulse delay period 220. In some embodiments, the duration of the inter-pulse delay period 220 is long enough such that the electroporation waveform 200 includes a series of energy pulses 210, such that the electroporation waveform 200 provides pulsed ablation energy rather than continuous wave ablation energy. For example, the inter-pulse delay period 220 may be at least 10 ms, for example up to 25 ms. For example, the percentage of the cycle 230 during which the energy pulse 210 is provided may be 5%, 4%, 3%, 2%, 1% or other percentages (e.g., but not greater than 5%) of the cycle 230. Most specifically, the percentage of the cycle 230 during which the energy pulse 210 is provided may be at least 0.1%, at most 0.3%, and / or nominally 0.2%.

[0103] In summary, a single cycle 230 of the electroporation waveform 200 may include an energy pulse 210 (e.g., an energy pulse including one or more different sine waves), followed by an inter-pulse delay period 220 during which no energy pulse 210 causing electroporation is applied.

[0104] In addition, the amplitude and frequency of each energy pulse 210 are sufficient to ablate the target tissue with each energy pulse. In this case, the energy pulse 210 can be referred to as an ablation pulse 210. For example, the frequency of the pulse can be at least a minimum frequency of X kHz and / or not exceed a maximum frequency of Y kHz; and the amplitude can be between a minimum voltage of at least M volts and / or not exceed a maximum voltage of N volts. By way of example only, the inter-pulse delay period can be between a minimum of 2 ms and / or a maximum of 2000 ms. In other embodiments, the inter-pulse delay period 220 can be at least 15 ms and / or not exceed 100 ms, for example, when the period 220 is at least 15 ms and / or not exceed 50 ms.

[0105] Additionally referring Figure 3 , an example of a portion of an electroporation waveform consistent with the inventive concept is shown. Figure 3 The electroporation waveform 200 of Figure 2 can include a plurality of pulse trains 240, such as Figure 3 the pulse trains 240 shown in

[0106] As described herein, a pulse train 240 can include one or more energy pulses 210, each energy pulse 210 separated by an inter-pulse delay period 220. The inter-pulse delay period 220 can include a fixed delay period and / or a variable delay period, for example, both a fixed period and a variable period (e.g., a fixed period and a variable period that together define the duration of the inter-pulse delay period 220), such as the fixed inter-pulse delay period 2201 and the variable inter-pulse delay period 2202 described herein. A sequence 250 can include one or more pulse trains 240, each pulse train 240 separated by an inter-train delay period 260. The inter-train delay period 260 can include a fixed delay period and / or a variable delay period (e.g., a fixed period and a variable period that together define the duration of the inter-train delay period 260). The electroporation waveform 200 (e.g., the waveform 200 provided to the tissue in total during a single energy release process) can include one or more sequences 250, each sequence 250 separated by an inter-sequence delay period 270. The inter-sequence delay period 270 can include a fixed delay period and / or a variable delay period (e.g., a fixed period and a variable period that together define the duration of the inter-sequence delay period 270).

[0107] Each energy pulse 210 may include at least one different sine wave. In some embodiments, the energy pulse 210 includes no more than 50 different sine waves, such as no more than 10 different sine waves. In some embodiments, one or more energy pulses 210 of the electroporation waveform 200 (e.g., two consecutive energy pulses 210 in the pulse train 240) include different numbers of different sine waves. In some embodiments, the number of sine waves of the energy pulse 210 is variable, e.g., the number of sine waves generated as a pseudo-random number (e.g., a pseudo-random number generated by algorithm 25), and / or when the number of sine waves of the energy pulse 210 is determined by the system 10 (e.g., determined by algorithm 25 based on one or more system and / or patient parameters (e.g., based on the temperature of the tissue near the electrode 311)). For example, in some embodiments, a functional element such as a functional element including a thermocouple (e.g., functional element 99) is used to monitor the temperature of one or more electrodes 311 of the catheter 300. The energy pulse 210 may be applied at a rate of at least 1 energy pulse per cardiac cycle, and / or at a rate of no more than 100 energy pulses per cardiac cycle, such as at a rate of about 50 energy pulses per cardiac cycle. In some embodiments, the application rate may remain constant until the recorded temperature exceeds a threshold (e.g., a threshold of at least 38 °C or 45 °C). Once the recorded temperature exceeds the threshold, the algorithm 25 may be configured to reduce this rate of the number of pulses per cardiac cycle (e.g., reduce the rate proportionally based on the recorded temperature). In some embodiments, if the recorded temperature is below the threshold, the rate may be increased (e.g., increased to the original rate). In some embodiments, the threshold temperature may include a temperature of at least 38 °C, and / or a temperature of no more than 80 °C.

[0108] The duration of the inter-pulse delay period 220 may be at least 1 ms, such as at least 15 ms. In some embodiments, the duration of the inter-pulse delay period 220 does not exceed 2000 ms, such as does not exceed 60 ms.

[0109] The interleaved offset period 2203 may include a duration of at least 0.5 ms. In some embodiments, the interleaved offset period 2203 includes a duration of no more than 2 ms.

[0110] The inter-burst delay period 260 may include a duration of at least 100 ms. In some embodiments, the inter-burst delay period 260 includes a duration of no more than 5000 ms.

[0111] The inter-sequence delay period 270 may include a duration of at least 2000 ms, such as at least 5000 ms. In some embodiments, the inter-sequence delay period 270 includes a duration of no more than 20000 ms, such as no more than 10000 ms.

[0112] The controller 110 may also be configured to set the inter-pulse delay period 220 based on the received conductivity measurement data. The selection of the inter-pulse delay period 220 may be achieved by obtaining the inter-pulse delay period 220 from a look-up table based on the conductivity measurement result. Such a look-up table may be stored in a memory as part of the controller 110 (e.g., stored in the memory 112), or may be stored in a memory that communicates with the controller 110 but is separated from the controller 110. Alternatively, any other suitable method for obtaining the inter-pulse delay period 220 based on the received conductivity measurement result may be used. Providing the selection of the inter-pulse delay period 220 based on the received conductivity measurement result may allow the inter-pulse delay period 220 to be adjusted to the target tissue to be ablated, where the conductivity measurement result is the conductivity measurement result of the target tissue. Such a configuration may be beneficial because the conductivity of different types of tissue affects the formation of microbubbles, and thus it may be necessary to increase the inter-pulse delay period 220 to avoid or reduce the formation of microbubbles. Alternatively, certain tissue types may not easily form microbubbles, and thus the inter-pulse delay period 220 can be reduced without significantly increasing the formation of microbubbles.

[0113] The received conductivity measurement data may be received in response to the controller 110 signaling a conductivity sensor (e.g., the functional element 99 and / or 399 that includes one or more conductivity sensors) configured to cause the conductivity sensor to perform a conductivity measurement. The controller 110 may also be configured to receive the conductivity measurement data from the conductivity sensor. Alternatively, the conductivity measurement data may be received from a user input device. Thus, the controller 110 may be configured to receive conductivity data by controlling an external conductivity sensor or via user input. This may provide the user with variable functionality depending on the availability or condition of the coupled conductivity sensor, or may provide a backup redundancy in the event that the conductivity sensor is not functioning properly.

[0114] Additionally referring Figures 3A to 3D to, there is shown a graph of harmonics of various frequencies under different conditions consistent with the inventive concept. Figure 3A There is shown an example of harmonics of a frequency with a fixed period length when applied to an ideal resistive load. Figure 3B There is shown a representative example of a reduction in harmonics of a frequency with a fixed period length that uses 20 periods to expand the spectrum in a uniform step distribution when applied to an ideal resistive load. The reduction amount at each harmonic is approximately 12 dB.Figure 3C An example of the harmonics of the frequency of a fixed period length when applied to a representative non-linear load is shown. Figure 3D A representative example of the reduction of the harmonics of the frequency of a fixed period length that expands the spectrum in a uniform step distribution using 20 periods when applied to a representative non-linear load is shown. The reduction amount at each harmonic is approximately 12 dB.

[0115] In some embodiments, the energy pulses 210 separated by the inter-pulse delay period 220 generate energy at a frequency that is the reciprocal of the frequency of the inter-pulse period. For example, an inter-pulse period of 20 ms will generate a frequency of 50 Hz and its even harmonics. The combination of the PFA energy pulses with this lower pulse repetition frequency is functionally an amplitude modulated (AM) signal, where the PFA energy pulses are a square wave AM modulated by the pulse repetition frequency. Most tissues exhibit a partial or complete non-linear response to this form of energy release, and just as non-linear circuit elements such as diodes can rectify and demodulate AM radio waves, muscles can be stimulated if the pulse repetition frequency is low enough, the periodicity is strong enough, and the amplitude is large enough. By varying the inter-pulse delay to change the period, the synthesized low-frequency spectrum can be expanded, thereby reducing the amplitude at any given frequency (e.g., reducing the likelihood of muscle stimulation). Figures 3A to 3D This reduction of the harmonics is shown.

[0116] In some embodiments, the system 10 is configured to create lesions on ablated tissue by applying the electroporation waveform 200 to the tissue via the electrodes 311 of the catheter 300 and / or external electrodes 60 (e.g., one or more patch electrodes located on the patient's skin). For example, the system 10 can apply a monopolar energy pulse 210 between one or more electrodes 311 and one or more external electrodes 60, as described herein. The monopolar signal can include a voltage of at least 1000 V (e.g., at least 1500 V) and / or no more than 4000 V (e.g., no more than 3000 V). The monopolar signal can include a frequency of at least 10 kHz (e.g., at least 25 kHz), and / or no more than 100 kHz (e.g., no more than 75 kHz). In some embodiments, a train of monopolar energy pulses 210 (e.g., the pulse train 240) can include approximately 3 or 4 energy pulses 210, which are collectively applied over a time of no more than 500 ms (e.g., 250 ms). The monopolar energy release can create lesions in the ablated tissue, where the lesion depth is at least 5 mm (e.g., at least 10 mm, 15 mm, or 20 mm).

