Electroporation System

Abstract

The present invention provides systems, devices, and methods for delivering electroporation energy to treat target tissue. The system includes a generator for providing an electroporation waveform. The generator includes a signal generator for generating the electroporation waveform and a controller for providing signaling that causes the signal generator to generate the electroporation waveform. The system further includes a catheter including at least one catheter electrode. The signal generator provides the electroporation waveform to the at least one catheter electrode. The electroporation waveform includes multiple energy pulses, each energy pulse separated by an inter-pulse delay period.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 410,391, entitled "A Controller for an Electroporation Apparatus," filed September 27, 2022, which is incorporated by reference.

[0002] This application does not claim priority, but may be related to the following: U.S. Patent Application No. 17 / 686,001, filed March 3, 2022, entitled "Ablation Equipment to Treat Target Regions of Tissue in Organs"; U.S. Patent Application No. 17 / 686,027, filed March 3, 2022, entitled "Ablation Equipment to Treat Target Regions of Tissue in Organs"; U.S. Patent Application No. 17 / 939,465, filed September 7, 2022, entitled "Systems, Methods and Devices for Non-Thermal Ablation of Target Tissue"; U.S. Patent Application No. 18 / 001,041, filed December 7, 2022, entitled "Ablation Equipment to Treat Target Regions of Tissue in Organs"; U.S. Patent Application No. 18 / 258,466, filed 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 June 20, 2023, entitled "Power Unit for Delivering Coherent Sine Burst Irreversible Electroporation Energy to a Biological Tissue"; Each of the above documents is incorporated herein by reference.

[0003] The present disclosure relates to an electroporation system, an electroporation controller, a method for controlling an electroporation system, and a computer program product including computer program code configured to cause a controller to perform the method. [Background technology]

[0004] Tissue ablation is used in many medical procedures to treat patients. Ablation can be performed to remove or modify unwanted tissue, such as cardiac cells. Ablation can be performed by passing energy, such as electrical energy, through one or more electrodes, killing the tissue where the electrodes contact the tissue. Ablation procedures can be performed on patients with any cardiac arrhythmia, such as atrial fibrillation (AF), by ablating tissue within the heart. Summary of the Invention [Means for solving the problem]

[0005] 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. The generator includes a signal generator configured to generate the electroporation waveform and a controller configured to provide signaling 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 multiple energy pulses, each energy pulse separated by an inter-pulse delay period.

[0006] In some embodiments, the inter-pulse delay period includes a first delay period and a second delay period, where the first delay period includes a fixed period between each of the multiple energy pulses, and the second delay period includes a variable period between each of the multiple energy pulses. Each variable period can include a positive duration, a negative duration, or both. The inter-pulse delay period can include a first inter-pulse delay period between a first energy pulse of the multiple energy pulses and a second inter-pulse delay period between a second energy pulse of the multiple energy pulses and a third energy pulse of the multiple energy pulses, where the first inter-pulse delay period can include a first variable period and the second inter-pulse delay period can include a second variable period. 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 period can be equal to the absolute value of the duration of the second variable period. The variable periods can include durations based on pseudorandom numbers.

[0007] In some embodiments, the inter-pulse delay period includes a variable period between each energy pulse. The variable period can include a duration based on a pseudo-random number. The variable period can be configured to reduce harmonics generated by the delivery of the energy pulse. The variable period can be configured to reduce the harmonics by at least 10 dB.

[0008] In some embodiments, the electroporation waveform further comprises a cycle length, the cycle length comprising the duration from the start of a first energy pulse of the plurality of energy pulses to the start of a subsequent energy pulse of the plurality of energy pulses. The cycle length can be configured to minimize microbubble formation. The cycle length can comprise a duration of at least 30 ms.

[0009] In some embodiments, the inter-pulse delay period comprises a duration of at least 1 ms.

[0010] In some embodiments, the inter-pulse delay period comprises a period of 2000 ms or less.

[0011] In some embodiments, the controller includes a processor and a memory storage component coupled to the processor, the memory storage component storing instructions for the processor to execute an algorithm. The algorithm can be configured to determine one or more parameters of an 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 exhibits the following trends: a specific frequency range, a specific ratio of bipolar to monopolar energy delivery, a specific phase difference between sine waves, a specific voltage or voltage range, a specific delay between energy delivery such as a specific inter-pulse delay, and combinations thereof.

[0012] In some embodiments, the 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 of the second set of non-adjacent catheter electrodes can be disposed between the first catheter electrode and the second catheter electrode of the first set of non-adjacent catheter electrodes. A first energy pulse of the plurality of energy pulses can be provided to the first set of non-adjacent catheter electrodes, and a second energy pulse of the plurality of energy pulses can be provided to the second set of non-adjacent catheter electrodes. A third energy pulse of 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 configuration.

[0013] In some embodiments, the at least one catheter electrode comprises a plurality of electrodes, the plurality of electrodes comprising a first catheter electrode and a set 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 set of at least two additional catheter electrodes. The generator can be configured to provide an electroporation waveform to the first catheter electrode and the set of at least two additional catheter electrodes in a bipolar arrangement. Each electrode of the plurality of electrodes can comprise a similar surface area. Each electrode of the plurality of electrodes can be equally spaced from each adjacent electrode.

[0014] In some embodiments, the system further includes one or more external electrodes, and the signal generator is configured to provide the electroporation waveform to the 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, each of which can be individually selected to provide the electroporation waveform to either the at least one catheter electrode or the at least two external electrodes. The controller can be further configured to select one or more of the at least two external electrodes to provide the electroporation waveform to, such that the target tissue to be treated by delivery of the electroporation waveform can be positioned relatively between the at least one catheter electrode and the at least one or more selected external electrodes.

[0015] In some embodiments, the at least one catheter electrode includes a plurality of catheter electrodes, and the generator is configured to provide the electroporation waveform in a bipolar configuration between two or more of the plurality of catheter electrodes.

[0016] In some embodiments, the system further includes one or more external electrodes, and the electroporation waveform is configured to be delivered to the at least one catheter electrode and the at least one or more external electrodes in a monopolar configuration. The electroporation waveform can be configured to be delivered in both a monopolar and a bipolar configuration. The electroporation waveform can include a first signal including a first sine wave, a second signal including a second sine wave, and a third signal including a combined reference of the first sine wave and the second sine wave, where the first sine wave and the second sine wave can include a phase offset. 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. The electroporation waveform can be delivered in a monopolar configuration when the phase offset between the first signal and the second signal is 0°. The electroporation waveform can be provided in both monopolar and bipolar configurations when the phase offset between the first and second signals is greater than 0° and less than or equal to 180°. The relative intensity of the monopolar energy delivery can be configured to vary relative to the intensity of the bipolar energy delivery based on the phase angle.

[0017] The technology described herein, together with its attributes and attendant advantages, will best be understood and appreciated in consideration of the following detailed description taken in connection with the accompanying drawings, in which representative embodiments are set forth by way of example.

[0018] Incorporation by Reference All publications, patents, and patent applications mentioned herein are herein incorporated 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 contents of all publications, patents, and patent applications mentioned herein are incorporated by reference in their entirety for all purposes. [Brief explanation of the drawings]

[0019] [Figure 1] FIG. 1 shows a schematic example of a system including a catheter and generator for providing electroporation consistent with the concepts of the present invention.

[0020] [Figure 2] FIG. 1 shows some example electroporation waveforms consistent with the concepts of the present invention.

[0021] [Figure 3] FIG. 1 shows some example electroporation waveforms consistent with the concepts of the present invention.

[0022] [Figure 3A] 10A-10C show graphs of harmonics of various frequencies under various conditions consistent with the concepts of the present invention. [Figure 3B] 10A-10C show graphs of harmonics of various frequencies under various conditions consistent with the concepts of the present invention. [Figure 3C] 10A-10C show graphs of harmonics of various frequencies under various conditions consistent with the concepts of the present invention. [Figure 3D] 10A-10C show graphs of harmonics of various frequencies under various conditions consistent with the concepts of the present invention.

[0023] [Figure 4] FIG. 1 shows graphs of some experimental results and electroporation waveforms consistent with the concepts of the present invention. [Figure 4A] FIG. 1 shows graphs of some experimental results and electroporation waveforms consistent with the concepts of the present invention.

[0024] [Figure 5] FIG. 1 shows a plot of stimulus intensity versus duration consistent with the concepts of the present invention.

[0025] [Figure 6]FIG. 1 shows an example of an electroporation waveform including a compensation signal consistent with the concepts of the present invention.

[0026] [Figure 7] FIG. 1 shows an example of an electroporation waveform including a compensation signal consistent with the concepts of the present invention.

[0027] [Figure 8] FIG. 1 shows an example of an electroporation waveform including a simultaneous compensation signal consistent with the concepts of the present invention.

[0028] [Figure 9A] 1 shows a side anatomical view of a catheter including multiple electrodes positioned adjacent to tissue and a representation of the effective electric field generated by each electrode, consistent with the concepts of the present invention. [Figure 9B] 1 shows a side anatomical view of a catheter including multiple electrodes positioned adjacent to tissue and a representation of the effective electric field generated by each electrode, consistent with the concepts of the present invention.

[0029] [Figure 10A] 1 shows a side anatomical view of a catheter including multiple electrodes positioned adjacent to tissue and a representation of the effective electric field generated by each electrode, consistent with the concepts of the present invention. [Figure 10B] 1 shows a side anatomical view of a catheter including multiple electrodes positioned adjacent to tissue and a representation of the effective electric field generated by each electrode, consistent with the concepts of the present invention. [Figure 10C] 1 shows a side anatomical view of a catheter including multiple electrodes positioned adjacent to tissue and a representation of the effective electric field generated by each electrode, consistent with the concepts of the present invention.

[0030] [Figure 11A] 1 shows a representation of the damage to tissue caused by various forms of electroporation consistent with the concepts of the present invention. [Figure 11B] 1 shows a representation of the damage to tissue caused by various forms of electroporation consistent with the concepts of the present invention.

[0031] [Figure 12] 1 shows a side view of a catheter including multiple electrodes consistent with the concepts of the present invention.

[0032] [Figure 13] 1 shows a perspective view of a catheter including a curved array of electrodes consistent with the concepts of the present invention.

[0033] [Figure 14] 1 shows a perspective view of a catheter including an expandable array of electrodes consistent with the concepts of the present invention.

[0034] [Figure 15] 1 shows a visual representation of a method for delivering electroporation therapy consistent with the concepts of the present invention.

[0035] [Figure 16A] 1 shows two anatomical representations and graphs of lesion depth, and two representations of tissue damage and graphs of ablation parameters, consistent with the concepts of the present invention. [Figure 16B] 1 shows two anatomical representations and graphs of lesion depth, and two representations of tissue damage and graphs of ablation parameters, consistent with the concepts of the present invention. [Figure 16C] 1 shows two anatomical representations and graphs of lesion depth, and two representations of tissue damage and graphs of ablation parameters, consistent with the concepts of the present invention. [Figure 16D] 1 shows two anatomical representations and graphs of lesion depth, and two representations of tissue damage and graphs of ablation parameters, consistent with the concepts of the present invention. [Figure 16E]1 shows two anatomical representations and graphs of lesion depth, and two representations of tissue damage and graphs of ablation parameters, consistent with the concepts of the present invention. [Figure 16F] 1 shows two anatomical representations and graphs of lesion depth, and two representations of tissue damage and graphs of ablation parameters, consistent with the concepts of the present invention. [Figure 16G] 1 shows two anatomical representations and graphs of lesion depth, and two representations of tissue damage and graphs of ablation parameters, consistent with the concepts of the present invention.

[0036] [Figure 17] 1 shows a schematic diagram of a system for implementing unipolar and / or phase-coupled energy delivery using multiple external patch electrodes consistent with the concepts of the present invention.

[0037] [Figure 17A] 1 shows a cross-sectional view of a finite element analysis setup and analysis results consistent with the concepts of the present invention. [Figure 17B] 1 shows a cross-sectional view of a finite element analysis setup and analysis results consistent with the concepts of the present invention. [Figure 17C] 1 shows a cross-sectional view of a finite element analysis setup and analysis results consistent with the concepts of the present invention. [Figure 17D] 1 shows a cross-sectional view of a finite element analysis setup and analysis results consistent with the concepts of the present invention. [Figure 17E] 1 shows a cross-sectional view of a finite element analysis setup and analysis results consistent with the concepts of the present invention.

[0038] [Figure 18A] 1A and 1B show graphs of cell membrane potential during an action potential and examples of various pulse timing methods, respectively, consistent with the concepts of the present invention. [Figure 18B] 1A and 1B show graphs of cell membrane potential during an action potential and examples of various pulse timing methods, respectively, consistent with the concepts of the present invention. [Figure 18C]1A and 1B show graphs of cell membrane potential during an action potential and examples of various pulse timing methods, respectively, consistent with the concepts of the present invention.

[0039] [Figure 19A] 1 shows diagrams of various energy delivery modalities consistent with the concepts of the present invention. [Figure 19B] 1 shows diagrams of various energy delivery modalities consistent with the concepts of the present invention. [Figure 19C] 1 shows diagrams of various energy delivery modalities consistent with the concepts of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0040] Reference will now be made in detail to the present embodiments of the present technology, examples of which are illustrated in the accompanying drawings. Like reference numerals may be used to refer to like elements. However, the description is not intended to limit the disclosure to the particular embodiments, but should be construed to include various modifications, equivalents, and / or alternatives to the embodiments described herein.

[0041] The words (comprise in any form, such as "comprise" and "comprises"), (any form of having, such as "have" and "has"), (any form of inclusion, such as "includes" and "include"), or (any form of inclusion, such as "contains" and "contains"), when used herein, specify the presence of stated features, integers, steps, operations, elements, and / or components, but are understood not to exclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof.

[0042] Terms such as first, second, and third may be used herein to describe various limits, elements, components, regions, layers, and / or sections, but these limits, elements, components, regions, layers, and / or sections should not be limited by these terms. These terms are used only to distinguish one limit, element, component, region, layer, or section from another limit, element, component, region, layer, or section. Thus, a first limit, element, component, region, layer, or section described below could be referred to as a second limit, element, component, region, layer, or section without departing from the teachings of the present application.

[0043] When an element is referred to as being "on," "attached," "connected," or "coupled" to another element, it is further understood that it is directly on or above, connected to, or coupled to the other element, or that one or more intervening elements may be present. In contrast, when an element is referred to as being "directly on," "directly attached," "directly connected," or "directly coupled" to another element, there are no intervening elements present. Other terms used to describe relationships between elements should be interpreted in a similar manner (e.g., "between" vs. "directly between," "adjacent" vs. "directly adjacent," etc.).

[0044] It is further understood that when a first element is referred to as being "in," "on," and / or "within" a second element, the first element may be disposed within an interior space of the second element, within a portion of the second element (e.g., within a wall of the second element), on an exterior and / or interior surface of the second element, and within one or more combinations thereof.

[0045] As used herein, the term "proximate," when used to describe a first component or location being proximate to a second component or location, is intended to include one or more locations near the second component or location, as well as locations within, on, and / or within the second component or location. For example, a component positioned proximate to an anatomical location (e.g., a target tissue location) is intended to include a component positioned near the anatomical location, as well as a component positioned within, on, and / or within the anatomical location.

[0046] Spatially relative terms such as "below," "below," "below," "above," "on," and the like may be used to describe the relationship of an element and / or feature to another element and / or feature, for example, as shown in the figures. It is further understood that the spatially relative terms are intended to encompass different orientations of the device in use and / or operation in addition to the orientation shown in the figures. For example, if the device in the figures were turned over, elements described as "below" and / or "below" other elements or features would now be oriented "on" the other elements or features. The device can be oriented in other directions (e.g., when rotated 90 degrees or at other orientations), and the spatially relative descriptors used herein would be interpreted accordingly.

[0047] The terms "reduce," "reducing," "reduction," and the like, as used herein, include a reduction in quantity, including a reduction to zero. Reducing the likelihood of occurrence is intended to include prevention of occurrence. Similarly, the terms "prevent," "preventing," and "prevention" are intended to include the acts of "reducing," "reducing," and "reducing," respectively.

[0048] The term "and / or," as used herein, is considered a specific disclosure of each of the two specified features or components, with or without the other. For example, "A and / or B" is considered a specific disclosure of each of (i) A, (ii) B, and (iii) A and B, as if each were individually set forth herein.

[0049] The term "one or more," as used herein, can mean one, two, three, four, five, six, seven, eight, nine, ten or more, up to any number.

[0050] The terms "and combinations thereof" and "and combinations thereof," respectively, may be used herein after a list of items to be included singly or collectively. For example, components, processes, and / or other items selected from the group consisting of A; B; C; and combinations thereof would include: a set of one or more components that includes one, two, three, or more of item A, one, two, three, or more of item B, and / or one, two, three, or more of item C.

[0051] As used herein, unless otherwise stated, "and" can mean "or," and vice versa. For example, if a feature is described as having A, B, or C, the feature can 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 can have only one or two of A, B, or C.

[0052] As used herein, when a quantifiable parameter is described as having a value "between" a first value X and a second value Y, it is intended to include parameters having values ​​at least X, less than or equal to Y, and / or at least X, less than or equal to Y. For example, a length between 1 and 10 is intended to include a length of at least 1 (including values ​​greater than 10), less than 10 (including values ​​less than 1), and / or values ​​greater than 1 and less than 10.

[0053] As used in this disclosure, the term "configured" may be used interchangeably with terms such as "suitable," "capable of," "designed," "adapted," "made," and "capable," depending on the context. The term "configured" does not mean only "specially designed" in hardware. Alternatively, in some contexts, the term "device configured to" may mean that the device is capable of operating in conjunction with another device or component.

[0054] As used herein, the term "threshold" refers to a maximum level, a minimum level, and / or a range of values ​​associated with a desired or undesirable condition. In some embodiments, a system parameter is maintained above a minimum threshold, below a maximum threshold, within a threshold range of values, and / or outside a threshold range of values ​​to cause a desired effect (e.g., effective treatment) and / or prevent or reduce an undesirable event (e.g., adverse device and / or clinical event). In some embodiments, a system parameter is maintained above a first threshold (e.g., above a first temperature threshold to produce a desired therapeutic effect on tissue) and below a second threshold (e.g., below a second temperature threshold to prevent undesirable tissue damage). In some embodiments, thresholds are determined to include a safety margin, such as by considering patient variability, system variability, tolerances, etc. As used herein, "above threshold" refers to a parameter being above a maximum threshold, below a minimum threshold, within a threshold range, and / or outside a threshold range.

[0055] The term "diameter" as used herein to describe non-circular geometries is considered to be the diameter of an imaginary circle that approximates the described geometry. For example, when describing a cross-section, such as a cross-section of a component, the term "diameter" is considered to represent the diameter of an imaginary circle having the same cross-sectional area as the cross-section of the described component.

[0056] As used herein, the terms "major axis" and "minor axis" of a component are the length and diameter, respectively, of an imaginary cylinder of smallest volume that can completely enclose the component.

[0057] As used herein, the term "functional element" is intended to include one or more elements constructed and arranged to perform a function. A functional element may include a sensor and / or a transducer. In some embodiments, a functional element is configured to deliver energy and / or perform a treatment on tissue (e.g., a functional element configured as a treatment element). Alternatively or additionally, a functional element (e.g., a functional element including a sensor) may be configured to record one or more parameters, such as patient physiological parameters, patient anatomical parameters (e.g., tissue geometry parameters), patient environment parameters, and / or system parameters. In some embodiments, a sensor or other functional element is configured to perform a diagnostic function (e.g., collecting data for use in performing a diagnosis). In some embodiments, a functional element is configured to perform a therapeutic function (e.g., delivering therapeutic energy and / or a therapeutic agent). In some embodiments, a functional element includes one or more elements configured and arranged to perform a function selected from the group consisting of: Delivering energy, extracting energy (e.g., cooling a component), delivering drugs or other agents, manipulating system components or patient tissue, recording or sensing parameters such as patient physiological parameters or system parameters, and combinations of one or more of these. A functional element can include a fluid and / or a fluid delivery system. A functional element can include a reservoir, such as an inflatable balloon or other fluid-maintaining reservoir. A "functional assembly" can include an assembly constructed and arranged to perform a function, such as a diagnostic and / or therapeutic function. A functional assembly can include an expandable assembly. A functional assembly can include one or more functional elements.

[0058] As used herein, the term "transducer" is intended to include any component or combination of components that receives energy or any input and generates 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, a transducer converts an electrical signal into any output. The any output can include 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 deliver ultrasound energy), pressure (e.g., applied pressure or force), thermal energy, cryogenic energy, chemical energy, mechanical energy (e.g., a transducer including a motor or solenoid), magnetic energy, and / or another electrical signal (e.g., different from the input signal to the transducer), etc. Alternatively or additionally, a transducer can convert a physical quantity (e.g., a variation in a physical quantity) into an electrical signal. A transducer can include any component that delivers energy and / or a substance to tissue, such as a transducer configured to deliver one or more of the following: Electrical energy to tissue (e.g., a transducer including one or more electrodes), optical energy to tissue (e.g., a transducer including a laser, light emitting diode and / or optical components such as a lens or prism), mechanical energy to tissue (e.g., a transducer including a tissue manipulation element), acoustic energy to tissue (e.g., a transducer including a piezo crystal), chemical energy, electromagnetic energy, magnetic energy, and combinations of one or more of these.

[0059] As used herein, the term "fluid" can refer to a liquid, gas, gel, or any flowable material, for example, a material that can be propelled through a lumen and / or opening.

[0060] As used herein, the term "material" can refer to a single material or a combination of two, three, four, or more materials.

[0061] It will be understood that certain features of the inventive concept, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, for brevity, various features of the inventive concept, which are described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. For example, it will be understood that all features (whether independent or dependent) recited in any claim may be combined in any desired manner.

[0062] At least some of the illustrations and descriptions of the inventive concepts have been simplified to focus on elements relevant to a clear understanding of the inventive concepts, but for clarity, other elements that one skilled in the art would understand may form part of the inventive concepts, but because such elements are well known to those skilled in the art and because they do not necessarily facilitate a better understanding of the inventive concepts, descriptions of such elements are not provided herein.

[0063] The terms defined in this disclosure are used only to describe specific embodiments of the present disclosure and are not intended to limit the scope of the present disclosure. Terms provided in the singular are intended to include the plural unless the context clearly indicates otherwise. All terms used herein, including technical or scientific terms, have the same meaning as commonly understood by those skilled in the relevant art, unless otherwise defined herein. Terms defined in commonly used dictionaries should be interpreted as having the same or similar meaning as the contextual meaning of the relevant art, and should not be interpreted as having an ideal or exaggerated meaning unless explicitly defined herein. In some cases, the terms defined in this disclosure should not be interpreted to exclude embodiments of the present disclosure.

[0064] Tissue ablation is used in many medical procedures to treat one or more medical conditions in a patient. Ablation can be performed to remove or modify unwanted tissue, such as cardiac cells associated with arrhythmia. Ablation can be performed by passing energy, such as electrical energy, through one or more electrodes to kill tissue in proximity to the electrodes (e.g., when the heat generated by the application of energy is sufficient to cause cell death and / or when the electric field generated is sufficient to irreversibly electroporate the tissue). Ablation procedures can be performed on cardiac tissue in patients with any form of cardiac arrhythmia, such as atrial fibrillation (AF).

[0065] Radiofrequency ablation (RFA) is a medical procedure in which tissue that is part of the cardiac electrical conduction system, tumor tissue, and / or other dysfunctional tissue is ablated using heat generated from the delivery of alternating current. Typical frequencies of alternating current in this context may be considered to be 350 kHz to 500 kHz.

[0066] In particular, in these types of ablation procedures, an energy delivery device, such as a catheter or other probe with one or more electrodes, is inserted near the target tissue to cause destruction of the targeted area of ​​cardiac tissue through the application of thermal energy. Indeed, electrically induced thermal ablation, such as RFA, can be used to effectively and continuously ablate tissue sites locally when the energy delivery device is placed on the tissue surface. While RFA can effectively ablate targeted tissue volumes, this thermal technology has limitations. One of the issues often cited when using this procedure during cardiac ablation is heat sinking. This is the process by which heat generated on the ablation element is removed / dissipated by cool blood flow over the element, one aspect of which can involve blood flow. This heat dissipation effect can alter (e.g., undesirably reduce) both the shape and maximum volume of tissue ablated.

[0067] Recently, pulsed electric fields (PEF) have been used as an alternative to RFA for ablation of cardiac and / or other organ tissues. PEF refers to the application of short (e.g., microsecond or nanosecond) periods of intermittent, high-intensity electric fields, resulting in cellular electroporation of tissue. Electroporation is the process by which the applied electric field (i.e., PEF) creates pores in cell membranes. Pore formation results in permeability and can be reversible or irreversible, depending on the parameters of the applied PEF.

[0068] In reversible electroporation, electroporated cells remain viable. This approach is the basis for electrochemotherapy and gene electrotransfer. In contrast, in irreversible electroporation (IRE), cells and tissues become nonviable because this technique induces the activation of a programmed cell death cascade.

[0069] While IRE is a well-established treatment for solid tumors, IRE may also be useful in cardiology, particularly cardiac ablation, especially given the limitations of current heat-based approaches.

[0070] When used to ablate cardiac tissue, irreversible electroporation (IRE) applies electrical pulses to target tissue in the microsecond to nanosecond range, potentially causing nanoscale, non-thermally generated defects in cell membranes. These defects can lead to disruption of cell membrane homeostasis, thereby causing irreversible cell membrane permeability that induces cell death without significantly increasing the temperature of the tissue ablation zone. In some embodiments, systems, devices, and methods of the present concept are configured to avoid increasing the temperature of tissue adjacent to the tissue ablation zone by a maximum of 13°C or less, e.g., 10°C, 7°C, or 4°C or less, and / or to avoid increasing the temperature of tissue adjacent to the tissue ablation zone by a maximum of 50°C or less, e.g., 47°C or 44°C or less.

[0071] The present application relates to providing an electroporation waveform that includes multiple energy pulses, each comprising a sinusoidal signal, where the energy pulses are separated by an inter-pulse delay period. By providing the inter-pulse delay period, as well as other delay periods described herein, it is possible to successfully induce targeted cell death while avoiding undesirable heating at the target treatment site and avoiding or at least reducing the formation of microbubbles.

[0072] Referring now to FIG. 1 , a schematic example of a system including a catheter and generator for providing electroporation is shown consistent with the concepts of the present invention. System 10 can include generator 100, each including a controller 110 configured to control one or more signal generators, such as signal generator 120, as shown. System 10 can include one or more power supply assemblies, such as power supply 130 of generator 100. Power supply 130 can be configured to provide power to signal generator 120. Generator 100 can be configured to provide electrical energy including one or more waveforms, such as electroporation waveform 200, described in detail herein. System 10 can include one or more patient treatment devices, such as catheter 300, as shown. Catheter 300 can include one or more electrode arrays, such as electrode array 310 including electrode 311, as shown. Catheter 300 can be operably attached to generator 100 such that electroporation waveform 200 can be provided by generator 100 and delivered to a patient via catheter 300, as described herein. Delivery of electroporation waveform 200 to one or more electrodes 311 can result in one or more electric fields, single or collective electric fields 290, being generated at electrodes 311 of catheter 300 proximate to tissue. As described herein, the parameters and method of delivery of electroporation waveform 200 can be configured to effectively electroporate tissue within a portion of electric field 290 sufficient to electroporate the tissue, as described herein. In some embodiments, one or more components may not form part of generator 100. For example, an external power source can be used, and as such, power source 130 may not form part of generator 100. In other embodiments, signal generator 120 itself may also include power source 130, as opposed to the two components being provided separately.In some embodiments, the controller 110 may be powered by the power supply 130, while in other embodiments the controller 110 may be powered by other means.

[0073] In some embodiments, the electroporation waveform 200, when delivered to tissue, is configured to provide coherent sine wave burst electroporation (CSE), which, as described herein, involves delivering high voltage (e.g., at least 100 V or 1500 V) phased sine waves to ablate (e.g., irreversibly electroporate) tissue.

[0074] The generator 100 can include one or more isolation transformers. Sine waves are more compatible with isolation transformers than square waves because the energy of a sine wave can be concentrated at a single frequency within the isolation transformer's passband. Isolation transformers are considered the "gold standard" for patient safety because these types of transformers allow the patient's potential to "float" relative to the generator's potential, and all pulsed field ablation (PFA) energy must couple through the transformer's magnetic field to reach the patient. Therefore, an electrical fault on the primary side of the generator 100's transformer does not propagate to the secondary side attached to the catheter 300 due to the isolation created by the transformer's magnetic field. By providing a sine wave and leveraging the voltage gain enabled by a properly selected isolation transformer, the generator 100 can generate much higher voltages, i.e., much higher electric fields, than in a sine wave-based generator configuration, resulting in deeper propagation of irreversible PFA.

[0075] Furthermore, pure sine waves can be readily combined to constructively interfere with the generator 100 by varying the relative phase between multiple sine waves applied to adjacent activation electrodes, as described herein. When an external electrode 60 is connected and sine waves of a given frequency applied to adjacent activation electrodes 311 (e.g., electrodes placed on the endocardial surface) have no phase shift, a monopolar field is generated between the electrodes 311 and the external electrode 60 (e.g., including one or more patch electrodes). If the sine waves applied to adjacent activation electrodes 311 are the same frequency but 180° out of phase, the two waves constructively interfere and combine to produce a bipolar sine wave of twice the amplitude applied to each individual electrode 311. In this configuration, no external electrode 60 (e.g., no return patch electrode) is required.

[0076] Using a unipolar field, the system 10 can create deeper lesions than bipolar lesions for a given peak voltage. This increased depth is due to the field being directed outward from the endocardial tissue surface contacted by the electrode 311 through the thickness of the heart and through the rest of the body (e.g., toward one or more external electrodes 60), but tends to result in a greater degree of neuromuscular stimulation due to the greater number of muscle groups located between the electrode 311 and the external electrode 60. Depending on electrode 311 spacing and other factors, unipolar lesions can also result in less uniform "filling" between adjacent electrodes 311 and may include gaps. A bipolar field maintains its field locally because the endocardially placed electrodes 311 act as both a source and a sink, resulting in negligible neuromuscular stimulation and greater uniformity of filling without gaps between the electrodes. The more localized nature of bipolar fields leads to less tissue penetration for a given peak voltage, but the voltage doubling by driving out of phase can compensate, and therefore bipolar fields are often preferred in applications such as atrial fibrillation (AF), where the tissue to be ablated is often less than 5 mm thick relative to the epicardial surface.