[0117] In some embodiments, system 10 is configured to apply energy pulse 210, wherein the voltage of the energy pulse is at least 1500V (e.g., at least 2000V), and / or not more than 4000V (e.g., not more than 3500V). As described herein, in some embodiments, energy pulse 210 may include at least one first signal provided to at least one first electrode and at least one second signal provided to at least one second electrode. As used herein, monopolar energy release may include an energy release such as the following: the first signal is provided to a first internal electrode such as electrode 311 located near the target tissue (e.g., an electrode placed on the endocardium), and the second signal is provided to a patch electrode, such as external electrode 60 (e.g., an external electrode 60 located away from the target tissue (e.g., on the patient's skin)). Bipolar energy release may include an energy release such as the following: the first signal is provided to a first internal electrode such as first electrode 311 located near the target tissue (e.g., an electrode placed on the endocardium), and the second signal is provided to a second internal electrode such as second electrode 311 located near first electrode 311 and the target tissue (e.g., an electrode placed on the endocardium). When energy is released in a bipolar manner, no signal is provided to the patient patch including the electrode (e.g., external electrode 60), such that a unique potential is generated between the first electrode and second electrode 311 by applying an electrical signal. Phase-combined energy release may include an energy release such as the following: the first signal is provided to first internal electrode 311, and the second signal is provided to second internal electrode 311, and may include a third signal, wherein the third signal includes a reference signal provided to one or more patch electrodes (e.g., external electrode 60). When energy is released in a phase-combined energy release manner, a primary electric field is generated between first electrode 311 and second electrode 311, and a secondary electric field is generated between each of first electrode 311 and second electrode 311 and external electrode 60 (e.g., one or more patch electrodes located at one or more positions on the patient's skin). In some embodiments, the first signal and the second signal include sine waves, wherein the phase angle between the sine waves may be between 0° and 180°. The phase angle between the first signal and the second signal can be adjusted to change the relative intensities of the primary electric field generated between first electrode 311 and second electrode 311 and the secondary electric field generated between each of first electrode 311 and second electrode 311 and external electrode 60. For example, a phase angle of 180° maximizes the primary electric field relative to the secondary electric field. As the phase angle decreases (towards 0°), the field strength of the primary electric field decreases due to the decrease in the potential difference between first electrode 311 and second electrode 311. Monopolar, bipolar, and phase-combined energy releases may be configured as described with reference to Figures 19A to 19C and other parts of this document.

[0118] In some embodiments, the energy pulse 210 of the electroporation waveform 200 includes a sine wave, such as described herein. In some embodiments, the period length of the sine wave is at least 1 ms (e.g., at least 10 ms) and / or not more than 200 ms (e.g., not more than 50 ms). In some embodiments, the number of sine waves per pulse (e.g., per energy pulse 210) is not more than 10, e.g., 1 or 2 sine waves per pulse. Limiting the number of sine waves per pulse can reduce the likelihood of microbubble formation. In some embodiments, the number of periods (e.g., period 230) of the electroporation waveform 220 required to produce the maximum achievable damage in tissue is at least 30 periods (e.g., at least 100 periods) and / or not more than 600 periods (e.g., not more than 300 periods). In some embodiments, the length of the burst 240 of the electroporation waveform 200 does not exceed 250 ms, such that the electroporation waveform 200 can be provided in a manner synchronized with the ventricular refractory period to reduce ventricular excitation.

[0119] Now refer to Figure 4 and Figure 4A , which respectively show a portion of an electroporation waveform consistent with the inventive concept and a graph of experimental results. Figure 4 The example experimental results are shown, providing the total sine period length on the x-axis and the microbubble formation measured in nanoliters on the y-axis. Four measurements were made within each period length range, where the average microbubble formation volume is represented by the bar graph in the figure and the accompanying numbers. The error for each measurement is represented by the error bar graph presented. In these cases, the period length is proportional to the inter-pulse delay period 220, since in this experiment, the duration of the energy pulse 210 remains constant between period lengths. As can be seen from the figure, when changing from a low period length (0.5 ms to 5 ms) to a medium period length (5 ms to 30 ms), the microbubble formation is reduced to less than 1 / 5. When the period duration increases (30 ms to 100 ms), the microbubble formation is reduced even more.

[0120] Figure 4A Shows the electroporation waveform 200 (e.g., refer to Figure 1and is part of an embodiment of the electroporation waveform 200 described elsewhere in this document. The illustrated electroporation waveform 200 includes two energy pulses 210 separated by an inter-pulse delay period 220. In some embodiments, the inter-pulse delay period 220 includes two parts: a fixed inter-pulse delay period 2201 and a variable inter-pulse delay period 2202. For example, the duration of the inter-pulse delay period 220 can include the duration of the fixed inter-pulse delay period 2201 plus the duration of the variable inter-pulse delay period 2202. The duration of the variable inter-pulse delay period 2202 can be a positive and / or negative duration such that the inter-pulse delay period 220 is respectively longer and / or shorter than the fixed inter-pulse delay period 2201. The variable inter-pulse delay period 2202 can be limited to values that vary symmetrically with respect to the fixed inter-pulse delay period 2201, where the resulting value integrated over time is equal to the value of the fixed inter-pulse delay period 2201. For example, the first inter-pulse delay period 220 (e.g., the delay between the first energy pulse 210 and the second energy pulse 210) can include a duration of 35 ms, where the fixed inter-pulse delay period 2201 is 30 ms and the first variable inter-pulse delay period 2202 is +5 ms. A subsequent second inter-pulse delay period 220 (e.g., the delay between the second energy pulse 210 and the third energy pulse 210) can include a duration of 25 ms, where the fixed inter-pulse delay period 2201 is 30 ms and the second variable inter-pulse delay period 2202 is -5 ms. In this example, the first variable inter-pulse delay period 2202 and the second variable inter-pulse delay period 2202 are symmetric about 0 (±5 ms respectively), such that the average inter-pulse delay period 220 between the first energy pulse 210, the second energy pulse 210, and the third energy pulse 210 is equal to the fixed inter-pulse delay period, which is 30 ms in this example. In other words, in this example, the duration of the first variable inter-pulse application period 2202 can be equal to the absolute value of the duration of the second variable inter-pulse delay period. The variable inter-pulse delay period 2202 can vary by a fixed or variable amount for each period, such as a pseudo-random value (e.g., a pseudo-random value calculated by an algorithm 25).

[0121] The first inter-pulse delay period 220 between the first energy pulse 210 and the subsequent second energy pulse 210 can be different from the second inter-pulse delay period 220 between the second energy pulse 210 and the third energy pulse 210 that follows it immediately. That is, the duration of the inter-pulse delay period 220 can vary with the cycle 230. In some embodiments, the plurality of inter-pulse delay periods 220 in the electroporation waveform 200 can include inter-pulse delay periods 220 that are different from each other. In other embodiments, each inter-pulse delay period 220 in the electroporation waveform 200 can have an inter-pulse delay period 220 that is different from each other.

[0122] In some examples, the duration of each successive inter-pulse delay period 220 differs from the immediately preceding inter-pulse delay period 220 by a fixed period. It will be understood that the fixed duration can be a positive duration or a negative duration such that successive inter-pulse delay periods 220 can steadily increase or decrease in length. That is, the inter-pulse delay period 220 can increase or decrease stepwise. This configuration can start from a nominal inter-pulse delay period 220 and vary from that point. The nominal inter-pulse delay period 220 can be any inter-pulse delay period 220 within the range of possible inter-pulse delay periods 220. Additionally, one electroporation waveform 200 can be followed by another electroporation waveform 200, and successive electroporation waveforms 200 can include different inter-pulse delay periods 220 such that, for example, the first set of successive inter-pulse delay periods 220 of the first electroporation waveform 200 can include inter-pulse delay periods 220 that increase in an incremental manner, followed by a second set of successive inter-pulse delay periods 220 of the second electroporation waveform that include inter-pulse delay periods 220 that decrease in an incremental manner. Thus, over time, a series of electroporation waveforms 200 can provide groups of energy pulses 210 separated by inter-pulse delay periods 220, with the inter-pulse delay periods 220 of each series of electroporation waveforms 200 being different to reduce the effects of harmonic stimulation.

[0123] In other embodiments, the duration of each inter-pulse delay period 220 of the electroporation waveform 200 can be based on a pseudo-random number (e.g., as calculated by algorithm 25), where the pseudo-random number is independently selected for each inter-pulse delay period 220. If the selected pseudo-random numbers happen to be the same, the duration of the first inter-pulse delay period may be the same as the duration of the second inter-pulse delay period. However, the probability that multiple selected pseudo-random numbers are the same may be extremely small, depending on the range of unique numbers that can be selected from the set of pseudo-random numbers. Thus, in many embodiments, it is highly unlikely that two inter-pulse delay periods 220 in the electroporation waveform 200 have the same duration, especially two consecutive inter-pulse delay periods 220. In one or more embodiments, the controller can be configured to prevent consecutive delay periods from having the same duration.

[0124] In some embodiments, the duration of each inter-pulse delay period 220 can include both a fixed inter-pulse delay period 2201 and a variable inter-pulse delay period 2202, where the two delay periods are added together to obtain the total inter-pulse delay period 220. In these embodiments, the variable inter-pulse delay period 2202 can be based on a pseudo-random number (as described above), while the fixed inter-pulse delay period 2201 can be a predetermined period that does not change between delay periods. This configuration can provide a simple alternative to providing delay periods based on pseudo-random numbers.

[0125] The pseudo-random number can have a value from -1 to 1, and the variable inter-pulse delay period 2202 can be based on the nominal inter-pulse delay period multiplied by the pseudo-random number. In such an embodiment, the nominal inter-pulse delay period is the value multiplied by a scaling factor, where the scaling factor is the pseudo-random number. In other embodiments, the scaling factor can be a value from 0 to 1, or any other value. Using a pseudo-random number with a value from -1 to 1 allows a set of random numbers that vary between two boundaries equal to the fixed inter-pulse delay period 2201 plus the variable inter-pulse delay period 2202.