[0077] Finally, another advantage of sine-wave-based systems is that sine-wave-based PFA is more efficient than biphasic or monophasic square-wave-based PFA. Unlike standard RF ablation, which relies on the root mean square (RMS) of AC current to induce 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 than a square wave of the same amplitude and therefore generates less heat. Furthermore, some of the spectral energy of a square wave that induces heat is contained within odd harmonics. These harmonics are multiples of the fundamental frequency at which electroporation is ineffective due to the low penetration characteristics of biological tissue. In short, to generate a field of equivalent amplitude as a sine-wave-based system, a square-wave system requires more heat-generating energy at frequencies that have minimal impact on lesion creation.

[0078] System 10 can be configured to provide electroporation to a treatment site on a patient via catheter 300. In particular, electroporation techniques can include high frequency non-reversible electroporation, although in some embodiments system 10 can be configured to provide different types of electroporation, such as low frequency non-thermal non-reversible electroporation or reversible electroporation, and / or electrolytic electroporation, such as electrolytic electroporation, which includes a combination of low frequency and high frequency electroporation.

[0079] In some embodiments, when delivering the electroporation waveform 200, energy can be delivered between two or more adjacent and / or other endocardially placed electrodes, such as electrode 311 of catheter 300, in a bipolar configuration, as described herein. Additionally, or alternatively, energy can be delivered between an endocardially placed electrode 311 and one or more external patient return patches, such as the illustrated external electrode 60. The delivery of energy between an endocardially placed electrode (e.g., electrode 311) and one or more external patch electrodes (e.g., external electrode 60) can be described as delivering energy in a unipolar configuration. In some embodiments, for example, when system 10 utilizes a pure sine wave, electroporation waveform 200 can be delivered by generator 100 in a phase-coupled configuration (i.e., a combination of bipolar and unipolar delivery). Here, these pure sine waves can be combined to interfere constructively by varying the relative phase between the sine waves applied to adjacent active electrodes (e.g., electrode 311), and a reference voltage can be provided by generator 100 to external electrodes 60 (e.g., one or more patch electrodes placed on the patient's skin) as described herein.

[0080] Monopolar energy delivery methods can be used to create deeper lesions for a given peak voltage than lesions created using bipolar methods utilizing multiple endocardially placed electrodes (e.g., electrodes 311). This is because the direction of the resulting field (e.g., field 290) can be directed from the contacted endocardial tissue outward through the thickness of the heart wall tissue and through the rest of the body toward one or more patch electrodes on the patient's skin. This monopolar energy delivery tends to result in a greater degree of neuromuscular stimulation due to the greater number of muscle groups located on the path to the associated patient return electrode (e.g., external electrode 60). In some embodiments, depending on, for example, the spacing between the catheter 300 and electrodes 311 and other factors, lesions created using monopolar energy delivery can result in less uniform "filling" between adjacent electrodes 311 and may include gaps. A bipolar field maintains the field localized, eliminating gaps between electrodes, negating neuromuscular stimulation and enhancing the uniformity of filling, as the endocardially placed electrodes 311 act as both a source and a sink.

[0081] In some embodiments, the placement and / or selection of one or more external patch electrodes (e.g., external electrode 60) can enhance and / or reduce the size of the created unipolar component by pulling the field in a predetermined direction toward the activated patch electrode or electrodes. For example, if external electrode 60 includes a patch electrode positioned on the patient's skin such that the substrate to be ablated is tissue located between endocardially placed electrode 311 and external electrode 60, the size of the created lesion is enhanced (e.g., reaching a greater depth and forming a transmural lesion). System 10 can be configured to ablate one or more locations within any chamber of the heart, such as when configured to enable a clinician to ablate any location within the left atrium and / or other cardiac chambers. In some embodiments, electrode 60 includes multiple patch electrodes positioned at various locations on the patient's skin. Each electrode is independently activatable (e.g., configured to be selected as a return electrode). For example, a particular patch electrode can be activated to direct the field in one or more directions—anterior, posterior, superior, and / or inferior—to form a transmural lesion within the cardiac wall at the associated electrode 311. Unipolar energy delivery using an external electrode 60 comprising multiple patch electrodes can be similar to the unipolar and / or phase-coupled energy delivery described below with reference to FIG.

[0082] Controller 110 may include modules (e.g., electronic modules) that may be configured to perform and / or facilitate one or more functions of system 10, such as one or more processes. The processes may include energy delivery, such as delivery of electroporation waveforms, data analysis, data transfer, signal processing, and / or other functions of system 10 (herein "system 10 functions" or "system functions"). Controller 110 may include one or more electronic elements, electronic assemblies, and / or other electronic components, such as components selected from the group consisting of: Microprocessors, microcontrollers, state machines, memory storage components, analog-to-digital converters, rectifier circuits, filters and other signal conditioners, sensor interface circuits, transducer interface circuits, and combinations of one, two or more of these. For example, controller 110 can include at least one processor and at least one memory storage component, e.g., processor 111 and memory 112, each shown. Memory 112 can be coupled to processor 111. Memory 112 can store instructions used by processor 111 to execute one or more algorithms of system 10. For example, system 10 can include one or more algorithms, illustrated algorithm 25, executed by processor 111 and / or another similar arrangement of processors and instructions stored in memory. Algorithm 25 can include one or more machine learning, neural net, and / or other artificial intelligence algorithms ("AI algorithms" herein). All or a portion of algorithm 25 can be integrated into (e.g., stored in memory) one, two, or more of the various components of system 10, such as the processor and / or devices or other components of system 10, including the console. Controller 110 can include a microprocessor or other processing unit capable of receiving input data and providing output signals based on the input data. In some embodiments, the controller 110 is configured to receive input from a user input device and / or an automated computing device. The input from the user input device can come directly to the controller 110 and / or can be provided via one or more other electronic devices. The input received by the controller 110 can relate to specific parameters defining the electroporation waveform. For example, the received parameters can include the desired frequency, intensity, duration, phase, cycle length, or other parameters of the waveform. As an output, the controller 110 can be configured to provide signaling configured to interact with the signal generator 120 to cause the signal generator 120 to generate the desired electroporation waveform.

[0083] In some embodiments, generator 100 and / or another component of system 10 may include a user interface, such as user interface 150 of generator 100 shown, configured to provide and / or receive information to and / or from an operator of system 10. User interface 150 may be integrated into generator 100, as shown. Alternatively or additionally, user interface 150 may include a component separate from generator 100, such as a display separate from but operably attached to generator 100. User interface 150 may include one, two, or more user input and / or user output components. For example, user interface 150 may include a joystick, keyboard, mouse, touchscreen, speaker, light, transducer, and / or another human interface device, user interface device 151. In some embodiments, user interface 150 includes a display (e.g., a touchscreen display), such as display 152. In some embodiments, processor 111 may provide a graphical user interface, GUI 153, presented on and / or provided by display 152. The algorithm 25 can be configured to execute one or more software routines that enable user control of one or more functions of the system 10. The one or more software routines executed by the algorithm 25 can include a graphical user interface, such as a GUI 153. The user interface device 151 can include input and / or output devices selected from the group consisting of: Speakers, indicator lights such as LED indicators, tactile feedback devices such as devices including vibration alert components, foot pedals, switches such as momentary switches, microphones, cameras, for example where processor 111 enables eye tracking and / or other input via image processing, and combinations thereof. In some embodiments, catheter 300 includes at least a portion of user interface 150, such as user input device 151, for example, when functional elements 399 of catheter 300 include buttons or other interface devices 151 of user interface 150. Additionally or alternatively, catheter 300 can include user interface device 151 including, for example, a user output device such as a light configured to indicate the readiness state of system 10 (e.g., a light configured to indicate when system 10 is ready and / or not ready to provide electroporation waveform 200) or a speaker.

[0084] In some embodiments, system 10 includes server 400, which is a data storage and processing device. Server 400 can include an “off-site” server (e.g., 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 can include a cloud-based server. Server 400 can include the illustrated processing unit 410, which can be configured to perform one or more functions of system 10, such as one or more functions described herein. Processing unit 410 can include one or more algorithms, such as algorithm 25 described herein. Processing unit 410 can include memory (not shown) capable of storing instructions for executing algorithm 25. Server 400 can be configured to receive and store various types of data, such as treatment data, diagnostic data, planning data, and / or treatment outcome data collected by system 10, data 420. In some embodiments, the data 420 may include data collected from multiple patients (e.g., multiple patients treated with the system 10), such as data collected during and / or after a clinical procedure in which the electroporation waveform 200 was delivered to the patients via the system 10. In some embodiments, the generator 100 and the server 400 may communicate over a network, e.g., a wide area network such as the Internet. Alternatively or additionally, the system 10 may include a virtual private network (VPN) through which various devices of the system 10 transfer data.

[0085] As described herein, one or more functions of system 10 performed by controller 110 and / or processing unit 410 may be performed by either or both devices. For example, in some embodiments, processed data may be collected by controller 110 of generator 100. The treatment data may then be forwarded to server 400, where the data is processed to identify one or more trends, such as, for example, one or more trends in the effectiveness of various parameters of the electroporation waveforms 200 described herein. Insights gained from server 400's data processing may then be forwarded to generator 100, for example, to inform a decision-making process (e.g., decisions made by algorithm 25 and / or an operator of system 10) regarding one or more parameters of the electroporation waveforms 200 provided to treat a patient.

[0086] In some embodiments, algorithm 25 is configured to adjust (e.g., automatically and / or semi-automatically, such as adjustments made based on one or more biases included in algorithm 25, as described herein) one or more operating parameters of system 10, such as one or more parameters of 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 sensor-based functional elements of the inventive concepts described herein. Algorithm 25 can be configured to adjust (e.g., automatically adjust and / or recommend adjustments to) operating parameters selected from the group consisting of: Which one or more electrodes of an electrode set provide the electroporation waveform 200 (e.g., one or more electrodes 311 and / or one or more external electrodes 60), which energy modality to deliver the energy with, the phase angle between two or more signals of the electroporation waveform 200, which tissue location to deliver the energy to, e.g., a location determined by analyzing cardiac mapping data, which external electrode 60 to deliver the electroporation waveform 200 to direct the generated electric field to the target tissue, and combinations of two or more of these.

[0087] In some embodiments, algorithm 25 is configured to determine one or more parameters of the stimulation waveform. In these embodiments, algorithm 25 can include one or more biases, such as a bias to generate a stimulation waveform with the following trends: A particular frequency range, a particular ratio of bipolar to unipolar energy delivery, a particular phase difference between the included sine waves, a particular voltage or voltage range, a particular delay between energy deliveries such as a particular inter-pulse delay, and any combination of one or more of these.

[0088] As used herein, the term "signaling" refers to one or more signals provided by controller 110 and includes information interpreted by signal generator 120 or, optionally, by another component of system 10. The signaling can be provided by one or more wired connections and / or wireless modes of data communication. As noted above, the signaling can be provided to signal generator 120, as in the embodiment of FIG. 1, and / or it can be provided to the power source itself, which is configured to generate an electroporation waveform as described herein.

[0089] In some embodiments, algorithm 25 can 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, such as catheter 300. Method 510 can include providing signaling from controller 110 to signal generator 120. The signaling can be configured to cause signal generator 120 to generate electroporation waveform 200. The electroporation waveform can include multiple pulses. Each energy pulse is separated by an inter-pulse delay period, such as energy pulses 210 separated by inter-pulse delay period 220, as shown in FIG. 2 and described herein. In some embodiments, each energy pulse can include one or more separate sinusoidal signals, as described herein. Method 510 can further include generating the electroporation waveform based on the signaling (e.g., signal generator 120 can generate electroporation waveform 200 based on signaling from controller 110). The method 510 can include providing the electroporation waveform 200 from a signal generator to an electroporation catheter, such as catheter 300, to provide the electroporation waveform 200 to a target region.

[0090] In some embodiments, algorithm 25 can be configured to cause system 10 to perform a method 520 for providing an electroporation waveform and one or more compensation signals, as described below with reference to FIGS. 5-7 . In some embodiments, method 520 includes providing signaling (e.g., signaling from controller 110) to cause an electroporation waveform 200 to be provided. The electroporation waveform 200 includes one or more energy pulses 210 provided sequentially. Each energy pulse 210 is configured to cause electroporation. Method 520 can further include providing signaling 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 a treatment location on the patient. The accumulated charge is caused by one or more of the multiple stimulation signals (e.g., the multiple energy pulses 210). In some embodiments, the controller 110 can be configured to provide this signaling to the signal generator 120 to cause the signal generator 120 to provide an electroporation waveform 200 that includes an energy pulse and a charge-reducing compensation signal. In some embodiments, the compensation signal is added to the electroporation waveform 200.

[0091] In some embodiments, algorithm 25 can be configured to cause system 10 to perform method 530. Method 530 can include providing first signaling configured to cause application of 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 non-adjacent (e.g., non-adjacent) to the first electrode. Method 530 can further include providing second signaling configured to cause application of a second potential difference between a third electrode and a fourth electrode (e.g., third electrode 311 and fourth electrode 311 of catheter 300) when the third electrode is adjacent (e.g., adjacent) to the first electrode and the fourth electrode is non-adjacent to the third electrode. In some embodiments, the first potential difference is applied between the first electrode and the second electrode asynchronously from application of the second potential difference between the third electrode and the fourth electrode. The method 530 can be applied across multiple electrodes and electrode pairs, resulting in a contiguous cell ablation lesion.

[0092] Signal generator 120 may include any suitable signal generator for generating an electroporation waveform including an electrical signal for energizing one or more electrodes 311 of catheter 300. That is, the electroporation waveform is configured to cause application of a voltage field to biological tissue via electrodes 311 of catheter 300. In particular, signal generator 120 may include a sine wave generator configured to generate a signal including one or more sine waves. Power source 130 may include any suitable device for supplying power to at least signal generator 120.

[0093] The catheter 300 can include a plurality of electrodes 311 (e.g., electrodes 311 of an electrode array 310 described herein). The electrodes 311 can be positioned either on or near the target tissue to be electroporated by the system 10. The electrodes 311 can be configured such that a potential difference is generated between activated electrodes 311 in response to an electroporation waveform provided thereto.

[0094] In some embodiments, system 10 and / or one or more components of system 10 further include one or more functional elements (herein “functional elements”), each of which is shown as functional element 99, functional element 199 of generator 100, and / or functional element 399 of catheter 300. 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 the 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 such as ultrasonic flow sensors, gas detection sensors such as ultrasonic bubble detectors, acoustic sensors such as ultrasonic sensors, impedance sensors, charge sensors, and combinations thereof. Each functional element may include a physiological sensor selected from the following group: Pressure sensors such as blood pressure sensors, blood gas sensors, flow sensors such as blood flow sensors, temperature sensors such as blood or other tissue temperature sensors, and combinations thereof. In some embodiments, system 10 may further comprise one or more algorithms, such as algorithm 25 described herein, configured to process signals generated by the sensor-based functional elements. Each functional element may comprise one or more transducers. Each functional element may include one or more transducers selected from the group consisting of: heating elements, such as a heating element configured to provide heat sufficient to ablate tissue; cooling elements, such as a cooling element configured to provide cryogenic energy to ablate tissue; acoustic transducers, such as an ultrasonic transducer; vibration transducers; and combinations thereof. In some embodiments, functional element 399 includes one or more vacuum ports fluidly connected (e.g., via a lumen of catheter 300) to functional element 199 that includes a vacuum source. In these embodiments, vacuum can 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 maintained in contact with tissue via the applied vacuum.

[0095] Referring now to FIG. 2, some example electroporation waveforms are shown consistent with the concepts of the present invention. In some embodiments, the waveform of FIG. 2 includes a series of energy pulses with a fixed inter-pulse delay, e.g., as described herein. FIG. 2 illustrates an exemplary electroporation waveform 200 including multiple energy pulses 210 and multiple inter-pulse delay periods 220. Each period 220 is positioned between pairs of energy pulses 210 such that the energy pulses 210 are spaced apart in time. A single cycle 230 of the electroporation waveform 200 can be defined 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 multiple cycles 230, bursts 240. It will be understood that this is merely an example, as a cycle 230 can be equally defined between any two similar points on consecutive energy pulses 210 or consecutive delay periods 220. In FIG. 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 portions, such as a fixed inter-pulse delay period 2201 and a variable inter-pulse delay period 2202, not shown but as described in FIG. 4A and herein.

[0096] In some embodiments, system 10 is configured to provide a first portion of electroporation waveform 200 from a first set of electrodes 311 and a second portion of electroporation waveform 200 from a second set of electrodes 311, such as delivering electroporation waveform 200 in an interleaved pattern, as shown in FIGS. 18A-C and described herein. In some embodiments, burst 240 can include a first set of energy pulses, energy pulse 210m, and a second set of energy pulses, energy pulse 210n. Energy pulse 210m is delivered from the first set of electrodes 311 (e.g., electrodes 311a, c shown in FIG. 15). Energy pulse 210n is delivered from the second set of electrodes 311 (e.g., electrodes 311b, d shown in FIG. 15). In some embodiments, each cycle 230 can include energy pulse 210m and energy pulse 210n. Electrode 311b is positioned between electrodes 311a, 311c, as described below, and electroporation waveform 200 is provided in an interleaved pattern from non-adjacent electrodes. In some embodiments, an inter-pulse delay period 220 comprises the duration between a first set of energy pulses 210 delivered from a first set of electrodes 311 (e.g., energy pulse 210m). In some embodiments, at least a second energy pulse 210 (e.g., energy pulse 210n) is delivered from a second set of electrodes 311 within the inter-burst delay period 220 of the first set of energy pulses 210m. The inter-pulse delay period 220 can include an interleaving offset period 2203. The interleaving offset period 2203 comprises 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 interleaving offset period 2203 comprises a period equal to one-half the inter-pulse delay period 220, such that each energy pulse 210 (e.g., energy pulses 210m and 210n) is delivered at an equal frequency, as shown, for example, in FIG. 18B.Alternatively or additionally, the interleaving offset period 2203 may comprise a period less than half the duration of the inter-pulse delay period 220, such that the energy pulses 210m and 210n are delivered within the first half of the cycle 230, as shown, for example, in FIG. 18C.

[0097] In some embodiments, the system 10 is configured to provide portions of the electroporation waveform 200 to two, three, four, or more sets of electrodes 311 in an interleaved pattern. For example, a first portion, energy pulse 210m, of the electroporation waveform 200 may be delivered via each third electrode 311, such as electrodes 311-1, 4, 7, and 10 (e.g., electrodes 311 of a linear array 310 of consecutively numbered electrodes 1 through 12). A second portion, energy pulse 210n, may be delivered from electrodes 311-2, 5, 8, and 11. A third portion, energy pulse 210o, may be delivered from electrodes 311-3, 6, 9, and 12. A cycle 230 may include one delivery of each energy pulse 210m, n, o. In some embodiments, the interleaving offset periods 2203 between energy pulses 210m, n and 210n, o may include similar and / or different time periods. 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) of the energy pulse cycle 230 can include a period that is shorter than the refractory period of the action potential (AP) elicited by the first energy pulse 210m, for example, as shown in FIG. 18C and described herein.

[0098] As defined herein, electroporation waveform 200 includes all waveforms provided for the application of reversible electroporation, irreversible electroporation, or both. In one or more embodiments, electroporation waveform 200 can be an ablation waveform that includes ablation pulses configured to cause cell death via irreversible electroporation.

[0099] The electroporation waveform 200 can include multiple energy pulses 210. In some embodiments, each energy pulse 210 includes one or more separate sinusoidal signals. For example, the electroporation waveform 200 can include multiple energy pulses 210. Each energy pulse 210 includes multiple separate sinusoidal signals. It will be understood that the phrase "separate sinusoidal signals" is used herein to define multiple sinusoidal signals that are distinguishable from one another. This configuration of signals can relate to completely separate sinusoidal waves in that they begin at a reference voltage, pass through a reference voltage, and end at substantially the same reference voltage before the next sinusoidal wave begins. The reference voltage can be 0 volts, although it is also possible for the reference voltages to have different values. Separate sinusoidal waves can also relate to partially overlapping sinusoidal waves, where the sinusoidal waveforms of each sinusoidal wave are distinguishable. Sine waves that overlap in a constructively interfering manner to produce a summed sine wave of greater amplitude, or that form a sine wave or other waveform with a wider linewidth than any of the original sine waves (e.g., if the constituent sine waves are not individually distinguishable), are not necessarily considered separate sine wave signals. In some embodiments, each energy pulse 210 can include a single separate sine wave. It will be understood that "single separate sine wave" defines that only one separate sine wave is provided, with no other distinguishable sine waves present within each energy pulse 210. This configuration does not prohibit multiple sine waves from overlapping with each other, provided that the overlapping of the sine waves provides a valid single separate sine wave, as defined above. In an example where a single separate sine wave is used in each energy pulse 210, the frequency of the single separate sine wave is between 20 kHz and 200 kHz, and the amplitude is between 500 V and 3 kV, which provides a maximum to minimum amplitude difference of 1 kV to 6 kV. The frequency may specifically be approximately 50 kHz. It will be appreciated that the sine wave may be applied to two electrodes (e.g., two adjacent or non-adjacent electrodes 311) and / or two groups of one or more electrodes to provide a potential difference therebetween.When the phase difference between the sine wave applied to the first electrode (or first electrode group) and the sine wave applied to the second electrode (or second electrode group) is 0 degrees, the resulting signal is unipolar, e.g., as described herein. When 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 resulting signal is bipolar, e.g., as described herein (e.g., when no signal is applied to the outer electrode 60). Alternatively, the phase difference can have another value that results in a signal having both unipolar and bipolar components, e.g., when configured for phase-coupled energy delivery, as described herein.

[0100] The electroporation waveform 200 can include a pulse waveform, and the signal between the start of a first pulse and the start of a subsequent pulse can be defined as a single cycle 230 of the electroporation waveform 200. The delivery of an energy pulse 210 to the electrode 311 of the catheter 300 provides the generation of a potential difference, which in turn generates an electric field that causes the desired electroporation. It will be understood that causing electroporation can refer to causing reversible or irreversible electroporation. Between the first energy pulse and a subsequent energy pulse, there can be an inter-pulse delay period 220 during which no energy pulse 210 is delivered. It will be understood that, while noise or other signals can be delivered during the inter-pulse delay period 220, no pulses having pulse characteristics suitable for stimulating electroporation are delivered during the delay period 220. Providing a pulse that does not cause electroporation during the inter-pulse delay period 220 can allow for, for example, the delivery of an offset pulse that is provided to counteract charge buildup in the patient due to the aforementioned pulse. By providing an inter-pulse delay period 220 that does not cause electroporation, a reduction in microbubbles can be achieved compared to systems that do not provide such an inter-pulse delay period 220. In some embodiments, the inter-pulse delay period 220 is of sufficient duration so that the electroporation waveform 200 includes a series of energy pulses 210 and the electroporation waveform 200 provides pulsed ablation energy as opposed to continuous wave ablation energy. For example, the inter-pulse delay period 220 can be at least 10 ms, e.g., up to 25 ms. For example, the percentage of a single cycle 230 in which an energy pulse 210 is provided can be 5%, 4%, 3%, 2%, 1%, or a different percentage (e.g., 5% or less) of the cycle 230. In particular, the percentage of a single cycle 230 in which an energy pulse 210 is provided can be at least 0.1%, at most 0.3%, and / or nominally 0.2%.

[0101] In summary, a single cycle 230 of the electroporation waveform 200 can include an energy pulse 210 (e.g., an energy pulse including one or more distinct sine waves) followed by an inter-pulse delay period 220 during which no electroporation-inducing energy pulse 210 is provided.

[0102] Furthermore, the amplitude and frequency of each energy pulse 210 may be sufficient to provide ablation of the target tissue. In such cases, the energy pulse 210 may be referred to as an ablation pulse 210. For example, the pulse frequency may be at least a minimum frequency of X kHz and / or a maximum frequency of Y kHz. The amplitude may be between a minimum voltage of at least M volts and / or a maximum voltage of N volts. By way of example only, the inter-pulse delay period may be between a minimum of 2 ms and / or a maximum of 2000 ms. In other embodiments, the inter-pulse delay period 220 may be at least 15 ms and / or 100 ms, such as when the period 220 is at least 15 ms and / or 50 ms.

[0103] 3, some examples of electroporation waveforms consistent with the concepts of the present invention are shown. The electroporation waveform 200 of FIG. 3 can include multiple bursts 240, such as the bursts 240 shown in FIG. 2. In some embodiments, the electroporation waveform 200 of FIG. 3 includes one or more time interval groups, or sequences 250, of the bursts 240. Each sequence 250 can include a series of one, two, or more bursts 240, with each burst 240 separated by an inter-burst delay period 260. In some embodiments, the electroporation waveform 200 can include two or more sequences 250, such as two or more sequences 250 each separated by an inter-sequence delay period 270.

[0104] As described herein, a burst 240 can include one or more energy pulses 210, each separated by an inter-pulse delay period 220. The inter-pulse delay period 220 can include both fixed and variable periods (e.g., fixed and variable periods that together define the duration of the inter-pulse delay period 220), such as the fixed inter-pulse delay period 2201 and variable inter-pulse delay period 2202 described herein. A sequence 250 can include one or more bursts 240, each separated by an inter-burst delay period 260. The inter-burst delay period 260 can include fixed and / or variable delay periods (e.g., fixed and variable periods that together define the duration of the inter-burst delay period 260). An electroporation waveform 200 (e.g., a waveform 200 provided to tissue as a whole in a single energy delivery process) can include one or more sequences 250, each separated by an inter-sequence delay period 270. The inter-sequence delay period 270 may include a fixed delay period and / or a variable delay period (eg, a fixed and variable period that together define the duration inter-sequence delay period 270).

[0105] Each energy pulse 210 can include at least one distinct sine wave. In some embodiments, the energy pulse 210 includes 50 or fewer distinct sine waves, e.g., 10 or fewer distinct sine waves. In some embodiments, one or more energy pulses 210 of the electroporation waveform 200 (e.g., two consecutive energy pulses 210 of a burst 240) include different numbers of distinct sine waves. In some embodiments, the number of sine waves in the energy pulse 210 is variable, such as by the amount of sine waves generated pseudo-randomly (e.g., pseudo-random numbers generated by the algorithm 25) and / or the number of sine waves in the energy pulse 210 is determined by the system 10 (e.g., determined by the algorithm 25 based on one or more system and / or patient parameters, such as based on the temperature of the tissue-proximate electrode 311). For example, in some embodiments, a functional element (e.g., functional element 99), such as a functional element including a thermocouple, is used to monitor the temperature of one or more electrodes 311 of the catheter 300. The energy pulses 210 can be delivered at a rate of at least one energy pulse per cardiac cycle and / or at a rate of no more than 100 energy pulses per cardiac cycle, e.g., at a rate of about 50 energy pulses per cardiac cycle. In some embodiments, the delivery rate can 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 can be configured to decrease the rate of pulses per cardiac cycle (e.g., decrease the rate proportionally to the recorded temperature). In some embodiments, if the recorded temperature falls below the threshold, the rate can be increased (e.g., increase to the original rate). In some embodiments, the threshold temperature can include a temperature of at least 38°C and / or no more than 80°C.

[0106] The inter-pulse delay period 220 can include a period of at least 1 ms, such as at least 15 ms. In some embodiments, the inter-pulse delay period 220 can include a period of 2000 ms or less, such as 60 ms or less.

[0107] The interleaving offset period 2203 may include a period of at least 0.5 ms, hi some embodiments, the interleaving offset period 2203 may include a period of 2 ms or less.

[0108] The inter-burst delay period 260 can include a period of at least 100 ms or less, hi some embodiments, the inter-burst delay period 260 can include a period of 5000 ms or less.

[0109] Inter-sequence delay period 270 may include a period of at least 2000 ms, such as at least 5000 ms. In some embodiments, inter-sequence delay period 270 includes a period of 20,000 ms or less, such as 10,000 ms or less.

[0110] The controller 110 can be further configured to set the inter-pulse delay period 220 based on the received conductivity measurement data. Selection of the inter-pulse delay period 220 can be achieved by retrieving the inter-pulse delay period 220 from a lookup table based on the conductivity measurement. Such a lookup table can be stored in a memory as part of the controller 110 (e.g., stored in memory 112) or in a memory separate from the controller 110 with which the controller 110 is in communication. Alternatively, any other suitable method for retrieving the inter-pulse delay period 220 based on the received conductivity measurement can be used. Providing selection of the inter-pulse delay period 220 based on the received conductivity measurement allows the inter-pulse delay period 220 to be tailored to the target tissue being ablated. In this case, the conductivity measurement is that of the target tissue. This configuration can be beneficial because the conductivity of different types of tissue can affect microbubble formation, and therefore the inter-pulse delay period 220 may need to be increased to avoid or reduce microbubble formation. Alternatively, certain types of tissue may be less prone to microbubble formation, and therefore the inter-pulse delay period 220 may be reduced without significantly increasing microbubble formation.

[0111] The received conductivity measurement data can be received in response to the controller 110 providing signaling to a conductivity sensor (e.g., functional element 99 and / or 399 including one or more conductivity sensors) configured to cause the conductivity sensor to perform a conductivity measurement. The controller 110 can be further configured to receive the conductivity measurement data from the conductivity sensor. Alternatively, the conductivity measurement data can be received from a user input device. Thus, the controller 110 can be configured to receive the conductivity data by controlling an external conductivity sensor or by user input. This can provide variable functionality to the user depending on the status or availability of the coupled conductivity sensor, or can provide backup redundancy in case the conductivity sensor is not functioning properly.

[0112] Additionally, Figures 3A-3D show graphs of harmonics at various frequencies under various conditions consistent with the concepts of the present invention. Figure 3A shows an example of harmonics at fixed cycle lengths when supplied to an ideal resistive load. Figure 3B shows a representative example of the reduction in harmonics at fixed cycle lengths when supplied to an ideal resistive load. 20 cycles of evenly stepped distribution are used to broaden the spectrum. The reduction is approximately 12 dB at each harmonic. Figure 3C shows an example of harmonics at fixed cycle lengths when supplied to a representative nonlinear load. Figure 3D shows a representative example of the reduction in harmonics at fixed cycle lengths when supplied to a representative nonlinear load. 20 cycles of evenly stepped distribution are used to broaden the spectrum. The reduction is approximately 12 dB at each harmonic.