[0126] In other examples, the fixed inter-pulse delay period 2201 may not be provided, but rather the inter-pulse delay period 220 can vary entirely based on a pseudo-random number. It will also be understood that while pseudo-random numbers are mainly discussed herein, true random numbers can alternatively and equivalently be used. True random numbers can be obtained via a white noise generator or other suitable device; however, this method is generally computationally expensive and may be otherwise undesirable.

[0127] Generally, regardless of whether the inter-pulse delay period 220 is based on a random number generator, a pseudo-random number generator, or a step change in the inter-pulse delay period, there can be a fixed minimum difference between different total cycle lengths (which depend on the inter-pulse delay period 220). For example, the cycle length can differ from the nominal cycle length value by 30%, 40%, or 50%. The minimum difference in cycle lengths can be between 0.3% and 10% of the nominal cycle length. For example, in the case where the electroporation waveform includes 16 cycles with a nominal cycle length of 20 ms, 16 steps can be used from 15 ms to 25 ms, with an interval of 0.625 between different cycle lengths. This configuration can be converted to a step size of 3.125% of the nominal cycle length. Further, for example, in the case where the electroporation waveform includes 24 cycles and the nominal cycle length is 20 ms, 24 steps can be used from 15 ms to 25 ms, with a step size of approximately 2% of the nominal cycle length.

[0128] Now referring to Figure 5 , a graph of stimulus intensity versus duration consistent with the inventive concept is shown. Figure 5 An example graph showing stimulus duration (shown along the x-axis) and stimulus intensity (shown along the y-axis) is presented, where the plotted curve is an intensity-duration curve that describes the minimum combination of stimulus duration and stimulus intensity required to cause muscle or cardiac stimulation (e.g., stimulation to be avoided). Stimulus intensity can be measured as current; however, the same trend holds in the case where the stimulus intensity is voltage. Cellular stimulation (whether cardiac or muscular) is a function of the amplitude of the applied stimulus and the duration of the applied stimulus. Rheobase can be defined as the stimulus intensity that causes a stimulus of infinite duration (effectively approximately 300 ms). Chronaxi is defined as the minimum stimulus duration that produces a stimulus with a stimulus intensity twice that of rheobase. Intensity-duration pulses above or to the right of the plotted intensity-duration curve will produce a stimulus, while intensity-duration pulses below or to the left of this line will not produce a stimulus.

[0129] For pulsed field ablation (PFA), the effective stimulation duration is a trade-off between field strength and duration. Shorter pulses require a larger pulsed field strength to achieve a similar treatment depth. Thus, ideally, the frequency of the pulsed field should be selected to be as low as possible, but higher than the chronaxie. The pulsed field energy repeatedly applied at these frequencies in the electroporation waveform should be able to create a lasting lesion while avoiding muscle stimulation, cardiac stimulation, or both muscle stimulation surrounding cardiac stimulation. Simulations conducted by the applicant have shown that even for a theoretically perfect biphasic square wave below the chronaxie, the inherent nonlinearity of tissue will result in residual charge. If subsequent energy pulses in the electroporation waveform are repeated fast enough, these residual charges may accumulate over time and lead to undesired stimulation.

[0130] Alternatively or additionally, to avoid stimulating muscle or cardiac tissue, the controller 110 of system 10 (e.g., the system 10 referenced Figure 1 and described elsewhere in this document) can be configured to provide the following charge accumulation compensation scheme.

[0131] To provide the electroporation waveform 200 for charge accumulation compensation (e.g., the electroporation waveform 200 referenced Figure 1 and described elsewhere in this document), the controller 110 can be configured to provide one or more temporally spaced energy pulses 210, where each energy pulse 210 is configured to cause electroporation. In one or more embodiments, each energy pulse 210 can be an ablation pulse configured to cause irreversible electroporation that results in ablation of the target tissue.

[0132] The controller 110 can also be configured to provide a signal notification that is configured to provide one or more compensation signals as part of the electroporation waveform 200. The compensation signals are configured to reduce charge accumulation caused by one or more of the plurality of energy pulses 210 at the target treatment location on the patient. The compensation signals can be configured to reduce charge accumulation by having a predetermined polarity. This polarity can be the opposite polarity of the accumulated charge. For example, this opposite polarity can be the opposite polarity of the average polarity of each energy pulse 210 or the average polarity of a plurality of consecutive energy pulses 210.

[0133] In cases where each energy pulse 210 includes one or more single-phase pulses and thus includes an inherent predetermined polarity, it is possible that the average polarity of each energy pulse 210 is non-zero. In other embodiments, the energy pulse 210 can include one or more bipolar signals, such as bipolar square wave signals and / or bipolar sine wave signals. One or more bipolar signals can include an average polarity that may be caused by, for example, an asymmetry in the intensities of the positive and negative portions of the signal. The asymmetry of the bipolar energy pulse 210 can cause charge accumulation at the target tissue. Even in a completely uniform bipolar energy pulse 210 that includes a net zero average polarity, charge accumulation may occur at the target tissue due to the inherently non-linear nature of the tissue, which can result in residual charge accumulation.

[0134] Compared to anodic pulses, cathodic pulses are more likely to stimulate muscle or cardiac tissue. Thus, in some embodiments, the compensation signal can include anodic pulses to counteract the charge accumulation caused by the cathodic energy pulse.

[0135] Now referring to Figure 6 , an example of an electroporation waveform including a compensation signal is shown that is consistent with the inventive concept. Figure 6 An example of an electroporation waveform is shown, such as Figure 1 and the electroporation waveform 200 in other parts of this document. The electroporation waveform 200 can include one or more single-phase energy pulses, a single-phase energy pulse 2101 (e.g., when the energy pulse 210 includes the single-phase energy pulse 2101), and one or more compensation signals, a compensation signal 2102. The compensation signal 2102 can be a single-phase or bipolar compensation signal. In the case of a single-phase compensation signal 2102, the polarity is determined by whether the signal includes a positive amplitude or a negative amplitude. In the case of a bipolar signal, the polarity of the signal can be defined by whether the signal initially includes a positive amplitude or a negative amplitude. The frequency and pulse width of the bipolar compensation signal 2102 can be the same as or substantially the same as the frequency and pulse width of the corresponding energy pulse 210. The amplitude of the compensation signal 2102 can be, for example, at least 1% and / or not more than 20% of the amplitude of the corresponding single-phase energy pulse 2101. Alternatively, the amplitude of the compensation signal 2102 can be, for example, at least 5% and / or not more than 15% of the amplitude of the corresponding single-phase energy pulse 2101. Additionally, the amplitude of the compensation signal 2102 can be approximately 10% of the amplitude of the corresponding single-phase energy pulse 2101.

[0136] Now referring to Figure 7 , an example of an electroporation waveform including a compensation signal is shown that is consistent with the inventive concept. Figure 7 An example of an electroporation waveform is shown, such as Figure 1and the electroporation waveform 200 shown elsewhere in this document. The electroporation waveform 200 can include one or more biphasic energy pulses, the biphasic energy pulse 2103 (e.g., when the energy pulse 210 includes the biphasic energy pulse 2103), and one or more compensation signals 2102. It can be seen that in this example, the polarity of the compensation signal 2102 (including the biphasic compensation signal 2102) is opposite to the polarity of the biphasic energy pulse 2103.

[0137] In some embodiments, a compensation signal 2102 including a single-phase compensation signal 2102 can be provided in the electroporation waveform 200 including the biphasic energy pulse 2103. The polarity of the compensation signal 2102 can be opposite to the average polarity of the biphasic energy pulse 2103. For example, the waveform of each biphasic energy pulse 2103 can be slightly asymmetric, which can result in the average polarity of the electroporation waveform 200 and thus charge accumulation at the treatment location. In other examples, not every biphasic energy pulse 2103 includes asymmetry, or the asymmetry of the biphasic energy pulse 2103 can vary slightly with each pulse, but over time, the average polarity of the electroporation waveform 200 may occur, which can result in charge accumulation. In either case, one or more compensation signals 2102 can be configured to have a polarity opposite to the average polarity of the energy pulses 2101 and / or 2103 of the electroporation waveform 200. The intensity of the compensation signal 2102 may not be sufficient to ablate the target tissue but is mainly or solely configured to reduce charge accumulation at the target treatment location. In addition to reducing charge accumulation, the compensation signal 2102 may not provide any therapeutic effect. Specifically, the compensation signal 2102 can be configured such that it does not cause electroporation at the target treatment location. By avoiding causing electroporation (e.g., avoiding irreversible electroporation), the compensation signal parameters alone will not be sufficient to cause cardiac or muscle stimulation.

[0138] The polarity of the compensation signal 2102 can be a "factory-set" polarity. For example, in cases where it is known that charge accumulation will have a specific polarity due to a predetermined factor (e.g., the structure of the waveform 200 or the nature of the target tissue), the factory-set polarity may be appropriate. In these embodiments, the factory-set polarity has the opposite polarity to the expected charge accumulation. The factory-set polarity will be set during device manufacturing or initial configuration. The factory-set polarity of the compensation signal 2102 can be fixed and unchangeable, or it can be adjustable to a different type of polarity, such as a polarity set by the user at a later time.

[0139] Alternatively, the polarity of the compensation signal 2102 can be a user-set polarity. This can allow the user to set the polarity of the compensation signal 2102 to a desired value based on the user's own observations of charge accumulation. The user can also control one or more other parameters of the compensation signal 2102. For example, the user can set the intensity, frequency, or line width of the compensation signal 2102. Additionally, the user can set the compensation signal delay of the compensation signal 2102, which controls the relative time at which the compensation signal 2102 is provided after the start of the energy pulse 210. It may be most useful to measure the time of the compensation signal 2102 relative to the start rather than the end of the energy pulse 210, because in some embodiments, the compensation signal 2102 can be provided simultaneously with at least a portion of the energy pulse 210.