[0113] In some embodiments, energy pulses 210, separated by an inter-pulse delay period 220, generate energy at a frequency that is the inverse of the inter-pulse period frequency. For example, a 20 ms inter-pulse period generates a 50 Hz frequency at its even harmonics. PFA energy pulses combined with this low pulse repetition frequency are functionally amplitude-modulated (AM) signals; the PFA energy pulses are square-wave AM modulated by the pulse repetition frequency. Most tissues exhibit partial or total nonlinear responses to this form of energy delivery, and just as nonlinear circuit elements such as diodes can rectify and demodulate AM radio waves, muscle stimulation is possible if the pulse repetition frequency is sufficiently low, sufficiently periodic, and of sufficient amplitude. By varying the period using a variable inter-pulse delay, the resulting low-frequency spectrum can be broadened, thus reducing the amplitude at any given frequency (e.g., reducing the likelihood of muscle stimulation). Figures 3A-D illustrate this reduction in harmonics.

[0114] In some embodiments, the system 10 is configured to generate ablated tissue lesions by delivering an electroporation waveform 200 to tissue via electrodes 311 of the catheter 300 and / or external electrodes 60 (e.g., one or more patch electrodes placed on the patient's skin). For example, the system 10 can deliver monopolar energy pulses 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 burst (e.g., burst 240) of monopolar energy pulses 210 can include about three or four energy pulses 210, delivered together within 500 ms, such as within 250 ms. Monopolar energy delivery can produce ablated tissue lesions having a lesion depth of at least 5 mm, such as at least 10 mm, 15 mm, or 20 mm.

[0115] In some embodiments, system 10 is configured to deliver energy pulse 210, where the energy pulse comprises a voltage of at least 1500 V, e.g., at least 2000 V and / or 4000 V or less, e.g., 3500 V or less. As described herein, in some embodiments, energy pulse 210 can include at least a first signal provided to at least a first electrode and at least a second signal provided to at least a second electrode. As used herein, monopolar energy delivery can include energy delivery where a first signal is provided to a first internal electrode (e.g., an electrode positioned endocardially) such as electrode 311 positioned proximate to the target tissue, and a second signal is provided to a patch electrode (e.g., an external electrode 60 positioned away from the target tissue, such as the patient's skin) such as external electrode 60. Bipolar energy delivery can include energy delivery in which a first signal is provided to a first internal electrode (e.g., an electrode positioned endocardially), such as first electrode 311 positioned proximate to the target tissue, and a second signal is provided to the first electrode 311 and a second internal electrode (e.g., an electrode positioned endocardially), such as second electrode 311 positioned proximate to the target tissue. When energy is delivered in a bipolar manner, no signal is supplied to a patient patch including an electrode, such as external electrode 60, and the only electrical potential generated by the delivery of the electrical signal is generated between the first and second electrodes 311. Phase-coupled energy delivery can include energy delivery in which a first signal is provided to the first internal electrode 311 and a second signal is provided to the second internal electrode 311, and can include a third signal, where the third signal includes a reference signal provided to one or more patch electrodes, such as external electrode 60. When energy is delivered in a phase-coupled energy delivery manner, a primary electric field is generated between the first and second electrodes 311, and a secondary electric field is generated between each of the first and second electrodes 311 and an external electrode 60 (e.g., one or more patch electrodes placed at one or more locations on the patient's skin). In some embodiments, the first and second signals comprise sine waves, and the phase angle between the sine waves can be between 0° and 180°.The phase angle between the first and second signals can be adjusted to change the relative strength of the primary electric field generated between the first electrode 311 and the second electrode and the secondary electric field generated between the first electrode 311, the second electrode, and the 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 (approaching 0°), the electric field strength of the primary electric field decreases because the potential difference between the first electrode 311 and the second electrode 311 decreases. Unipolar, bipolar, and phase-coupled energy delivery can be configured as described with reference to Figures 19A-C and elsewhere herein.

[0116] In some embodiments, the energy pulse 210 of the electroporation waveform 200 comprises a sine wave, for example, as described herein. In some embodiments, the cycle length of the sine wave is at least 1 ms, such as at least 10 ms, and / or 200 ms or less, such as 50 ms or less. In some embodiments, the number of sine waves per pulse (e.g., per energy pulse 210) is 10 or less, such as 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 cycles (e.g., cycles 230) of the electroporation waveform 220 required to generate the maximum achievable lesion in tissue is at least 30 cycles, such as at least 100 cycles, and / or 600 cycles or less, such as 300 cycles or less. In some embodiments, the burst 240 of the electroporation waveform 200 comprises a length of 250 ms or less, such that the electroporation waveform 200 can be provided in a manner synchronized with the ventricular refractory period to reduce ventricular activation.

[0117] Reference is now made to the figures. Figures 4 and 4A show experimental results consistent with the concepts of the present invention and graphs of a portion of an electroporation waveform, respectively. Figure 4 shows example experimental results providing microbubble formation measured in total sinusoidal cycle length along the x-axis and nanoliters along the y-axis. Four measurements were taken under each cycle length condition, with the average microbubble formation volume indicated by the bar and accompanying number on the diagram. The error for each measurement is provided by the error bars provided. In this experiment, the duration of the energy pulse 210 does not change between cycle lengths; therefore, in these cases, the cycle length is directly proportional to the inter-pulse delay period 220. As can be seen, microbubble formation decreases by more than fivefold when moving from a low (0.5 ms to 5 ms) cycle length to a moderate (5 ms to 30 ms) cycle length. An even greater reduction in microbubble formation is achieved when moving to an improved cycle length (30 ms to 100 ms).

[0118] 4A illustrates a portion of an embodiment of an electroporation waveform 200, such as the electroporation waveform 200 illustrated in FIG. 1 and described herein. 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 portions: 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 and the duration of the variable inter-pulse delay period 2202. The duration of the variable inter-pulse delay period 2202 can be positive and / or negative in duration, such that the inter-pulse delay period 220 is longer and / or shorter, respectively, 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, in which case the resulting integral over time is equal to the value of the fixed inter-pulse delay period 2201. For example, a 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 with a fixed inter-pulse delay period 2201 of 30 ms and a first variable inter-pulse delay period 2202 of +5 ms. A second subsequent 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 with a fixed inter-pulse delay period 2201 of 30 ms and a second variable inter-pulse delay period 2202 of −5 ms. In this example, the first and second variable inter-pulse delay periods 2202 are symmetric about zero (+ / − 5 ms, respectively) such that the average inter-pulse delay period 220 between the first, second, and third energy pulses 210 is equal to the fixed inter-pulse delay period of 30 ms, in this example. In other words, in this example, the first variable inter-pulse delivery period 2202 can have a duration equal to the absolute value of the duration of the second variable inter-pulse delay period. The variable inter-pulse delay periods 2202 can vary each period by an amount that can be either fixed or variable, such as a pseudo-random value (e.g., a pseudo-random value calculated by algorithm 25).

[0119] The first inter-pulse delay period 220 between the first energy pulse 210 and the second subsequent 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 following the second energy pulse 210. That is, the inter-pulse delay period 220 can vary in duration from cycle to cycle 230. In some embodiments, multiple inter-pulse delay periods 220 in an electroporation waveform 200 can include inter-pulse delay periods 220 that are different from one another. In yet other embodiments, each inter-pulse delay period 220 in an electroporation waveform 200 can have an inter-pulse delay period 220 that is different from the other inter-pulse delay periods 220.

[0120] In some embodiments, 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 appreciated that the fixed period can be of positive or negative duration, such that successive inter-pulse delay periods 220 are steadily longer or shorter. That is, the inter-pulse delay periods 220 can increase or decrease in steps. This configuration can start with a nominal inter-pulse delay period 220 and vary from that point on. 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, and successive electroporation waveforms 200 can include different inter-pulse delay periods 220, e.g., a first set of successive inter-pulse delay periods 220 of a first electroporation waveform 200 can include incrementally increasing inter-pulse delay periods 220, followed by a second set of successive inter-pulse delay periods 220 of a second electroporation waveform including incrementally decreasing inter-pulse delay periods 220. Thus, over time, a series of electroporation waveforms 200 can provide sets of energy pulses 210 separated by inter-pulse delay periods 220 that vary for each successive electroporation waveform 200 in order to reduce the effects of harmonic stimulation.

[0121] 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., 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, it is possible for a first inter-pulse delay period to have the same duration as a second inter-pulse delay period. However, the likelihood of multiple selected pseudo-random numbers being the same can be extremely small, depending on the range of unique numbers that can be selected among the set of pseudo-random numbers. Thus, in many embodiments, it is extremely unlikely that two inter-pulse delay periods 220 of the electroporation waveform 200 will have the same duration, and in particular, it is extremely unlikely that two consecutive inter-pulse delay periods 220 will have the same duration. In one or more embodiments, the controller can be configured to prevent consecutive delay periods from having the same duration.

[0122] 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 sum to provide a 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, and 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 approach to providing a pseudo-random number-based delay period.

[0123] The pseudo-random number can have a value between -1 and 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 multiplied by a scaling factor, where the scaling factor is the pseudo-random number. In other embodiments, the scaling factor can have a value between 0 and 1, or any other value. By using a pseudo-random number with a value between -1 and 1, it is possible to obtain 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.

[0124] In other embodiments, there may be no fixed inter-pulse delay period 2201; instead, the inter-pulse delay period 220 may be entirely variable based on pseudo-random numbers. While pseudo-random numbers are primarily described herein, it will be further understood that true random numbers may alternatively and equivalently be used. True random numbers may be obtained via a white noise generator or other suitable means, although such an approach is generally computationally expensive and may otherwise be undesirable.

[0125] In general, whether each inter-pulse delay period 220 is based on a random number generator, a pseudo-random number generator, or a step variation of the inter-pulse delay period, there can be a fixed minimum difference between different total cycle lengths depending on the inter-pulse delay period 220. For example, the cycle length can vary by 30, 40, or 50% from the nominal cycle length value. The minimum difference in cycle length can be between 0.3 and 10% of the nominal cycle length. For example, if there is an electroporation waveform including 16 cycles with a nominal cycle length of 20 ms, 16 steps from 15 ms to 25 ms can be used, with a 0.625 interval between the different cycle lengths. This configuration can be converted to a step size of 3.125% of the nominal cycle length. As a further example, if there is an electroporation waveform including 24 cycles and a nominal cycle length of 20 ms, 24 steps from 15 ms to 25 ms can be used, with a step size of approximately 2% of the nominal cycle length.

[0126] Referring now to FIG. 5, a plot of stimulus intensity versus duration is shown consistent with the concepts of the present invention. FIG. 5 illustrates an example plot of stimulus duration along the x-axis and stimulus intensity along the y-axis. 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, but the same trend follows when stimulus intensity is voltage. Cardiac or muscle cell stimulation is a function of both the amplitude of the applied stimulus and the duration of time the stimulus is applied. The rheobase can be defined as the stimulus intensity that causes stimulation of infinite duration, which in practice is approximately 300 milliseconds. The chronaxie is defined as the minimum stimulus duration that produces stimulation at a stimulus intensity twice the rheobase. Intensity-duration pulses that fall above or to the right of the plotted intensity-duration curve will produce stimulation, while those below or to the left of the line will not produce stimulation.

[0127] In pulsed field ablation (PFA), stimulation duration for effectiveness is a trade-off between field strength and duration. Because shorter pulses require greater pulse field strength to achieve a similar depth of treatment, ideally, the pulse field frequency is selected to be as low as possible but above the chronaxie. Multiple repetitions of pulsed field energy in an electroporation waveform at these frequencies can produce durable lesions while avoiding muscle stimulation, cardiac stimulation, or both. Simulations performed by the applicant show that even with a theoretically perfect biphasic square wave below the chronaxie, inherent tissue nonlinearities result in residual charge. If subsequent energy pulses in the electroporation waveform are repeated rapidly enough, this residual charge can integrate over time and lead to undesired stimulation.

[0128] To avoid stimulation of muscle or cardiac tissue, the controller 110 of the system 10 (e.g., the system 10 of FIG. 1 and described herein) may alternatively or additionally be configured to provide a charge accumulation compensation scheme as described below.

[0129] To provide an electroporation waveform 200 that provides charge accumulation compensation (e.g., the electroporation waveform 200 described in FIG. 1 and herein), the controller 110 can be configured to provide one or more time-spaced energy pulses 210, each energy pulse 210 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.

[0130] The controller 110 can also be configured to provide signaling configured to provide one or more compensation signals as part of the electroporation waveform 200. The compensation signals are configured to reduce charge buildup at the target treatment site of the patient caused by one or more of the multiple energy pulses 210. The compensation signals can be configured to reduce charge buildup by having a predetermined polarity. The polarity can be opposite to the polarity of the charge buildup. The opposite polarity can be, for example, opposite to the average polarity of each energy pulse 210 or the average polarity of the multiple sequential energy pulses 210.

[0131] A non-zero average polarity of each energy pulse 210 can occur when each energy pulse 210 includes one or more monophasic pulses, each of which includes a unique, predetermined polarity. In other embodiments, the energy pulses 210 can include one or more biphasic signals, such as a biphasic square wave signal and / or a biphasic sine wave signal. The one or more biphasic signals can include an average polarity that can result, for example, from an asymmetry in the intensity of the positive and negative portions of the signal. Asymmetry in the biphasic energy pulse 210 can result in charge accumulation in the target tissue. Even with a completely uniform, bipolar energy pulse 210 that includes a net-zero average polarity, charge accumulation in the target tissue can still occur because the inherent nonlinearity of the tissue can result in residual charge accumulation.

[0132] Cathodic pulses are more likely to cause stimulation of muscle or cardiac tissue than anodic pulses, so the compensation signal, in some embodiments, can include anodic pulses to counteract the buildup of charge resulting from cathodic energy pulses.

[0133] Referring to FIG. 6, an example of an electroporation waveform including a compensation signal is shown consistent with the concepts of the present invention. FIG. 6 illustrates an example of an electroporation waveform, such as the electroporation waveform 200 of FIG. 1. The electroporation waveform 200 can include one or more monophasic energy pulses, monophasic energy pulse 2101 (e.g., when the energy pulse 210 includes a monophasic energy pulse 2101), and one or more compensation signals, compensation signal 2102. The compensation signal 2102 can be a monophasic or biphasic compensation signal. For a monophasic compensation signal 2102, the polarity is determined by whether the signal includes a positive or negative amplitude. For a biphasic signal, the polarity of the signal can be defined by whether the signal initially includes a positive or negative amplitude. The frequency and pulse width of the biphasic 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 20% or less of the amplitude of the corresponding monophasic energy pulse 2101. Alternatively, the amplitude of the compensation signal 2102 can be, for example, at least 5% and / or 15% or less of the amplitude of the corresponding monophasic energy pulse 2101. Furthermore, the amplitude of the compensation signal 2102 can be approximately 10% of the amplitude of the corresponding monophasic energy pulse 2101.

[0134] Referring to Figure 7, an example of an electroporation waveform including a compensation signal is shown consistent with the concepts of the present invention. Figure 7 shows an example of an electroporation waveform, such as electroporation waveform 200 of Figure 1. Electroporation waveform 200 can include one or more biphasic energy pulses, biphasic energy pulse 2103 (e.g., if energy pulse 210 includes biphasic energy pulse 2103), and one or more compensation signals 2102. As can be seen, in this example, the polarity of compensation signal 2102, including biphasic compensation signal 2102, is opposite to the polarity of biphasic energy pulse 2103.

[0135] In some embodiments, a compensation signal 2102, including a monophasic compensation signal 2102, can be provided to an electroporation waveform 200 that includes biphasic energy pulses 2103. The polarity of the compensation signal 2102 can be opposite to the average polarity of the biphasic energy pulses 2103. For example, each biphasic energy pulse 2103 can include a slight asymmetry in its waveform, resulting in an average polarity in the electroporation waveform 200 that can lead to charge accumulation at the treatment location. In other examples, not all biphasic energy pulses 2103 can include asymmetry, or the asymmetry of the biphasic energy pulses 2103 can vary slightly with each pulse, but over time there can be an average polarity of the electroporation waveform 200 that leads to 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 strength of the compensation signal 2102 can be insufficient to cause ablation of the target tissue, and instead is configured to primarily or solely reduce charge accumulation at the target treatment location. The compensation signal 2102 may not provide a therapeutic effect that counteracts the reduction of charge accumulation. In particular, the compensation signal 2102 can be configured to avoid causing electroporation at the target treatment location. By avoiding electroporation, such as avoiding irreversible electroporation, the compensation signal parameters are insufficient by themselves to cause cardiac or muscular stimulation.

[0136] The polarity of the compensation signal 2102 can be a "factory-set" polarity. Factory-set polarity may be appropriate, for example, when charge accumulation is known to have a particular polarity as a result of predetermined factors, such as the structure of the waveform 200 or the properties of the target tissue. In these embodiments, the factory-set polarity has a polarity opposite to the expected charge accumulation. The factory-set polarity is set at the time of manufacture or initial configuration of the device. The factor-set polarity of the compensation signal 2102 may be fixed and unchangeable, or it may be adjustable to a different type of polarity, such as a user-set polarity, at a later date.

[0137] Alternatively, the polarity of the compensation signal 2102 may be user-configurable. This allows a user to set the polarity of the compensation signal 2102 to a desired value as a result of the user's own observations of charge accumulation. The user may further control one or more other parameters of the compensation signal 2102. For example, the user may set the intensity, frequency, or linewidth of the compensation signal 2102. Additionally, the user may set a compensation signal delay for the compensation signal 2102, which controls the relative time that the compensation signal 2102 is provided after the start of the energy pulse 210. In some embodiments, the compensation signal 2102 may be provided simultaneously with at least a portion of the energy pulse 210, so it may be most useful to measure the time that the compensation signal 2102 is provided relative to the start of the energy pulse 210, rather than the end of the energy pulse 210.

[0138] In some embodiments, the polarity of the compensation signal 2102 can be based on measured charge accumulation at the target treatment location. For example, the controller 110 can be configured to receive signaling from a charge sensor (e.g., one or more electrodes 311, functional element 199 of the generator 100, and / or functional element 399 of the catheter 300 including and / or configured as a charge sensor) configured to detect charge accumulation at the target treatment location, such as the target tissue or nearby 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, can be configured to detect the magnitude of the charge accumulation in addition to any other useful parameter. The magnitude of the charge accumulation and any other parameter can also be provided to the controller 110 in addition to the polarity of the charge accumulation. The controller 110 can be configured to set the polarity of the compensation signal 2102 to be opposite to the polarity of the detected charge accumulation. The controller 110 can further control one or more other parameters of the compensation signal 2102 based on the signaling received from the charge sensor.

[0139] In one or more embodiments, the controller 110 can be configured to be switchable between different methods of setting the polarity of the compensation signal 2102. For example, the controller 110 can be configured to be switchable between two or more of: factory-set polarity, user-set polarity, and setting the polarity based on measured polarity.

[0140] At least one compensation signal 2102 can be provided before the charge accumulation reaches a predetermined threshold. The predetermined threshold of charge accumulation can be a level of charge accumulation that results in muscle stimulation when an energy pulse is delivered. That is, each energy pulse is configured with parameters such that neither muscle nor cardiac stimulation is induced without charge accumulation, and each energy pulse 210 is under chronaxie. Charge accumulation biases the effective charge experienced by the target tissue when the energy pulse 210 is applied. Thus, the threshold can be based on the minimum current of stimulation minus the stimulation intensity (amplitude) of the energy pulse for the duration of stimulation being used.

[0141] The controller 110 can be configured to determine (e.g., estimate, calculate, and / or otherwise determine) the total charge accumulation based on an expected charge accumulation derived from parameters of the energy pulse 210. Alternatively or additionally, the controller 110 can be configured to determine the total charge accumulation based on a signal received from a charge sensor. The charge sensor (e.g., one or more electrodes and / or functional elements described herein) can provide charge information to the controller 110 via a signal representative of one or more of the polarity, magnitude, and / or other parameters related to charge accumulation at or near the target tissue in the target treatment region. Thus, the controller 110 can be configured to determine the total charge accumulation based on one or more sensed parameters related to charge accumulation.

[0142] Based on the determined or estimated charge accumulation, the controller 110 can be configured to provide at least one compensation signal 2102 before the charge accumulation reaches a predetermined threshold. For example, the compensation signal 2102 can be provided after an energy pulse 210 to reduce the level of charge accumulation. Thus, by way of example, the compensation signal 2102 can be provided after a certain number of energy pulses 210, such as after 5, 10, 20, or 100 pulses 210.

[0143] In one or more embodiments, the controller 110 can 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 can be provided immediately after the energy pulse 210 or after an inter-ablation compensation delay, where the inter-ablation compensation delay is a period of time during which no ablation or compensation signal is provided between the provision of these two signals. That is, each compensation signal 2102 can be provided during a delay period between successive energy pulses 120. In this example, the compensation signal 2102 should not overlap any of the energy pulses 210.

[0144] Referring to FIG. 8, an example of an electroporation waveform including a simultaneous compensation signal is shown consistent with the concepts of the present invention. FIG. 8 illustrates an example of an electroporation waveform, such as electroporation waveform 200 of FIG. 1. In some embodiments, controller 110 is configured to cause provision of a compensation signal (e.g., compensation signal 2102 described herein) simultaneously with at least a portion of an energy pulse 210 (e.g., the illustrated biphasic energy pulse 2103), multiple ablation signals, or each ablation signal. In some embodiments, biphasic energy pulse 2103 can include at least one positive portion, positive portion 2104, and / or at least one negative portion, negative portion 2105. In some embodiments, positive portion 2104 includes a portion of biphasic energy pulse 2103 that exceeds a reference voltage REF, such as 0 V as shown, and / or a reference voltage greater than 0, such as a DC offset for biphasic energy pulse 2103, as shown. Similarly, the negative portion 2105 can include a portion of the biphasic energy pulse 2103 below a reference voltage REF, such as 0 V, as shown, and / or a reference voltage greater than zero, such as a DC offset of the biphasic energy pulse 2103. In some embodiments, the biphasic energy pulse 2103 includes a signal that includes only a positive signal, for example, 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 can be provided to constructively and / or destructively interfere with at least a portion of the corresponding biphasic energy pulse 2103. For example, a monophasic compensation signal 2102 can be provided to destructively interfere with each biphasic energy pulse 2103 during the second half of the biphasic energy pulse 2103, as in the example shown in FIG. 8 . In FIG. 8, compensation signal 2102 cannot be seen independently, but destructively interferes with negative portion 2105, such that negative portion 2105 includes a smaller amplitude than positive portion 2104, as shown (e.g., negative portion 2105 includes compensation signal 2102 as shown).This configuration results in the apparent amplitude of the negative portion 2105 of the energy pulse 210 having a reduced amplitude 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 can 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 (where the negative portion 2105 of the energy pulse 210 destructively interferes with the positive compensating signal 2102) can 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 0.8 A, as shown in the example of FIG. 8 . In other examples, the value of X may be greater than 1. This configuration may be where the compensation signal 2102 constructively interferes with the negative portion 2105 of the energy pulse 210 to provide an apparent intensity greater than amplitude A. It will be appreciated that in this example, amplitude A is the unadjusted amplitude of the biphasic energy pulse 2103 signal. Correspondingly, the compensation signal 2102 may be provided to overlap the positive portion 2104 of the energy pulse 210, or to overlap both the positive and negative portions 2104, 2105 of the energy pulse 210. The phrase "apparent intensity" is used above to refer to the measured intensity of the negative portion of the energy pulse that has been destructively interfered with by the compensation signal. This intensity may be different from the intensity of the negative portion when not interfered with, and therefore may provide an apparent intensity that is different from the intensity when not interfered with.

[0145] In yet other examples, some compensation signals 2102 may be provided sequentially after each of the energy pulses 210, and other compensation signals 2102 may be provided simultaneously with at least a portion of one or more energy pulses 210 of the electroporation waveform 200.

[0146] When the compensation signal 2102 includes a biphasic sinusoidal signal, the energy pulse 210 can include one or more separate sinusoidal signals. It should be understood that the term “separate sinusoidal signals” is used herein to define sinusoidal signals that are distinguishable from one another. This term can refer to sinusoidal waves that are completely separate from one another in that they begin at a reference voltage, pass through a reference voltage, and end at substantially the same reference voltage before the next sinusoidal wave begins. The reference voltage can be 0 volts, but it is also possible for the reference voltage to have different non-zero values. Separate sinusoidal waves can also refer to sinusoidal waves that partially overlap but whose sinusoidal waveforms are distinguishable. Sine waves that overlap in such a way that they constructively interfere to produce a summed sinusoidal wave of a larger amplitude, or sinusoidal waves that form a sinusoidal or other waveform with a wider period (e.g., linewidth) than either of the original sinusoidal waves, where the constituent sinusoidal waves are not separately distinguishable, are not necessarily considered separate sinusoidal signals.

[0147] While charge accumulation at a target treatment location is discussed herein in connection with the configuration of the compensation signal 2102, this discussion is provided to explain the purpose of the compensation signal 2102. Based on this goal, it will be understood that the compensation signal 2102 has specific parameters, such as polarity and signal strength, that provide the desired functionality. The presence of target tissue is not required for the controller 110 to provide signaling that triggers the delivery of both the energy pulse 210 and the compensation signal 2102.

[0148] 9A and 9B, respectively, show an anatomical side view of a catheter including multiple electrodes positioned adjacent to tissue and a display of the effective electric field generated by the electrodes, consistent with the concepts of the present invention. Other components of catheter 300 and / or system 10 described with reference to FIGS. 9A and 9B and herein may have a similar structure and arrangement to similar components described with reference to FIG. 1 and herein. FIGS. 9A and 9B show an exemplary electroporation catheter 300 including multiple electrodes 311, such as electrodes 311a and 311b, alternating along the length of the distal portion of catheter 300. FIGS. 9A and 9B illustrate a method of performing electroporation in which each of the electrodes 311 of electroporation catheter 300 has an alternating voltage applied thereto (e.g., as shown, an alternating voltage is applied to electrodes 311a and 311b) such that electroporation is applied simultaneously along a portion of electroporation catheter 300. An electric field 290 generated in this manner is shown in FIG. 9B. This method of performing electroporation can result in several high-temperature regions, such as the illustrated region 291, centered around each overlapping electrode 311, providing significant, undesirable heating of local tissue. The creation of the high-temperature regions 291 can also result in the formation of microbubbles, which further pose irreversible electroporation problems. The high-temperature regions 291 here refer to areas of locally increased heating around the electrodes. The presence of microbubbles can cause various types of problems for patients, such as cerebral microembolism.

[0149] 10A-10C show an anatomical side view of a catheter including multiple electrodes positioned near tissue and a display of the effective electric field generated by the electrodes, respectively, consistent with the concepts of the present invention. The catheter 300 and / or other components of the system 10 described with reference to FIGS. 10A-10C may be similar in structure and arrangement to the similar components described with reference to FIG. 1 and other similar components described herein. FIGS. 10A and 10B show the electrode 311 of the catheter 300 positioned near tissue, e.g., cardiac tissue. The catheter 300 may be operably attached to a signal generator, such as the signal generator 120 of the generator 100 described herein, but not shown. In some embodiments, the system 10 may be configured to operate asynchronously, such as by delivering sequentially interleaved bipolar and / or phase-coupled energy delivery, as described herein. FIG. 10C shows the aggregate results of the asynchronous energy delivery described herein.

[0150] The electroporation catheter 300 includes a plurality of electrodes 311 arranged sequentially along its length. The electroporation catheter 300 can include an elongated member, such as a distal portion of the array 310, having electrodes 311 along its length. In some embodiments, the elongated member can have the shape of a cylindrical rod having a circular cross-section or a cross-section of a different shape. The elongated member can be a straight elongated member, or the elongated member can have a curved portion defining at least a partial arc. Different configurations of the electroporation catheter 300 including non-linear elongated members are described with reference to FIGS. 13 and 14 or elsewhere herein. In embodiments including an elongated member, whether the electroporation catheter 300 is straight or not, sequential arrangement of the electrodes 311 means that the electrodes 311 are arranged one after the other such that no two electrodes 311 are located at the same longitudinal point along the length of the electroporation catheter 300. For example, as shown, electrodes 311 can include electrodes 311a-h positioned from distal to proximal along a distal portion of catheter 300. Electrodes 311a-h can include similar or different spacing, such as equal spacing along catheter 300 as shown (e.g., each electrode 311 is positioned equally spaced from each adjacent electrode). In some examples, electrodes 311 include spacing between each electrode ("electrode spacing") of 10 mm or less, such as about 6 mm electrode spacing or 3 mm electrode spacing.

[0151] In some embodiments, the electroporation catheter 300 can be shaped to include a two-dimensional grid of electrodes 311 thereon. That is, the two-dimensional grid of electrodes 311 can include a grid of 2×4 electrodes. In such embodiments, the plurality of electrodes 311 can be defined as being arranged contiguously or substantially contiguously in an arrangement in which they are arranged one after the other. This contiguous arrangement of electrodes 311 can include a subgroup of all electrodes on the electroporation catheter 300. In the example of a grid of 2×4 electrodes, a single line of electrodes 311 (a 1×4 subgrid of the 2×4 grid of electrodes) can be considered a contiguous arrangement of electrodes 311 in accordance with the present disclosure. As another example, a grid of 4×4 electrodes 311 can include several subgrids of electrodes 311 that can be activated in accordance with the present disclosure. It will be understood that one-dimensional grids, such as a 1×4 or 1×M array of electrodes 311, where M is an integer greater than or equal to 4, can also be considered a grid. The requirement for M to be greater than or equal to 4 is described in more detail below.

[0152] In a continuous array, or grid, of electrodes, each electrode 311a-h has at least one neighboring electrode 311 in the array. Neighboring electrodes 311, as used herein, include electrodes 311 adjacent to another electrode 311 without any intervening electrodes 311 between them. For example, in the case of a line of electrodes 311, electrodes 311 at either end of the line of electrodes 311, such as electrodes 311a and 311h, have a single neighboring electrode 311, such as electrodes 311b and 311g, respectively. Each of electrodes 311b-g that are not at the ends of a continuously arranged line of electrodes 311 has two neighboring electrodes 311. For electrodes 311 arranged in a two-dimensional grid, an electrode 311 at a corner of the grid has two neighboring electrodes 311 (one along the y-axis and one along the x-axis), a non-corner electrode 311 along the edge of the grid has three neighboring electrodes (two along the first axis and one along the second axis), and a non-corner, non-edge electrode 311 has four neighboring electrodes (one on either side of the electrode along each axis). For a given electrode 311 in the array of electrodes 311, any electrode 311 that is not a neighbor may be considered a non-neighboring electrode. An electrode 311 in the two-dimensional grid that is positioned diagonally from the electrode relative to the continuous array of electrodes defined by the controller may also be considered a non-neighboring electrode.