[0140] In some embodiments, the polarity of the compensation signal 2102 can be based on the charge accumulation measured at the target treatment location. For example, the controller 110 can be configured to receive a signal notification from a charge sensor (e.g., one or more electrodes 311, a functional element 199 of the generator 100, and / or a functional element 399 of the catheter 300 that includes and / or is configured as a charge sensor), the charge sensor being configured to detect charge accumulation at the target treatment location (e.g., on or near the target tissue). The charge sensor can be any suitable sensor configured to measure charge accumulation or another parameter indicative of charge accumulation at the target treatment location. The charge sensor can be configured to detect only the polarity of the charge accumulation, or in other embodiments, in addition to any other useful parameters, the charge sensor can be configured to also detect the magnitude of the charge accumulation. In addition to the polarity of the charge accumulation, the magnitude of the charge accumulation and any other parameters can be provided to the controller 110. The controller 110 can be configured to set the polarity of the compensation signal 2102 to be opposite to the detected polarity of the charge accumulation. The controller 110 can also control one or more other parameters of the compensation signal 2102 based on the signal notification received from the charge sensor.

[0141] In one or more embodiments, the controller 110 can be configured to be able to switch between different methods of setting the polarity of the compensation signal 2102. For example, the controller 110 can switch between two or more of setting the polarity based on a factory-set polarity, a user-set polarity, and a measured polarity.

[0142] Prior to the charge accumulation reaching a predetermined threshold, at least one compensation signal 2102 may be provided. The predetermined threshold of charge accumulation may be the level of charge accumulation that causes muscle stimulation when an energy pulse is provided. That is, each energy pulse is configured to have parameters such that, in the absence of charge accumulation, neither muscle stimulation nor cardiac stimulation is induced: each energy pulse 210 is below the chronaxie. The accumulation of charge biases the effective charge experienced by the target tissue when the energy pulse 210 is applied. Thus, the threshold may be based on the minimum current for stimulation minus the stimulation intensity (amplitude) of the energy pulse over the stimulation duration used.

[0143] The controller 110 may be configured to determine (e.g., estimate, calculate, and / or otherwise determine) the total charge accumulation based on the expected charge accumulation derived from the parameters of the energy pulse 210. Alternatively or additionally, the controller 110 may be configured to determine the total charge accumulation based on signals received from a charge sensor. The charge sensor (e.g., one or more of the electrodes and / or functional elements described herein) may provide charge information to the controller 110 via signals that represent one or more of the polarity, amplitude, and / or other parameters related to charge accumulation at or near the target tissue of the target treatment area. Thus, the controller 110 may be configured to determine the total charge accumulation based on one or more sensed parameters related to charge accumulation.

[0144] Based on the determined or estimated charge accumulation, the controller 110 may be configured to provide at least one compensation signal 2102 before the charge accumulation reaches the predetermined threshold. For example, the compensation signal 2102 may be provided after the energy pulse 210 to reduce the level of charge accumulation. Thus, the compensation signal 2102 may be provided after a certain number of energy pulses 210 (e.g., after 5, 10, 20, or 100 pulses 210).

[0145] In one or more embodiments, the controller 110 may be configured to sequentially provide the compensation signal 2102 after one or more energy pulses 210 or after each energy pulse 210. For example, the compensation signal 2102 may be provided immediately after the energy pulse 210 or immediately after an inter-ablation compensation delay, during which no ablation signal or compensation signal is provided between the two signals of the compensation signal 2102 and the energy pulse 210. That is, each compensation signal 2102 may be provided during a delay period between consecutive energy pulses 120. In this example, the compensation signal 2102 may not overlap with any energy pulse 210.

[0146] Now referring to Figure 8 , an example of an electroporation waveform including a concurrent compensation signal consistent with the inventive concept is shown.Figure 8 illustrates an example of an electroporation waveform, such as Figure 1 and the electroporation waveform 200 shown in other parts of this document. In some embodiments, the controller 110 is configured to provide a compensation signal (e.g., the compensation signal 2102 described herein) simultaneously with an energy pulse 210 (e.g., the biphasic energy pulse 2103 shown), multiple ablation signals, or at least a portion of each ablation signal. In some embodiments, the biphasic energy pulse 2103 may include at least one positive portion (positive portion 2104) and / or at least one negative portion (negative portion 2105). In some embodiments, the positive portion 2104 includes a reference voltage greater than zero (e.g., the DC offset of the biphasic energy pulse 2103, as shown) and / or the portion of the biphasic energy pulse 2103 that is above the reference voltage REF (e.g., 0V, as shown). Similarly, the negative portion 2105 may include a reference voltage greater than zero (e.g., the DC offset of the biphasic energy pulse 2103, as shown) and / or the portion of the biphasic energy pulse 2103 that is below the reference voltage REF (e.g., 0V, as shown). In some embodiments, the biphasic energy pulse 2103 contains a signal that includes only a positive signal, such as when the DC offset of the biphasic energy pulse 2103 is greater than the negative amplitude of the negative portion 2105. In some embodiments, the compensation signal 2102 may be provided such that it undergoes constructive or destructive interference with at least a portion of the corresponding biphasic energy pulse 2103. For example, a single-phase compensation signal 2102 may be provided such that it undergoes destructive interference with each biphasic energy pulse 2103, and in Figure 8 the case of the depicted example, undergoes destructive interference with the second half of the biphasic energy pulse 2103. In Figure 8 this, the compensation signal 2102 cannot be seen separately, but it undergoes destructive interference with the negative portion 2105 such that the negative portion 2105 includes an amplitude smaller than that of the positive portion 2104, as shown (e.g., the negative portion 2105 includes the compensation signal 2102, as shown). This configuration results in a reduction in the apparent amplitude of the negative portion 2105 of the energy pulse 210 compared to the positive portion 2104 of the energy pulse 210. For example, the amplitude of the positive portion 2104 of the biphasic energy pulse 2103 may have an amplitude of "A" (e.g., the absolute amplitude of the positive portion 2104 relative to the reference voltage of the biphasic energy pulse 2103), while the apparent intensity of the negative portion 2105 of the biphasic energy pulse 2103 (the negative portion 2105 of the energy pulse 210 undergoes destructive interference with the positive compensation signal 2102) may have an intensity of "XA" (e.g., the apparent intensity of the negative portion 2105 relative to the reference voltage of the biphasic energy pulse 2103), where X is a number between 0 and 1. For example, XA may be equal to 0.8A, as Figure 8As shown in the example. In other examples, the value of X can be greater than 1. This configuration can be such that the compensation signal 2102 undergoes constructive interference with the negative portion 2105 of the energy pulse 210 to provide an apparent intensity greater than the amplitude A. It can be understood that in this example, the amplitude A is the unadjusted amplitude of the biphasic energy pulse 2103 signal. Correspondingly, the compensation signal 2102 can be set such that it overlaps with the positive portion 2104 of the energy pulse 210, or such that it overlaps with both the positive portion 2104 and the negative portion 2105 of the energy pulse 210 simultaneously. The phrase "apparent intensity" used above refers to the measured intensity of the negative portion of the energy pulse that has undergone destructive interference with the compensation signal. This intensity may be different from the intensity of the negative portion when no interference has occurred, and thus the provided apparent intensity is different from the intensity without interference.

[0147] In other examples, some compensation signals 2102 can be provided sequentially after a corresponding one in the energy pulse 210, and other compensation signals 2102 can be provided simultaneously with at least a portion of one or more energy pulses 210 of the electroporation waveform 200.

[0148] When the compensation signal 2102 includes a biphasic sine wave signal, the energy pulse 210 can include one or more different sine wave signals. It will be understood that the phrase "different sine wave signals" used herein is to define sine wave signals that can be distinguished from each other. This term can refer to sine waves that are completely discrete from each other, i.e., they start from a reference voltage, cross the reference voltage, and end at substantially the same reference voltage before the next sine wave begins. The reference voltage can be zero volts, but the reference voltage can also have different non - zero values. Different sine waves can also refer to sine waves that partially overlap but the sine wave forms of the two sine waves can be distinguished. Sine waves that overlap such that constructive interference occurs to produce a sine wave with a greater total amplitude, or sine waves that form a sine wave or other waveform with a wider period (e.g., line width) than any of the original sine waves (in cases where the component sine waves cannot be individually distinguished) are not necessarily considered to be different sine wave signals.

[0149] Although the charge accumulation at the target treatment location is discussed herein in the context of the configuration of the compensation signal 2102, this discussion is provided to explain the purpose of the compensation signal 2102. It will be understood that based on this objective, the compensation signal 2102 will have certain parameters (e.g., polarity and signal strength) that are provided for the desired functionality. The presence of the target tissue is not necessary for the controller 110 to provide a signal notification that causes the provision of both the energy pulse 210 and the compensation signal 2102.

[0150] Now refer to Figure 9A and Figure 9B, respectively show an anatomical side view of a catheter including a plurality of electrodes positioned close to tissue, consistent with the inventive concept, and a representation of the effective electric field generated by the electrodes. Refer to Figure 9A and Figure 9B The catheter 300 and / or other components of the system 10 described in Figure 1 and elsewhere herein may have a construction and arrangement similar to that of similar components described in Figure 9A and Figure 9B show an exemplary electroporation catheter 300 that includes a plurality of electrodes 311, such as the illustrated electrodes 311a and 311b, where the electrodes 311a and 311b are alternately arranged along the length of the distal portion of the catheter 300. Figure 9A and Figure 9B depict a method of performing electroporation in which an alternating current voltage is applied to each electrode 311 of the electroporation catheter 300 (e.g., an alternating current voltage is applied to electrodes 311a and 311b as shown), such that electroporation is applied simultaneously along a portion of the electroporation catheter 300. Figure 9B shows the electric field 290 generated using this method. This method of performing electroporation creates a number of high-temperature regions (such as the illustrated region 291) centered on each electrode 311, which overlap with each other, thereby causing significant undesired heating of the local tissue. The generation of the high-temperature region 291 may also cause microbubble formation, which further leads to problems with irreversible electroporation. The high-temperature region 291 herein refers to a region where local heating around the electrode is enhanced. The presence of microbubbles may cause various types of problems to the patient, such as cerebral microembolism.