[0153] It will be appreciated that the controller 110 can be configured to individually address the electrodes 311a-h and provide signaling to individually control the application of voltages to the electrodes. Furthermore, each of the electrodes 311a-h is suitable for providing electroporation to target tissue at the target treatment location. In particular, the electrodes 311a-h are suitable for applying irreversible electroporation to target tissue at the target treatment location. In some embodiments, the controller 110 is configured to individually activate and send signals to multiple patch electrodes (e.g., an external electrode 60 including two or more patch electrodes).

[0154] As described herein, the controller 110 of the generator 100 can be configured to provide signaling configured to cause application of a first potential difference between one or more pairs of first electrodes (e.g., one or more pairs of electrodes 311 and / or electrodes 60) and one or more pairs of second electrodes (e.g., one or more pairs of electrodes 311 and / or electrodes 60). In some embodiments, the pair of first and second electrodes includes any electrodes of the system 10 configured to deliver energy to tissue, such as any endocardially placed electrode (e.g., electrode 311), an electrode of another catheter of the system 10, and / or a patient patch including an electrode such as the external electrode 60. For example, the controller 110 can be configured to provide signaling configured to cause application of a first potential difference (e.g., an energy pulse 210m described herein) between a first electrode 311a and a second electrode 311c of a plurality of consecutively placed electrodes 311a-h. The controller 110 can also be configured to provide signaling configured to trigger application of a second potential difference (e.g., an energy pulse 210n described herein) between a third electrode 311b and a fourth electrode 311d of the plurality of consecutively arranged electrodes 311a-h. 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 electrode adjacent to the first electrode 311a. In one or more embodiments, the fourth electrode 311d may also be an electrode adjacent to the second electrode 311c, although in some embodiments, the fourth electrode 311d may be an electrode not adjacent to the second electrode 311c. That is, the third electrode 311b can be disposed 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 an electrode 311a-h disposed between two other electrodes is not necessarily meant to be the only electrode disposed between those two electrodes, but defines its general placement relative to the other two electrodes.For example, if the third electrode 311b is disposed between the first electrode 311a and the second electrode 311c, a further electrode (e.g., a fifth electrode) can be disposed directly between the third electrode 311b and the second electrode 311c, and in such an example, the third electrode 311b would still be considered to be between the first electrode 311a and the second electrode 311c.

[0155] 10A shows an example of an electroporation catheter 300 in which a first potential difference (e.g., electroporation waveform 200) is applied between first electrode 311a and second electrode 311c, and no potential difference is applied between third electrode 311b and fourth electrode 311d. In some embodiments, a potential difference can also be applied between non-adjacent electrodes 311e and 311g (e.g., simultaneously with the first potential difference applied between electrodes 311a and 311c), and no potential difference is applied between non-adjacent electrodes 311f and 311h, as shown. FIG. 10B shows an example of an electroporation catheter 300 in which a second potential difference is applied between third electrode 311b and fourth electrode 311d, and no potential difference is applied between first electrode 311a and 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 a second potential difference applied between electrodes 311b and 311d), with no potential difference applied between non-adjacent electrodes 311e and 311g, as shown. In some embodiments, the first potential difference is applied asynchronously from the second potential difference. As used herein, asynchronous is used to describe that the first potential difference is applied for a different, non-overlapping period relative to the application of the second potential difference. It is preferable to have a potential difference delay period during which no potential difference is applied to any of electrodes 311a-h of electroporation catheter 300. This can provide time for the target tissue at the target treatment site to decrease in temperature.

[0156] By providing this asynchronous application of potential differences (e.g., energy pulses 210), localized heating around individual electrodes 311a-h, shown as hot regions 291, is kept more contained than when all of the electrodes 311a-h of electroporation catheter 300 apply a potential difference between them, as shown in the example of FIG. 9B. FIG. 10C illustrates the total heating (e.g., hot regions 291) and effective electric field 290 achieved when providing asynchronous application of potential differences between pairs of non-adjacent electrodes, as described herein. As can be seen by comparing FIGS. 9B and 10C, unwanted heating, hot regions 291, are significantly more limited in extent when using asynchronous application of potential differences than when applying a potential difference between all of the electrodes of a plurality of electrodes.

[0157] 11A and 11B, representations of damage to tissue caused by various forms of electroporation are shown consistent with the concepts of the present invention. FIG. 11A shows an exemplary depiction of the resulting tissue damage caused by electroporation in the mode described with reference to FIGS. 10A and 10B. The darkest region toward the bottom of FIG. 10A, region 2191, represents undesired damage caused by heating. The next, central region shown in FIG. 11A, region 2192, represents tissue that has been ablated, as desired during irreversible electroporation. The lightest region, region 2193, represents unaffected tissue (e.g., non-cauterized tissue).

[0158] FIG. 11B shows an example of the results of controlling an electroporation catheter in the mode described with reference to FIGS. 10A-C. The darkest region, region 2191, extends only slightly from the bottom of the figure and represents undesired damage caused by heating. The next central region, region 2192, shown in FIG. 11B represents tissue that has been ablated, as desired during irreversible electroporation. The brightest region, region 2193, represents unaffected tissue (e.g., non-ablated tissue). FIG. 11B is provided to the same scale as FIG. 11A and is therefore directly comparable. As can be seen, the amount of undesired damage region 2191 resulting from heating is significantly reduced in FIG. 11B compared to the same lesion in FIG. 11A. Furthermore, the penetration depth of the ablated tissue region 2192 can be increased by providing a potential difference between the alternating pair of electrodes 311 compared to the approach shown in FIGS. 10A and 10B. Thus, the advantages of using this approach are twofold. Providing alternating activation of the pair of electrodes 311 can be repeated for a desired period of time to provide a desired level of ablation.

[0159] It will be appreciated that applying a potential difference between two electrodes (e.g., two electrodes 311) requires providing different potentials between the two electrodes. Thus, for example, to provide a first potential difference, a relatively positive potential can be applied to the first electrode 311 and a relatively negative potential can be applied to the second electrode 311. Here, the potentials at a point are defined as relatively positive and negative, but they are relative to one another. Alternatively, the potentials at these points can be measured relative to another potential; in such cases, the potentials can be considered to be positive and negative, positive and neutral, positive and less than positive, negative and neutral, or negative and less than negative, respectively. In any of these cases, there is a difference between the potentials that provides the potential difference measured in volts. As described in more detail below, a potential can be provided between three electrodes (e.g., three electrodes 311) by applying the same first potential to two electrodes 311 and a different potential to another electrode 311 positioned between the two electrodes 311. This configuration provides the same first potential difference between two pairs of electrodes 311, with the middle electrode being one of both pairs of electrodes.

[0160] In some embodiments, the first electrode 311a and the second electrode 311c (e.g., of FIGS. 10A-10C) can be two electrodes of a first subset of electrodes of the plurality of electrodes 311a-h. Similarly, the third electrode 311b and the fourth electrode 311d can be two electrodes of a second subset of electrodes of the plurality of electrodes 311a-h. The first subset of electrodes 311 can be interleaved with the second subset of electrodes 311 such that each successive electrode of the plurality of electrodes 311a-h alternately belongs to the first subset of electrodes and the second subset of electrodes. That is, each of the electrodes 311 of the first subset of electrodes can be non-adjacent to one another, and each of the electrodes 311 of the second subset of electrodes can be non-adjacent to one another. In general, the electrodes 311 of any given subset of electrodes 311 can be non-adjacent to one another due to the interleaved arrangement of electrodes of different electrode subsets. In this example, the number of electrodes 311 in the second subset of electrodes includes n-1 electrodes through n+1 electrodes, where n is the number of electrodes in the first subset of electrodes. From the above discussion, it will be understood that because the second subset of electrodes 311 includes at least a third and a fourth electrode, the total number of electrodes 311 in the second subset of electrodes 311 must be at least equal to two. For example, if there are three electrodes 311 in the first subset of electrodes, there can be two electrodes 311 in the second subset of electrodes, each with an electrode 311 from the first subset on either side of them. Alternatively, there can be up to five electrodes 311 in the second subset of electrodes, with an electrode from the second subset of electrodes located on either side of each electrode in the first subset of electrodes.

[0161] In embodiments in which the first subset of electrodes 311 includes two or more electrodes 311, a first potential difference can be applied between each subset-adjacent electrode of the first subset of electrodes. A given subset-adjacent electrode for a given electrode can be the next electrode along the contiguous array of electrodes that are part of the same subset of electrodes. For example, the second electrode 311c is a subset-adjacent electrode of the first electrode 311a. The fifth electrode 311e can also be part of the first subset of electrodes, and the fourth electrode 311d can be located between the second electrode 311c and the fifth electrode 311e. In this embodiment, the fifth electrode 311e can also be a subset-adjacent electrode of the second electrode 311c rather than the first electrode 311a. In this example, the first electrode 311a and the fifth electrode 311e can be applied with a relatively positive potential, and the second electrode 311c can be applied with a relatively negative voltage such that a potential difference is established between the first electrode 311a and the second electrode 311c and between the second electrode 311c and the fifth electrode 311e. Similarly, the second subset of electrodes can further include a sixth electrode 311f, with the fifth electrode 311e disposed between the fourth electrode 311d and the sixth electrode 311f. A second potential can be applied between the third electrode 311b and the fourth electrode 311d and between the fourth electrode 311d and the sixth electrode 311f by applying a relatively positive potential to the third electrode 311b and the sixth electrode 311f and a relatively negative potential to the fourth electrode 311d.

[0162] 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 one another. In embodiments in which 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 across 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 the ablation or ablation depth at particular points along the length of the electroporation catheter 300.

[0163] Referring now to FIG. 12, a side view of a catheter including multiple electrodes consistent with the concepts of the present invention is shown. FIG. 12 illustrates an embodiment of an electroporation catheter 300 including multiple electrodes, with electrodes 311a-f shown, on which three pairs of electrodes 311 may be defined. In some embodiments, such as that shown in FIG. 12, controller 110 may be further configured to provide signaling to apply a third potential difference between fifth electrode 311e and sixth electrode 311f of electroporation catheter 300. Fifth electrode 311e may be positioned between second electrode 311c and third electrode 311b. Fourth electrode 311d may be positioned between third electrode 311b and sixth electrode 311f. That is, three pairs of electrodes 311a, c, 311b, d, and 311e, f may be defined such that each of the consecutively positioned electrodes alternately belongs to a first pair, a second pair, a third pair, and then back to the first pair. This interleaved arrangement can be further extended to an arrangement where there are three subsets of electrodes 311, where at least one of the subsets includes two or more electrodes 311, and all subsets are interleaved. In such an arrangement, between any two electrodes 311 of a given subset, there can be at least one electrode 311 from each of the other interleaved subsets of electrodes 311. In particular, in a fully interleaved arrangement, between any two electrodes 311 of a given subset, there can be a single electrode 311 from each of the other interleaved subsets of electrodes 311. This can be extended to scenarios where there are M subsets of electrodes, where M is an integer equal to two or more.

[0164] If the fifth electrode 311e and the sixth electrode 311f form a third pair or subset of electrodes 311 to which the third potential difference is applied, the controller 110 can be configured to cause the application of the third potential difference asynchronously from the application of both the first potential difference and the second potential difference.

[0165] In summary, the controller 110 can be configured to define two, three, four or more unique pairs or subsets of electrodes 311, and the controller 110 can be configured to apply alternating potential differences between those pairs or subsets of electrodes 311. In other embodiments, two, three, four or more subsets of electrodes 311, with at least two electrodes 311 per subset, can be defined such that a potential difference is applied between each pair of electrodes 311 adjacent to the subset within the subset.

[0166] Referring now to FIG. 13, a perspective view of a catheter including a curved array of electrodes consistent with the concepts of the present invention is shown. FIG. 13 illustrates an exemplary electroporation catheter 300 including an elongated member, as previously described. In this example, the electrode array 310 of the electroporation catheter 300 includes a substantially straight section, linear array 312, having a plurality of electrodes 311 therealong, and a curved section, curved array 313, also having a plurality of electrodes 311 therealong. The electrodes 311 of the linear array 312 and the electrodes of the curved array 313 can be controlled as a single plurality of electrodes 311, such that the electrodes 311 of the linear array 312 and the electrodes 311 of the curved array 313 belong to either a first subset of electrodes 311, a second subset of electrodes 311, or a higher-order subset of electrodes 311, as described above. Alternatively, the electrodes 311 in the linear array 312 and the curvilinear array 313 can be configured to be controlled separately, such that the electrodes 311 in the curvilinear array 313 can be controlled using parameters different from the parameters used to control the electrodes 311 in 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 alternating potential differences between the electrodes in the interleaved subsets of electrodes, as described herein.

[0167] Referring now to FIG. 14 , a perspective view of a catheter including an expandable array of electrodes is shown, consistent with the concepts of the present invention. FIG. 14 illustrates an exemplary electroporation catheter 300 in which the electrode array 310 includes an expandable array including a plurality of elongated members, such as the eight arms 314 shown, each arm 314 including a plurality of serially arranged electrodes 311. An electroporation catheter 300 having this configuration may be referred to as a balloon catheter. The arms 314 of the electrode array 310 of the electroporation catheter 300 may be flexible so that they can be pulled or pushed into a straight configuration, with the center of each arm 314 deviating from a central axis extending between the ends of the arms 314. In such an embodiment, each arm 314 may be controlled as a separate electroporation catheter 300 including a separate set of serially arranged electrodes 311. The controller 110 may be configured to control each set of electrodes 311 arranged along each arm 314. Each set of electrodes 311 along each arm 314 can be controlled, as described above, to provide alternating potential differences between the electrodes in the interleaved subsets of electrodes.

[0168] Referring now to FIG. 15, a visual representation of a method for delivering electroporation therapy is shown consistent with the concepts of the present invention. FIG. 15 illustrates an example of a method for controlling an electroporation catheter 300 according to the present disclosure. In some embodiments, a first potential difference (e.g., energy pulse 210m described herein) is applied between non-adjacent first and second electrodes 311a and 311c. A second potential difference (e.g., energy pulse 210n described herein) can be applied between non-adjacent third and fourth electrodes 311b and 311d. The potential differences can be applied asynchronously, whereby the effective electric field distribution generates a continuous cellular ablation lesion, as described with reference to FIGS. 10A-C and elsewhere herein.

[0169] Referring now to Figures 16A-G, two anatomical representations and graphs of lesion depth, as well as two representations of tissue damage and graphs of ablation parameters, are shown, respectively, consistent with the concepts of the present invention. Figures 16A and 16B illustrate two electroporation waveform delivery methods. Figure 16A illustrates a single-return bipolar method in which a single electrode, electrode 311a, is energized in combination with a single return electrode, electrode 311b (e.g., establishing a potential difference between electrodes 311a and 311b as shown). Figure 16B illustrates a multiple-return bipolar method in which a single electrode, electrode 311a, is energized in combination with a set of multiple return electrodes, such as electrodes 311b, c (e.g., establishing a potential difference between electrodes 311a and 311b, c), as shown. In some embodiments, catheter 300 includes fixed electrode size (e.g., surface area) and spacing. As shown in Figure 16B, the electric field (e.g., field 290) generated by the multiple-return method is focused at electrode 311 (e.g., the tip electrode). FIG. 16C shows a graph comparing the depth of lesions created using the single-return bipolar method of FIG. 16A and the multiple-return bipolar method of FIG. 16B. FIGS. 16D and 16E show example lesions created using these two methods, respectively. FIGS. 16F and 16G show additional graphs comparing these two methods of electroporation energy delivery. In the example shown, single-return bipolar energy delivery is provided between two similarly sized electrodes, such as two electrodes 311 having an approximately 1:1 ratio of surface areas. This single-return bipolar ablation method generates a nearly symmetrical electric field distribution between the two poles (e.g., between electrodes 311a and 311b). Multiple-return bipolar ablation using multiple return electrodes as described herein adjusts the ablation surface area ratio while using a fixed catheter configuration (e.g., a fixed catheter 300 geometry), thereby focusing the electric field 290 on a single electrode (e.g., electrode 311a). The multiple return bipolar ablation configuration of FIG. 16B involves shifting the surface area ratio (1:1.1 to 1:1000) in favor of lower total electrode surface area near the desired ablation location.This method enhances the lesion and focuses the cell ablation effect at the desired electrode without introducing a monopolar field.

[0170] Referring now to FIG. 17 , a schematic diagram of a system for implementing monopolar and / or phase-coupled energy delivery using multiple external patch electrodes is shown consistent with the concepts of the present invention. The catheter 300 and / or other components of FIG. 17 can have a similar structure and arrangement to similar components described with reference to FIG. 1 and described herein. In some embodiments, the external electrode 60 can include two, three, four, or more patch electrodes, such as the external electrodes 60a-e shown. In some embodiments, each of the external electrodes 60a-e is individually selectable (e.g., selectable by the controller 110) such that energy delivery can be provided between any one or more electrodes 311 and any one or more external electrodes 60. In some embodiments, the external electrodes 60 can be positioned on the patient's skin (e.g., positioned by a clinician or other operator of the system 10 before and / or during a clinical procedure) at locations selected to enhance the treatment provided by the system 10 to various portions of the tissue being treated. For example, energy delivery can be provided by generator 100 between electrode 311 and external electrode 60, which are generally positioned in an opposite direction from the intended target tissue, such as when external electrode 60e positioned on the patient's back is selected for unipolar and / or phase-coupled energy delivery when ablating the posterior wall of the heart. In some embodiments, external electrode 60 is positioned relatively close to the patient's heart (or other target tissue to be treated), such as on the patient's upper back, side, and / or chest. In some embodiments, controller 110 is configured to automatically and / or semi-automatically select one or more particular external electrodes 60 to be used as unipolar return electrodes based on the location of the target tissue to be treated. Additionally or alternatively, controller 110 can be configured to select external electrodes 60 based on measurements, such as measured impedance between electrode 311 and each external electrode 60, with the optimal one or more external electrodes 60 being selected based on the measurements.

[0171] 17A-17E, cross-sectional views of a finite element analysis setup and analysis results are shown consistent with the concepts of the present invention. FIG. 17A shows a model of a body used in a finite element analysis performed by applicant to quantify the effect of external electrode selection when implementing monopolar energy delivery. The model includes an anterior external electrode 60a and a posterior external electrode 60b. The heart is modeled near the anterior external electrode 60a, and the electrode 311 of the catheter 300 is positioned such that the modeled target tissue is located between the electrode 311 and the anterior external electrode 60a, as shown. FIG. 17B shows an expanded view of FIG. 17A with the model in a first configuration, in which the electrode 311 is in contact with the target tissue (e.g., positioned at a 0 mm offset). FIG. 17C shows an expanded view of FIG. 17A with the model in a second configuration, in which the electrode 311 is positioned at a 4 mm offset from the target tissue (e.g., not in contact with the target tissue). FIG. 17D shows the results of the finite element analysis. A 2250 V unipolar signal was modeled to be delivered between the anterior external electrode 60a, which was positioned at a 0 mm offset from the cardiac tissue, and the electrode 311, which was positioned at a 4 mm offset from the cardiac tissue. FIG. 17E shows the results of a finite element analysis. A 2250 V unipolar signal was modeled to be delivered between the posterior external electrode 60b, which was positioned at a 0 mm offset from the cardiac tissue, and the electrode 311, which was positioned at a 4 mm offset from the cardiac tissue. As shown in the figure, when the target tissue was positioned between the external electrode 60 (e.g., the anteriorly positioned external electrode 60a) and the electrode 311, the model showed increased cardiac tissue ablation in both the 0 mm and 4 mm offset models compared to similar energy delivery between the electrode 311 and the posterior external electrode 60b (e.g., when the target tissue was not located between the two electrodes). Modeling revealed a maximum lesion depth of 13.26 mm using the anteriorly positioned external electrode 60a and a maximum lesion depth of 4.77 mm using the posterior external electrode 60b. In vivo testing conducted by applicant has shown that when a unipolar signal of 2080V is applied between electrode 311 (anterior) and the anterior external electrode 60a, the lesion depth is 15.32mm (+ / - 5.18mm).Additionally, the lesion depth is 4.94 mm (+ / - 0.23 mm) when a unipolar signal of 2460 V is applied between electrode 311 (anterior) and the posterior external electrode 60b.

[0172] Graphs of cell membrane potential during an action potential and examples of various pulse timing methodologies are illustrated in Figures 18A-C, respectively, consistent with the concepts of the present invention. The electroporation waveform 200 and / or other components of Figures 18A-C can be configured and arranged similarly to the similar components described in Figure 1 and herein. In some embodiments, the electroporation waveform 200, for example, as described in Figure 1, is configured to provide coherent sinusoidal burst electroporation (CSE) when delivered to tissue. The electric field resulting from the CSE can increase the cell membrane potential. In excitable tissue, such as neurons or skeletal muscle tissue, action potentials (APs) can be generated as a result of the delivery of a CSE pulse (e.g., electroporation waveform 200). In some embodiments, the APs can integrate over time and cause a forceful muscle contraction. Figure 18A shows a graph of a cell's membrane potential over time when a stimulus, such as a 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, which is approximately 250 ms.

[0173] As described herein, the system 10 can be configured to deliver electroporation waveforms 200 (e.g., CSE) using a sequential pulse technique, for example, in which energy pulses 210 are delivered independently, such as alternately, through odd (e.g., non-adjacent) and even (e.g., non-adjacent) electrodes 311 (e.g., energy pulse 210m is delivered from first electrode 311a and second electrode 311c, followed by energy pulse 210n from third electrode 311b and fourth electrode 311d, as shown in FIGS. 10A-10C and described herein). In some embodiments, the time between each energy pulse 210 (e.g., the time between energy pulse 210m delivered from odd electrode 311 and energy pulse 210n delivered from even electrode 311), such as interleaving offset period 2203, comprises a time greater than the absolute refractory period of the AP, such as between 7 ms and 11 ms. As an example, in a process including 300 cycles containing 300 odd energy pulses 210m and 300 even energy pulses 210n (600 total energy pulses 210), a total of 600 APs may be generated during the process, as cell membranes have sufficient time to flex between pulses. In some cases, the 600 APs integrate to form a vigorous muscle contraction. As described with reference to FIGS. 2 and 3, an electroporation waveform 200 may include multiple sequences 250 of bursts 240 of energy pulses 210. In some embodiments, the process may include five sequences 250 containing five bursts 240, each containing 24 energy pulses 120 (e.g., 12 odd energy pulses 210m and 12 even energy pulses 210n). This process may result in 25 muscle contraction events (one event per burst 240 in each sequence 250), with 24 APs occurring per event. FIG. 18B shows an example of delivery of each odd and even energy pulse 210 m,n resulting in an AP.

[0174] In some embodiments, the electroporation waveform 200 is configured to reduce muscle excitation, for example, when the timing between the odd and even energy pulses 210m, 210n is configured to reduce muscle excitation. For example, the even energy pulse 210n can be followed by an odd energy pulse 210m with an interleaving offset period 2203 that is shorter than the absolute refractory period of the AP generated by the odd energy pulse 210m, e.g., less than 2 ms, such as about 500 μs. The period between the even energy pulse 210n and the subsequent odd energy pulse 210m can include a longer period, such as a period that includes the difference between the inter-pulse delay period 220 and the interleaving offset period 2203. For example, the period between odd energy pulses 210m (and between even energy pulses 210n) is equal to the inter-pulse delay period 220 and is the same or similar to the timing shown in Figure 18B, such as 12 ms to 21.5 ms between an even energy pulse 210n and a subsequent odd energy pulse 210m (e.g., if the period between odd energy pulses 210m is between 14 ms and 22 ms as shown). This timing adjustment can result in a 50% reduction in muscle excitation events. Figure 18C shows an example of this adjusted timing, resulting in reduced APs generated.

[0175] 19A-19C illustrate various energy delivery modalities consistent with the concepts of the present invention. The generator 100, catheter 300, and / or other components of FIGS. 19A-19C may have a similar structure and arrangement to similar components shown in FIG. 1 and described herein. FIG. 19A illustrates a monopolar energy delivery modality (e.g., as shown in FIGS. 3A-3D and described herein). Here, the electrical pulse 210 includes a first signal VE1 comprising a sine wave delivered to a first electrode 311a and a second signal VE2 comprising a sine wave delivered to a second electrode 311b. The phase offset between VE1 and VE2 includes a 0° offset, and a reference signal is applied to the outer electrode 60, as shown. When energy is delivered using this monopolar method, the resulting electric field extends primarily in a direction from each electrode 311 toward the outer electrode 60, as shown.

[0176] FIG. 19B illustrates a bipolar energy delivery modality (e.g., as illustrated in FIGS. 3A-3D and described herein). Here, the electrical pulse 210 includes a first signal VE1 including a sine wave delivered to the first electrode 311a and a second signal VE2 including a sine wave delivered to the second electrode 311b. As shown, signals VE1 and VE2 include a 180° phase offset, and the outer electrode 60 is not connected (e.g., no reference voltage is applied to the outer electrode 60). When energy is delivered using this bipolar method, the resulting electric field extends primarily between the electrodes 311, with no additional component toward the outer electrode 60, as illustrated.

[0177] FIG. 19C illustrates a phase-coupled energy delivery modality (e.g., as illustrated in FIGS. 3A-3D and described herein). Here, the electrical pulse 210 includes a first signal VE1 including a sine wave delivered to a first electrode 311a and a second signal VE2 including a sine wave delivered to a second electrode 311b. The signals VE1 and VE2 may include a phase offset greater than 0° and less than or equal to 180°. A reference signal is applied to the outer electrode 60, as shown. When energy is delivered using this phase-coupled method, the resulting electric field extends first between the electrodes 311 and second from the electrodes 311 toward the outer electrode 60, as shown. The phase angle between the signals VE1 and VE2 can be adjusted to adjust the relative strengths of the first and second components of the resulting electric field, for example, as described herein.

[0178] It should be understood that the above-described embodiments serve only as illustrative examples. Further embodiments are contemplated. Any feature described herein with respect to any one embodiment can be used alone or in combination with other features described, and can also be used in combination with one or more features of any other embodiment, or in any combination of any other embodiment. Moreover, equivalents and variations not described above may be used without departing from the scope of the inventive concept as defined in the appended claims.

Claims

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

2. 10. The system of claim 1, the inter-pulse delay period includes a first delay period and a second delay period; the first delay period comprises a fixed time period between each of the plurality of energy pulses; the second delay period comprises a variable period between each of the plurality of energy pulses. system.

3. 3. The system of claim 2, Each variable period may include a positive duration, a negative duration, or both; system.

4. 3. The system of claim 2, 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; a second inter-pulse delay period between the second energy pulse and a third energy pulse of the plurality of energy pulses; Including, the first inter-pulse delay period comprises a first variable period; the second inter-pulse delay period comprises a second variable period; system.

5. 5. The system of claim 4, the first variable delay period has a positive duration and the second variable delay period has a negative duration; system.

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

7. 3. The system of claim 2, the variable period includes a period based on a pseudo-random number; system.

8. 10. The system of claim 1, the inter-pulse delay period comprises a variable period between each energy pulse; system.

9. 9. The system of claim 8, the variable period includes a period based on a pseudo-random number; system.

10. 9. The system of claim 8, the variable duration is configured to reduce harmonics generated by the delivery of the energy pulse; system.

11. 11. The system of claim 10, The variable period is configured to reduce the harmonics by at least 10 dB. system.

12. 10. The system of claim 1, the electroporation waveform further comprises a cycle length; the cycle length comprises a period from the start of a first energy pulse of the plurality of energy pulses to the start of a subsequent energy pulse of the plurality of energy pulses; system.

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

14. 14. The system of claim 13, The cycle length comprises a period of at least 30 ms. system.

15. 10. The system of claim 1, the inter-pulse delay period comprises a period of at least 1 ms; system.

16. 10. The system of claim 1, The inter-pulse delay period comprises a period of 2000 ms or less. system.

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

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

19. 20. The system of claim 18, the algorithm includes one or more biases; system.

20. 20. The system of claim 19, The one or more biases may be configured to cause the electroporation waveform to: a particular frequency range, a particular ratio of bipolar to unipolar energy delivery, a particular phase difference between sine waves, a particular voltage or voltage range, a particular delay between energy delivery such as a particular inter-pulse delay, and combinations thereof; and determining one or more parameters of the electroporation waveform such that system.

21. 10. The system of claim 1, the at least one catheter electrode includes a first set of non-adjacent catheter electrodes and a second set of non-adjacent catheter electrodes; system.

22. 22. The system of claim 21, a first catheter electrode of the second set of non-adjacent catheter electrodes is disposed between a first catheter electrode of the first set of non-adjacent catheter electrodes and a second catheter electrode of the first set; system.

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

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

25. 24. The system of claim 23, the generator is configured to provide the electroporation waveform in a bipolar configuration. system.

26. 10. The system of claim 1, the at least one catheter electrode includes a plurality of electrodes; the plurality of electrodes includes a first catheter electrode and a set of at least two additional catheter electrodes; system.

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

28. 28. The system of claim 27, 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 configuration. system.

29. 27. The system of claim 26, each electrode of the plurality of electrodes comprises a similar surface area; system.

30. 27. The system of claim 26, Each electrode of the plurality of electrodes is disposed at an equal distance from each adjacent electrode. system.

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

32. 32. The system of claim 31, the one or more external electrodes include at least two external electrodes; each of the at least two external electrodes is independently selectable to provide the electroporation waveform to either the at least one catheter electrode or the at least two external electrodes; system.

33. 33. The system of claim 32, the controller is further configured to select one or more of the at least two external electrodes to provide the electroporation waveform; a target tissue to be treated by delivery of the electroporation waveform is positioned relative to the at least one catheter electrode and the one or more selected external electrodes; system.

34. 10. The system of claim 1, the at least one catheter electrode comprises a plurality of catheter electrodes; the generator is configured to provide the electroporation waveform in a bipolar configuration between two or more of the plurality of catheter electrodes. system.

35. 10. The system of claim 1, the electroporation waveform is configured to be delivered to the at least one catheter electrode and the one or more external electrodes in a monopolar configuration; system.

36. 36. The system of claim 35, The electroporation waveform is configured to be delivered in both monopolar and bipolar configurations. system.

37. 37. The system of claim 36, the electroporation waveform includes a first signal including a first sine wave, a second signal including a second sine wave, and a third signal including a combination of the first sine wave and the second sine wave; the first sine wave and the second sine wave include a phase offset; 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; the third signal is configured to be provided to at least one of the one or more external electrodes. system.

38. 38. The system of claim 37, the electroporation waveform is provided in a monopolar configuration when the phase offset of the first and second signals is 0°; system.

39. 38. The system of claim 37, the electroporation waveform is provided in both a monopolar and a bipolar configuration when the phase offset of the first and second signals is greater than 0° and less than or equal to 180°; system.

40. 40. The system of claim 39, a relative intensity of the monopolar energy delivery configured to vary relative to an intensity of the bipolar energy delivery based on the phase angle; system.

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