[0151] Now refer to Figures 10A to 10C , respectively show an anatomical side view of a catheter including a plurality of electrodes positioned close to tissue, consistent with the inventive concept, and a representation of the effective electric field generated by the electrodes. Refer to Figures 10A to 10C The catheter 300 and / or other components of the system 10 described in Figure 1 and elsewhere herein may have a construction and arrangement similar to that of similar components described in Figure 10A and Figure 10B show the electrodes 311 positioned close to tissue (e.g., heart tissue) in the catheter 300. The catheter 300 may be operably attached to a signal generator (e.g., the signal generator 120 of the generator 100), which is not shown but is described herein. In some embodiments, the system 10 may be configured to operate asynchronously, for example, by providing sequential interleaved bipolar and / or phase-combined energy releases, as described herein. Figure 10C shows the overall result of the asynchronous energy release described herein.

[0152] The electroporation catheter 300 includes a plurality of electrodes 311 disposed continuously along its length. The electroporation catheter 300 may include an elongate member (e.g., the distal portion of the array 310) that has electrodes 311 along its length. In some embodiments, the elongate member may have the shape of a cylindrical rod with a circular or other shaped cross-section. The elongate member may be a straight elongate member, or the elongate member may have a curved portion that at least defines a partial arc. Reference Figure 13 and Figure 14 and different configurations of the electroporation catheter 300 including non-straight elongate members are described elsewhere herein. In an example where the electroporation catheter 300 includes an elongate member (whether straight or of another type), the continuous arrangement of the electrodes 311 means that the electrodes 311 are arranged one after another such that along the length of the electroporation catheter 300, no two electrodes 311 are disposed at the same longitudinal point. For example, as shown, the electrodes 311 may include electrodes 311a-h arranged from the distal end to the proximal end along the distal portion of the catheter 300. The electrodes 311a-h may include similar or different spacings, e.g., as shown, equal spacing along the catheter 300 (e.g., the spacing between each electrode 311 and each adjacent electrode is equal). In some embodiments, the electrodes 311 include a spacing (“electrode spacing”) of no more than 10 mm between each electrode, e.g., an electrode spacing of about 6 mm or 3 mm.

[0153] In some embodiments, the electroporation catheter 300 may be shaped such that a two-dimensional grid of electrodes 311 is included thereon. That is, the two-dimensional grid of electrodes 311 may include a grid of 2x4 electrodes. In such an embodiment, the plurality of electrodes 311 may still be defined as being disposed in a continuous or substantially continuous arrangement such that the electrodes 311 are arranged one after another. Such a continuous arrangement of electrodes 311 may include a subgroup of all the electrodes on the electroporation catheter 300. In the example of a 2x4 grid of electrodes, a single row of electrodes 311 (a sub-grid of 1x4 electrodes in the 2x4 grid) may be considered a continuous arrangement of electrodes 311 according to the present disclosure. As another example, a 4x4 grid of electrodes 311 may include a number of sub-grids of electrodes 311 that may be activated according to the present disclosure. It will be understood that a one-dimensional grid (e.g., a 1x4 or 1xM arrangement of electrodes 311, where M is an integer greater than or equal to 4) may still be considered a grid. The requirement that M is greater than or equal to 4 is further explained in detail below.

[0154] In a continuous arrangement of electrodes or a grid of electrodes, each of the electrodes 311a-h includes at least one adjacent electrode 311 in the arrangement. Herein, an adjacent electrode 311 includes an electrode 311 that is adjacent to another electrode 311 with no electrode 311 therebetween. For example, in the case of electrodes 311 in a row, the electrodes 311 at the two ends of the row of electrodes 311 (e.g., electrodes 311a and 311h) will each have a single adjacent electrode 311, e.g., electrodes 311b and 311g respectively. Each of the electrodes 311b-g that is not at the end of a continuous arrangement of electrodes 311 in a row will have two adjacent electrodes 311. In the case of electrodes 311 arranged in a two-dimensional grid, the electrodes 311 at the corners of the grid will have two adjacent electrodes 311 (one electrode along the y-axis and one electrode along the x-axis); the electrodes 311 at non-corner locations along the edges of the grid will have three neighbors (two electrodes along the first axis and one electrode along the second axis); the electrodes 311 at non-corner and non-edge locations will include four adjacent electrodes (one electrode on either side of the electrode along each axis). For a given electrode 311 in the arrangement of electrodes 311, any electrode 311 that is not an adjacent electrode can be considered a non-adjacent electrode. With respect to a continuous arrangement of electrodes defined by the controller, the electrodes 311 in a two-dimensional grid arranged diagonally along the electrodes can also be considered non-adjacent electrodes.

[0155] It will be understood that the controller 110 can be configured to be able to address the electrodes 311a-h individually and provide signaling for individually controlling the voltage applied thereto. In addition, each of the electrodes 311a-h is adapted to provide electroporation to the target tissue at the target treatment location. Specifically, the electrodes 311a-h are adapted to apply irreversible electroporation to the target tissue at the target treatment location. In some embodiments, the controller 110 is configured to individually activate two or more patch electrodes (e.g., an external electrode 60 including two or more patch electrodes) and send signals thereto individually.

[0156] As described herein, the controller 110 of the generator 100 can be configured to provide a signal notification that is configured to cause a first potential difference to be applied between a group of one or more first electrodes (e.g., a group of one or more electrodes 311 and / or electrode 60) and a group of one or more second electrodes (e.g., a group of one or more electrodes 311 and / or electrode 60). In some embodiments, the group of first electrodes and the group of second electrodes include any electrodes in the system 10 that are configured to deliver energy to tissue, such as any endocardial electrodes (e.g., electrode 311), electrodes of another catheter in the system 10, and / or patient patches including electrodes (e.g., external electrode 60). For example, the controller 110 can be configured to provide a signal notification that is configured to cause a first potential difference (e.g., the energy pulse 210m described herein) to be applied between a first electrode 311a and a second electrode 311c among a plurality of electrodes 311a-h arranged in series. The controller 110 can also be configured to provide a signal notification that is configured to cause a second potential difference (e.g., the energy pulse 210n described herein) to be applied between a third electrode 311b and a fourth electrode 311d among the plurality of electrodes 311a-h arranged in series. The first electrode 311a and the second electrode 311c are non-adjacent electrodes. Similarly, the third electrode 311b and the fourth electrode 311d are non-adjacent electrodes. The third electrode 311b is an adjacent electrode to the first electrode 311a. In one or more embodiments, the fourth electrode 311d can similarly be an adjacent electrode to the second electrode 311c; however, in some embodiments, the fourth electrode 311d can be a non-adjacent electrode to the second electrode 311c. That is, the third electrode 311b can be arranged between the first electrode 311a and the second electrode 311c. The second electrode 311c can be disposed between the third electrode 311b and the fourth electrode 311d. It will be understood that the electrodes 311a-h being arranged between two other electrodes does not necessarily mean that it is the only electrode arranged between the two electrodes, but it does define its general placement relative to the two other electrodes. For example, when the third electrode 311b is arranged between the first electrode 311a and the second electrode 311c, another electrode (e.g., a fifth electrode) can be directly arranged between the third electrode 311b and the second electrode 311c, and in such an example, the third electrode 311b is still considered to be between the first electrode 311a and the second electrode 311c.

[0157] Figure 10AAn example of an electroporation catheter 300 is shown, where a first potential difference (e.g., electroporation waveform 200) is applied between a first electrode 311a and a second electrode 311c, while no potential difference is applied between a third electrode 311b and a fourth electrode 311d. In some embodiments, a potential difference can also be applied between non-adjacent electrodes 311e and 311g (e.g., applied simultaneously with the first potential difference applied between electrodes 311a and 311c), while no potential difference is applied between non-adjacent electrodes 311f and 311h, as shown. Figure 10B An example of an electroporation catheter 300 is shown, where a second potential difference is applied between a third electrode 311b and a fourth electrode 311d, while no potential difference is applied between a first electrode 311a and a second electrode 311c. In some embodiments, a potential difference can also be applied between non-adjacent electrodes 311f and 311h (e.g., applied simultaneously with the second potential difference applied between electrodes 311b and 311d), while no potential difference is applied between non-adjacent electrodes 311e and 311g, as shown. In some embodiments, the first potential difference and the second potential difference are applied asynchronously. As used herein, asynchronous is used to explain that the application period of the first potential difference is different from and does not overlap with the application period of the second potential difference. It may be preferred to have a potential difference delay period during which no potential difference is applied to any of the electrodes 311a-h of the electroporation catheter 300. This can provide time to reduce the temperature of the target tissue at the target treatment location.

[0158] Compared with the case where a potential difference is applied between all the electrodes 311a-h of the electroporation catheter 300 (as shown in the example of Figure 9B ), by providing such an asynchronous application of the potential difference (e.g., energy pulse 210), the local heating (the shown high-temperature region 291) around each electrode 311a-h is kept more restricted. Figure 10C The total heating (e.g., high-temperature region 291) and the effective electric field 290 achieved when providing an asynchronous application of the potential difference between non-adjacent electrode pairs are shown, as described herein. In comparison Figure 9B and Figure 10C it can be seen that, compared with applying a potential difference between all the electrodes among a plurality of electrodes, when using an asynchronous application of the potential difference, the range of undesired heating (high-temperature region 291) is more significantly restricted.

[0159] Now referring to Figure 11A and Figure 11B , representations of tissue damage caused by various forms of electroporation consistent with the inventive concept are shown. Figure 11A An example depiction of the resulting tissue damage is shown, which is caused by electroporation in the mode referred to in Figure 10A and Figure 10B towardsFigure 10A The darkest area (area 2191) at the bottom represents the undesired damage caused by heating. Figure 11A The next intermediate area (area 2192) shown in [figure] represents the ablated tissue, which is desired during irreversible electroporation. The brightest area (area 2193) represents the unaffected tissue (e.g., non-ablated tissue).

[0160] Figure 11B An example depiction of the results of controlling an electroporation catheter in the described mode is shown. The darkest area (area 2191) that extends only slightly from the bottom of the figure represents the undesired damage caused by heating. Figures 10A to 10C The next intermediate area (area 2192) shown in [figure] represents the ablated tissue, which is desired during irreversible electroporation. The brightest area (area 2193) represents the unaffected tissue (e.g., non-ablated tissue). Figure 11B The next intermediate area (area 2192) shown in [figure] represents the ablated tissue, which is desired during irreversible electroporation. The brightest area (area 2193) represents the unaffected tissue (e.g., non-ablated tissue). Figure 11B Provided in the same scale as Figure 11A so that direct comparison can be made. It can be seen that the number of the undesired damage areas 2191 caused by heating in [[figure]] is significantly reduced compared to the same damage in [[figure]]. In addition, compared to the methods depicted in [[figure]] and [[figure]], by providing an alternately applied potential difference across the staggered electrode pairs 311, the penetration depth of the ablated tissue area 2192 can be increased. Therefore, using this method has a two-fold advantage. The alternate activation of the electrode pairs 311 can be repeatedly provided for the required duration to provide the desired ablation level. Figure 11A in [[figure]] Figure 11B compared to the same damage in [[figure]], Figure 10A and Figure 10B [[figure]], by providing an alternately applied potential difference across the staggered electrode pairs 311, the penetration depth of the ablated tissue area 2192 can be increased. Therefore, using this method has a two-fold advantage. The alternate activation of the electrode pairs 311 can be repeatedly provided for the required duration to provide the desired ablation level.

[0161] It will be understood that applying a potential difference between two electrodes (e.g., two electrodes 311) requires providing different potentials between the two electrodes. Thus, a relatively positive potential can be applied, for example, at the first electrode 311, while a relatively negative potential can be applied at the second electrode 311 to provide the first potential difference. Although the potential at a point here is defined as relatively positive and relatively negative, they are interrelated. The potential of these points can also be measured relative to another potential, and in this case, the potentials can be regarded as: positive and negative; positive and neutral; positive and less positive; negative and neutral; negative and less negative, respectively. In any of these cases, there is a difference between the potentials, which provides the potential difference, measured in volts. As described in more detail below, the potential can be provided between three electrodes (e.g., three electrodes 311) in the following way: applying the same first potential at two electrodes 311 and applying a different potential at another electrode 311 disposed between the two electrodes 311. This configuration will provide the same first potential difference between two pairs of electrodes 311, where the intermediate electrode is one of the electrodes in the two pairs.

[0162] In some embodiments, (e.g., Figures 10A to 10C of) the first electrode 311a and the second electrode 311c may be two electrodes of a first subset of electrodes among the plurality of electrodes 311a-h. Similarly, the third electrode 311b and the fourth electrode 311d may be two electrodes of a second subset of electrodes among the plurality of electrodes 311a-h. The first subset of electrodes 311 may be interleaved with the second subset of electrodes 311 such that each successive electrode among the plurality of electrodes 311a-h alternately belongs to the first subset of electrodes and the second subset of electrodes. That is, each electrode 311 in the first subset of electrodes may be a non-adjacent electrode to each other, and each electrode 311 in the second subset of electrodes may also be a non-adjacent electrode to each other. Generally speaking, due to the interleaved arrangement of the electrodes of different electrode subsets, the electrodes 311 in any given subset of electrodes 311 may not be adjacent to each other. In this example, the number of electrodes 311 in the second subset of electrodes includes from n-1 electrodes to n+1 electrodes, where n is the number of electrodes in the first subset of electrodes. It will be understood that, based on the above description, the total number of electrodes 311 in the second subset of electrodes 311 must be at least equal to 2, because the second subset of electrodes 311 includes at least the third electrode and the fourth electrode. For example, in the case where there are three electrodes 311 in the first subset of electrodes, there may be two electrodes 311 in the second subset of electrodes, with electrodes 311 from the first subset of electrodes on each side of each electrode. Alternatively, there may be up to five electrodes 311 in the second subset of electrodes, where the electrodes from the second subset of electrodes are located on each side of each electrode in the first subset of electrodes.

[0163] In embodiments where a subset of the first electrodes 311 includes more than two electrodes 311, a first potential difference may be applied between each adjacent electrode of the subset of the first electrodes. An adjacent subset electrode of a given electrode in a given subset may be the next electrode in a contiguous arrangement of electrodes that is part of the same subset of electrodes. For example, the second electrode 311c is an adjacent subset electrode of the first electrode 311a. The fifth electrode 311e may also be part of the subset of the first electrodes, and the fourth electrode 311d may be disposed between the second electrode 311c and the fifth electrode 311e. In this embodiment, the fifth electrode 311e may also be an adjacent subset electrode of the second electrode 311c, but not an adjacent subset electrode of the first electrode 311a. In this example, the first electrode 311a and the fifth electrode 311e may be set to a relatively positive potential, while the second electrode 311c may be set to a relatively negative voltage, thereby providing a potential difference between the first electrode 311a and the second electrode 311c and between the second electrode 311c and the fifth electrode 311e. Similarly, the subset of the second electrodes may further include a sixth electrode 311f, where the fifth electrode 311e is disposed between the fourth electrode 311d and the sixth electrode 311f. By applying a relatively positive potential at the third electrode 311b and the sixth electrode 311f, and a relatively negative potential at the fourth electrode 311d, a second potential may be applied between the third electrode 311b and the fourth electrode 311d and between the fourth electrode 311d and the sixth electrode 311f.

[0164] It will be appreciated that the first potential difference and the second potential difference may be the same potential difference. Alternatively, the first potential difference and the second potential difference may be different from each other. In embodiments where multiple potential differences are provided between three or more electrodes 311 of a given subset of electrodes, the potential differences applied between adjacent pairs of electrodes may be the same or different. For example, it may be desirable to obtain uniform ablation over at least a portion of the length of the electroporation catheter 300 (e.g., along the length of the electrode array 310). In other examples, it may be desirable to increase ablation or ablation depth at certain points along the length of the electroporation catheter 300.

[0165] Now referring to Figure 12 , a side view of a catheter including a plurality of electrodes in accordance with the inventive concept is shown. Figure 12 An embodiment of an electroporation catheter 300 is shown that includes a plurality of electrodes (the electrodes 311a-f shown), on which three pairs of electrodes 311 may be defined. In some embodiments, for example Figure 12In the illustrated embodiment, the controller 110 may also be configured to provide a signal notification to cause a third potential difference to be applied between the fifth electrode 311e and the sixth electrode 311f of the electroporation catheter 300. The fifth electrode 311e is disposed between the second electrode 311c and the third electrode 311b. The fourth electrode 311d may be disposed between the third electrode 311b and the sixth electrode 311f. That is, three pairs of electrodes 311a,c, 311b,d, and 311e,f may be defined such that each of the continuously disposed electrodes alternately belongs to the first pair of electrodes, the second pair of electrodes, the third pair of electrodes, and then again to the first pair of electrodes, and so on. This alternating arrangement may be further extended to an arrangement where there are three subsets of electrodes 311, where at least one subset includes more than two electrodes 311, and all subsets are interleaved. In such an arrangement, there may be at least one electrode 311 from each of the other interleaved subsets of electrodes 311 between two electrodes 311 of a given subset. Specifically, for a fully interleaved arrangement, there may be a single electrode 311 from each of the other interleaved subsets of electrodes 311 between two electrodes 311 of a given subset. This may be extended to a scenario where there are M subsets of electrodes 311, where M is an integer equal to or greater than 2.

[0166] In the case where the fifth electrode 311e and the sixth electrode 311f form a third pair of electrodes 311 or a subset of electrodes 311 and a third potential difference is applied therebetween, the controller 110 may be configured to make the application of the third potential difference asynchronous with the application of both the first potential difference and the second potential difference.

[0167] In summary, the controller 110 may be configured to define two, three, four, or more unique pairs or subsets of electrodes 311, and the controller 110 may be configured to provide an alternating application of potential differences between these pairs or subsets of electrodes 311. In other embodiments, two, three, four, or more subsets of electrodes 311 may be defined, each subset having at least two electrodes 311, where a potential difference is applied between each pair of adjacent electrodes 311 in the subset.

[0168] Now referring to Figure 13 , a perspective view of a catheter including a curved electrode array is shown that is consistent with the inventive concept. Figure 13Illustrated is an exemplary electroporation catheter 300, which includes an elongate member as described above. In this example, the electrode array 310 of the electroporation catheter 300 includes a substantially straight portion (illustrated linear array 312) having a plurality of electrodes 311 along it and a curved portion (illustrated curved array 313) also having a plurality of electrodes 311 along it. The electrodes 311 of the linear array 312 and the electrodes 311 of the curved array 313 can be controlled as a single electrode among the plurality of electrodes 311 such that the electrodes 311 of the linear array 312 and the curved array 313 belong to one of a first electrode 311 subset, a second electrode 311 subset, or a higher order electrode 311 subset, as described above. Alternatively, the electrodes 311 of the linear array 312 and the curved array 313 can be configured to be controlled individually such that the electrodes 311 of the curved array 313 can be controlled using parameters different from those used to control the electrodes 311 of the linear array 312 of the electroporation catheter 300. In either case, the electrodes 311 on the electroporation catheter 300 herein can be controlled to provide an alternating potential difference between the electrodes in the interleaved electrode subsets, as described above.

[0169] Now referring to Figure 14 , a perspective view of a catheter including an expandable electrode array in accordance with the inventive concept is shown. Figure 14 Illustrated is an exemplary electroporation catheter 300, where the electrode array 310 includes an expandable array that includes a plurality of elongate members, such as the eight arms 314 illustrated, where each arm 314 includes a plurality of electrodes 311 arranged in series. The electroporation catheter 300 having this structure can be referred to as a balloon catheter. The arms 314 of the electrode array 310 of the electroporation catheter 300 can be flexible such that they can be pulled into a straight configuration or pushed such that the middle of each arm 314 is offset from the central axis extending between the ends of the arm 314. In such an embodiment, each arm 314 can be controlled as a separate electroporation catheter 300 that includes a separate group of electrodes 311 arranged in series. The controller 110 can be configured to control each group of electrodes 311 arranged along each arm 314. Each group of electrodes 311 along its respective arm 314 can be controlled to provide an alternating potential difference between the electrodes in the interleaved electrode subsets, as described above.

[0170] Now referring to Figure 15 , a visual representation of a method of performing electroporation therapy in accordance with the inventive concept is shown. Figure 15Illustrated is an example method of controlling an electroporation catheter 300 in accordance with the present disclosure. In some embodiments, a first potential difference (e.g., energy pulse 210m as described herein) is applied between non-adjacent first electrode 311a and second electrode 311c. A second potential difference (e.g., energy pulse 210n as described herein) can be applied between non-adjacent third electrode 311b and fourth electrode 311d. The potential differences can be applied in an asynchronous manner, whereby an effective field distribution creates a continuous cell ablation lesion, such as referenced Figures 10A to 10C and as described in other parts of this document.

[0171] Now referring to Figures 16A to 16G , there are shown two anatomical representations and graphs of lesion depth consistent with the inventive concept, as well as two representations of tissue damage and graphs of ablation parameters. Figure 16A and Figure 16B show two methods of applying electroporation waveforms. Figure 16A Shows a single-loop bipolar method of powering a combination of a single electrode (electrode 311a) and a single return electrode (electrode 311b) (e.g., providing a potential difference between electrodes 311a and 311b as shown). Figure 16B Shows a multi-loop bipolar method of powering a combination of a single electrode (electrode 311a) and a group of two or more return electrodes (e.g., electrodes 311b, c shown) (e.g., providing a potential difference between electrode 311a and electrodes 311b, c). In some embodiments, catheter 300 includes fixed electrode dimensions (e.g., surface area) and spacing. As Figure 16B shown, the electric field (e.g., field 290) generated using the multi-loop method is focused on electrode 311 (e.g., the tip electrode). Figure 16C Shows a comparison of the lesion depths of lesions produced using the Figure 16A single-loop bipolar method and the Figure 16B multi-loop bipolar method. Figure 16D and Figure 16E respectively show examples of lesions produced using these two methods. Figure 16F and Figure 16G Show additional graphs comparing these two methods of electroporation energy release. In the example shown, single-loop bipolar energy release is provided between two electrodes of similar size (e.g., two electrodes 311 with a surface area ratio of approximately 1:1). This single-loop bipolar ablation method creates a nearly symmetric electric field distribution between the two poles (e.g., between electrodes 311a and 311b). While using a fixed catheter configuration (e.g., fixed catheter 300 geometry), multi-loop bipolar ablation using multiple return electrodes as described herein regulates the ablation surface area ratio, thereby concentrating the electric field 290 at a single electrode (e.g., electrode 311a). Figure 16BThe multi-loop bipolar ablation configuration involves varying the surface area ratio (1:1.1 to 1:1000) to facilitate reducing the total electrode surface area near the desired ablation location. This method enhances lesioning and focuses the cellular ablation effect to the desired electrode without introducing a monopolar electric field.

[0172] Now referring to Figure 17 , there is shown a schematic diagram of a system consistent with the inventive concept for monopolar and / or phase-combined energy delivery through a plurality of external patch electrodes. Figure 17 The catheter 300 and / or other components in Figure 1 and elsewhere herein may have a construction and arrangement similar to that of the similar components described in reference

[0173] Additionally referring to Figures 17A to 17E , there is shown a cross-sectional view of a finite element analysis device consistent with the inventive concept and the analysis results. Figure 17AA mannequin is shown, which is used for finite element analysis performed by the applicant to quantify the influence of external electrode selection when performing monopolar energy release. The model includes a front external electrode (external electrode 60a) and a rear external electrode (external electrode 60b). The heart is modeled to be closer to the front external electrode 60a, and the electrode 311 of the catheter 300 is positioned such that the target tissue to be modeled is located between the electrode 311 and the front external electrode 60a, as shown. Figure 17B A magnified view is shown Figure 17A where the model is in a first configuration in which the electrode 311 is in contact with the target tissue (e.g., positioned with a 0 mm offset). Figure 17C A magnified view is shown Figure 17A where the model is in a second configuration in which the electrode 311 is positioned with a 4 mm offset from the target tissue (e.g., not in contact with the target tissue). Figure 17D The results of the finite element analysis are shown, in which the transmission of a 2250 V monopolar signal between the front external electrode 60a and the electrode 311 (positioned with a 0 mm offset from the heart tissue and a 4 mm offset from the heart tissue) is modeled. Figure 17E The results of the finite element analysis are shown, in which the transmission of a 2250 V monopolar signal between the rear external electrode 60b and the electrode 311 (positioned with a 0 mm offset from the heart tissue and a 4 mm offset from the heart tissue) is modeled. As shown, when the target tissue is located between the external electrode 60 (e.g., the front-placed external electrode 60a) and the electrode 311, the model shows that for both the 0 mm and 4 mm offset models, cardiac tissue ablation increases relative to a similar energy release between the electrode 311 and the rear external electrode 60b (e.g., when the target tissue is not located between the two electrodes). The modeling shows that when using the front-placed external electrode 60a, the maximum lesion depth is 13.26 mm; when using the rear external electrode 60b, the maximum lesion depth is 4.77 mm. In vivo tests conducted by the applicant showed that when a 2080 V monopolar signal was applied between the electrode 311 (facing the front) and the front external electrode 60a, the lesion depth was 15.32 mm (+ / - 5.18 mm). The in vivo tests also showed that when a 2460 V monopolar signal was provided between the electrode 311 (facing the front) and the rear external electrode 60b, the lesion depth was 4.94 mm (+ / - 0.23 mm).

[0174] Now referring to Figures 18A to 18C , graphs of cell membrane potential during action potential and examples of various pulse timing methods consistent with the inventive concept are shown, respectively. Figures 18A to 18C The electroporation waveform 200 and / or other components of Figure 1Construction and arrangement similar to those of similar components described in other parts of this document. In some embodiments, the electroporation waveform 200 is configured to provide coherent sinusoidal train electroporation (CSE) when applied to tissue, for example as referenced Figure 1 as described. The electric field generated by CSE can increase the cell membrane potential. In excitable tissues (e.g., neuronal or skeletal muscle tissue), an action potential (AP) can be generated due to the application of CSE pulses (e.g., electroporation waveform 200). In some embodiments, the AP integrates over time and can cause intense muscle contractions. Figure 18A Shows a graph of cell membrane potential over time when a stimulus (e.g., CSE pulse) triggers an AP. As shown, the absolute refractory period associated with these APs is approximately 1 - 2 ms. This absolute refractory period is much shorter than that of cardiac tissue (approximately 250 ms).

[0175] As described herein, the system 10 can be configured to apply the electroporation waveform 200 (e.g., CSE) using a sequential pulse method, for example, where the energy pulses 210 are applied independently via odd (e.g., non - adjacent) electrodes 311 and even (e.g., non - adjacent) electrodes 311, for example in an alternating manner (e.g., applying the energy pulse 210m from the first electrode 311a and the second electrode 311c, and then applying the energy pulse 210n from the third electrode 311b and the fourth electrode 311d, as referenced Figures 10A to 10C and described in other parts of this document). In some embodiments, the time period between each energy pulse 210 (e.g., the time period between the energy pulse 210m applied from the odd electrodes 311 and the energy pulse 210n applied from the even electrodes 311), for example the staggered offset period 2203, includes a time greater than the absolute refractory period of the AP, for example between 7 ms and 11 ms. For example, in a treatment including 300 cycles (including 300 odd energy pulses 210m and 300 even energy pulses 210n, a total of 600 energy pulses 210), since the cell membrane has sufficient time to refract between pulses, a total of 600 APs can be generated during the treatment. In some cases, these 600 APs integrate to form intense muscle contractions. As referenced Figure 2 and Figure 3 as described, the electroporation waveform 200 can include multiple sequences 250 of pulse trains 240 of energy pulses 210. In some embodiments, the treatment can include 5 sequences 250, each sequence including 5 pulse trains 240, and each pulse train 240 including 24 energy pulses 120 (e.g., 12 odd energy pulses 210m and 12 even energy pulses 210n). This treatment can produce 25 muscle contraction events (one event for each pulse train 240 of each sequence 250), where each event has 24 APs. Figure 18BIllustrates an example where each odd - numbered energy pulse 210m and each even - numbered energy pulse 210n are applied separately to generate an AP.

[0176] In some embodiments, the electroporation waveform 200 is configured to reduce muscle excitation. For example, when the timing between the odd - numbered energy pulse 210m and the even - numbered energy pulse 210n is configured to reduce muscle excitation. For example, the even - numbered energy pulse 210n can follow the odd - numbered energy pulse 210m with a staggered offset period 2203 that is less than the absolute refractory period of the AP generated by the odd - numbered energy pulse 210m. For example, the staggered offset period 2203 is less than 2 ms (e.g., about 500 μs). The period between the even - numbered energy pulse 210n and the subsequent odd - numbered energy pulse 210m can include a longer period, such as a period including the difference between the inter - pulse delay period 220 and the staggered offset period 2203. For example, such that the period between the odd - numbered energy pulses 210m (and the period between the even - numbered energy pulses 210n) is equal to the inter - pulse delay period 220 and is the same or similar to the Figure 18B timing shown. For example, the period between the even - numbered energy pulse 210n and the subsequent odd - numbered energy pulse 210m is between 12 ms and 21.5 ms (e.g., as shown in the figure, when the period between the odd - numbered energy pulses 210m is between 14 ms and 22 ms). This timing adjustment can reduce muscle excitation events by 50%. Figure 18C Illustrates an example of such adjusted timing, where the generated APs are reduced.

[0177] Now refer to Figures 19A to 19C , which shows a schematic diagram of various energy release methods consistent with the inventive concept. Figures 19A to 19C The generator 100, catheter 300, and / or other components in Figure 1 can have a construction and arrangement similar to those of the similar components described in reference to Figure 19A Illustrates a monopolar energy release method (e.g., as described in reference to Figures 3A to 3D and other parts of this document), where the electrical pulse 210 includes a first signal VE1 (including a sine wave applied to the first electrode 311a) and a second signal VE2 (including a sine wave applied to the second electrode 311b). The phase offset between VE1 and VE2 is a 0° offset, and the reference signal is applied to the external electrode 60, as shown. When energy is released using this monopolar method, the synthetic electric field mainly extends along the direction from each electrode 311 towards the external electrode 60, as shown.

[0178] Figure 19B Illustrates a bipolar energy release method (e.g., as described in reference to Figures 3A to 3Das described elsewhere in this document), where the electrical pulse 210 includes a first signal VE1 (including a sine wave applied to the first electrode 311a) and a second signal VE2 (including a sine wave applied to the second electrode 311b). The signals VE1 and VE2 include a 180° phase shift, and the external electrode 60 is not connected (e.g., no reference voltage is applied to the external electrode 60), as shown. When energy is released using this bipolar method, the resultant electric field extends mainly between each electrode 311, without an additional component towards the external electrode 60, as shown.

[0179] Figure 19C illustrates a phase-combined energy release mode (e.g., refer to Figures 3A to 3D as described elsewhere in this document), where the electrical pulse 210 includes a first signal VE1 (including a sine wave applied to the first electrode 311a) and a second signal VE2 (including a sine wave applied to the second electrode 311b). The signals VE1 and VE2 can include a phase shift greater than 0° and less than or equal to 180°. As shown, a reference signal is applied to the external electrode 60. When energy is released using this phase-combined method, the resultant electric field extends mainly between each electrode 311, and secondarily from each electrode 311 towards the external electrode 60, as shown. The phase angle between the signals VE1 and VE2 can be adjusted to adjust the relative intensities of the main and secondary components of the resultant electric field, as described herein, for example.

[0180] The above embodiments should be understood as illustrative examples only; other embodiments can be envisioned. Any feature described for any one embodiment can be used alone, or in combination with other described features, and can also be combined with one or more features of any other embodiment, or with any combination of other embodiments. Additionally, equivalent solutions and modifications not described above can also be adopted without departing from the scope of the inventive concept defined by the appended claims.

Claims

1. A system for delivering electroporation energy to a target tissue to be treated, the system comprising: A generator configured to provide an electroporation waveform, the generator including a signal generator and a controller, the signal generator being configured to generate the electroporation waveform, the controller being configured to provide a signal notification, the signal notification being configured to cause the signal generator to generate the electroporation waveform; A catheter including at least one catheter electrode, wherein the signal generator is configured to supply the electroporation waveform to the at least one catheter electrode, wherein the electroporation waveform includes a plurality of energy pulses, and wherein each energy pulse is separated by an inter-pulse delay period.

2. The system according to claim 1, wherein The inter-pulse delay period includes a first delay period and a second delay period, where, the first delay period includes a fixed duration between each of the plurality of energy pulses, while the second delay period includes a variable duration between each of the plurality of energy pulses.

3. The system according to claim 2, wherein Each variable duration includes a positive duration, a negative duration, or both the positive duration and the negative duration.

4. The system according to claim 2, comprising a first inter-pulse delay period between a first energy pulse of the plurality of energy pulses and a second energy pulse of the plurality of energy pulses, and a second inter-pulse delay period between the second energy pulse and a third energy pulse of the plurality of energy pulses, wherein, The first inter-pulse delay period includes a first variable duration, while the second inter-pulse delay period includes a second variable duration.

5. The system according to claim 4, wherein, The first variable delay period includes a positive duration, while the second variable delay period includes a negative duration.

6. The system according to claim 5, wherein, The duration of the first variable duration is equal to the absolute value of the duration of the second variable duration.

7. The system according to claim 2, wherein, The variable duration includes a duration based on a pseudo-random number.

8. The system according to claim 1, wherein, The inter-pulse delay period includes a variable duration between each energy pulse.

9. The system according to claim 8, wherein, The variable duration includes a duration based on a pseudo-random number.

10. The system according to claim 8, wherein, The variable duration is configured to reduce harmonics generated due to the release of energy pulses.

11. The system according to claim 10, wherein The variable duration is configured to reduce the harmonics by at least 10 dB.

12. The system according to claim 1, wherein The electroporation waveform further includes a period length, wherein, the cycle length includes the duration from the start of the first energy pulse among the plurality of energy pulses to the start of a subsequent energy pulse among the plurality of energy pulses.

13. The system according to claim 12, wherein, The cycle length is configured to minimize the formation of microbubbles.

14. The system according to claim 13, wherein The cycle length includes a duration of at least 30 ms.

15. The system according to claim 1, wherein The inter-pulse delay period includes a duration of at least 1 ms.

16. The system according to claim 1, wherein The inter-pulse delay period includes a duration not exceeding 2000 ms.

17. The system according to claim 1, wherein The controller includes a processor and a memory storage component coupled to the processor, wherein, the memory storage component stores instructions for causing the processor to execute an algorithm.

18. The system according to claim 17, wherein The algorithm is configured to determine one or more parameters of the electroporation waveform.

19. The system according to claim 18, wherein, The algorithm includes one or more biases.

20. The system according to claim 19, wherein The one or more biases are configured to determine the one or more parameters of the electroporation waveform such that the electroporation waveform tends to: a specific frequency range; a specific bipolar-to-unipolar energy release ratio; a specific phase difference between included sine waves; a specific voltage or voltage range; a specific delay between energy releases, such as a specific inter-pulse delay; and combinations thereof.

21. The system according to claim 1, wherein, The at least one catheter electrode includes a first set of non-adjacent catheter electrodes and a second set of non-adjacent catheter electrodes.

22. The system according to claim 21, wherein, A first catheter electrode of the second set of non-adjacent catheter electrodes is located between a first catheter electrode and a second catheter electrode of the first set of non-adjacent catheter electrodes.

23. The system according to claim 21, wherein, A first energy pulse of the plurality of energy pulses is provided to the first set of non-adjacent catheter electrodes, and a second energy pulse of the plurality of energy pulses is provided to the second set of non-adjacent catheter electrodes.

24. The system according to claim 23, wherein, A third energy pulse of the plurality of energy pulses is provided to the first set of non-adjacent catheter electrodes.

25. The system according to claim 23, wherein, The generator is configured to provide the electroporation waveform in a bipolar arrangement.

26. The system according to claim 1, wherein The at least one catheter electrode includes a plurality of electrodes, wherein, The plurality of electrodes includes a first catheter electrode and a group of at least two additional catheter electrodes.

27. The system according to claim 26, wherein, The signal generator is configured to provide the electroporation waveform to the first catheter electrode and the group of at least two additional catheter electrodes.

28. The system according to claim 27, wherein, The generator is configured to provide the electroporation waveform to the first catheter electrode and the at least two additional catheter electrodes in a bipolar arrangement.

29. The system according to claim 26, wherein Each electrode of the plurality of electrodes includes a similar surface area.

30. The system according to claim 26, wherein, Each electrode of the plurality of electrodes is equally spaced apart from each adjacent electrode.

31. The system according to claim 1, Among them, The system further includes one or more external electrodes, and wherein the signal generator is configured to provide the electroporation waveform to the at least one catheter electrode and the one or more external electrodes.

32. The system according to claim 31, Among them, The one or more external electrodes include at least two external electrodes, and wherein each of the at least two external electrodes can be individually selected such that the electroporation waveform can be provided to any one of the at least two external electrodes and the at least one catheter electrode.

33. The system according to claim 32, wherein, The controller is further configured to select one or more of the at least two external electrodes to provide the electroporation waveform such that the target tissue to be treated by the application of the electroporation waveform is relatively located between the at least one catheter electrode and the one or more selected external electrodes.

34. The system according to claim 1, Among them, The at least one catheter electrode includes a plurality of catheter electrodes, and wherein the generator is configured to provide the electroporation waveform in a bipolar arrangement between two or more of the plurality of catheter electrodes.

35. The system according to claim 1 further comprises one or more external electrodes, wherein, The electroporation waveform is configured to be applied to the at least one catheter electrode and the one or more external electrodes in a monopolar arrangement.

36. The system according to claim 35, wherein, The electroporation waveform is configured to be applied in both a monopolar arrangement and a bipolar arrangement.

37. The system according to claim 36, wherein, The electroporation waveform includes: a first signal, the first signal including a first sine wave; a second signal, the second signal including a second sine wave; and a third signal, the third signal including a combined reference of the first sine wave and the second sine wave, wherein the first sine wave and the second sine wave include a phase shift, and Wherein, the first signal is configured to be provided to a first electrode of the at least one catheter electrode, the second signal is configured to be provided to a second electrode of the at least one catheter electrode, and the third signal is configured to be provided to at least one of the one or more external electrodes.

38. The system according to claim 37, wherein, When the phase shift between the first signal and the second signal is 0°, the electroporation waveform is provided in a monopolar arrangement.

39. The system according to claim 37, wherein, When the phase shift between the first signal and the second signal is greater than 0° and not greater than 180°, the electroporation waveform is provided in both a monopolar arrangement and a bipolar arrangement.

40. The system according to claim 39, wherein, The relative intensity of the monopolar energy release is configured to vary based on the phase angle relative to the intensity of the bipolar energy release.

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