Energy delivery system for treating a patient

Abstract

Provided are systems, methods, and devices for delivering energy to a patient. A system includes a generator that provides energy. The system also includes an energy delivery device having at least one energy delivery element for delivering the energy from the generator to tissue and / or other material of the patient. The system tracks the energy delivered by the energy delivery device, and based on the energy delivered, the system estimates, monitors, records, and / or prognoses hemolysis and / or other side effects.

Description

Client Docket No. : ARG-011-PCTINTERNATIONAL PCT PATENT APPLICATION FOR ENERGY DELIVERY SYSTEM FOR TREATING A PATIENTInventors:Melvin Florencio Lorenzo, a citizen of The United States of America, residing at:7995 Civita Boulevard, Apt 336, San Diego, CA 92108Mark Andrew Zurcher, a citizen of The United States of America, residing at:3140 Via de Caballo, Encinitas, CA 92024Micah Aaron KeliiMaikai Lee, a citizen of The United States of America, residing at:2031 Julie Dawn Place, Escondido, CA 92026Randell L. Werneth, a citizen of The United States of America, residing at:7920 Dixie Lane, San Diego, CA 92127Timothy James Corvi, a citizen of The United States of America, residing at:13581 Cayucos Lane, San Diego, CA 92130Kenneth K.M. Mark, a citizen of The United States of America, residing at:1540 Pleasant Lane, Lafayette, CA 94549R. Maxwell Flaherty, a citizen of The United States of America, residing at:242 Ipswich Road, Topsfield, MA 01983J. Christopher Flaherty, a citizen of The United States of America, residing at:31 Seaman Point Road, Nottingham, NH 03290Assignee: Arga Medtech SA12220 World Trade Drive, Suite 100San Diego, CA 92128Entity: SmallClient Docket No. : ARG-011-PCTENERGY DELIVERY SYSTEM FOR TREATING A PATIENTRELATED APPLICATIONS

[0001] The present application claims the benefit of: United States Provisional Patent Application Serial Number 63 / 765,026 (Docket No. ARG-011-PR1), filed February 28, 2025, entitled “Energy Delivery System for Treating Patient”; United States Provisional Patent Application Serial Number 63 / 856,625 (Docket No. ARG-011-PR2), filed August 3, 2025, entitled “Energy Delivery System for Treating Patient”; and United States Provisional Patent Application Serial Number 63 / 887,900 (Docket No. ARG-011-PR3), filed September 25, 2025, entitled “Energy Delivery System for Treating Patient”; the contents of each of which are hereby incorporated by reference.

[0002] The present application, while not claiming priority to, may be related to: United States Patent Application Serial Number 17 / 686, 001 (Docket No. ARG-001-US-B), filed March 3, 2022, entitled “Ablation Equipment to Treat Target Regions of Tissue in Organs”; United States Patent Application Serial Number 17 / 686,027 (Docket No. ARG-001 -US- A), filed March 3, 2022, entitled “Ablation Equipment to Treat Target Regions of Tissue in Organs”; United States Patent Application Serial Number 17 / 939,465 (Docket No. ARG-003-US-CIP1), filed September 7, 2022, entitled “Systems, Methods and Devices for NonThermal Ablation of Target Tissue”; United States Patent Application Serial Number 18 / 001,041 (Docket No. ARG-004-US), filed December 7, 2022, entitled “Ablation Equipment to Treat Target Regions of Tissue in Organs”; United States Patent Application Serial Number 18 / 258,466 (Docket No. ARG-006-US), filed June 20, 2023, entitled “Electronic Apparatus for Delivering Coherent Sine Burst Irreversible Electroporation Energy to a Biological Tissue”; United States Patent Application Serial Number 18 / 338,135 (Docket No. ARG-007-US-CIP1), filed June 20, 2023, entitled “Power Unit for Delivering Coherent Sine Burst Irreversible Electroporation Energy to a Biological Tissue”; United States Patent Application Serial Number 19 / 115,161 (Docket No. ARG-008-US), filed March 25, 2025, entitled “Electroporation System”; and United States Provisional Patent Application Serial Number 63 / 849,519 (Docket No. ARG-010-PR1), filed July 23, 2025, entitled “Energy Delivery System for Treating Patient”; the contents of each of which are hereby incorporated by reference.Client Docket No. : ARG-011-PCTFIELD OF INVENTIVE CONCEPTS

[0003] The present disclosure relates to an energy delivery system for a patient, an energy controller, a method of controlling an energy delivery system and a computer program product comprising computer program code configured to cause a controller to perform the method.BACKGROUND

[0004] Tissue ablation is used in numerous medical procedures to treat a patient.Ablation can be performed to remove or denature undesired tissue such as cardiac cells. The ablation can be performed by passing energy, such as electrical energy, through one or more electrodes and causing tissue death where the electrodes are in contact with tissue. Ablation procedures can be performed on patients with any cardiac arrhythmia such as atrial fibrillation (AF) by ablating tissue in the heart. During energy delivery, one or more undesired side effects can occur, such as hemolysis. There is a need for improved energy delivery systems that are configured to avoid undesired side effects.SUMMARY

[0005] According to an aspect of the present inventive concepts, a system for delivering energy to a patient comprises: a generator configured to provide energy and an energy delivery device comprising at least one energy delivery element configured to deliver energy to tissue and / or other material of the patient. The system is configured to track the energy delivered by the energy delivery device and based on the energy delivered, estimate, monitor, record, and / or prognose hemolysis and / or other side effect.

[0006] In some embodiments, based on an estimation of the hemolysis level, the system is further configured to estimate, monitor, record, and / or prognose at least a second side effect.

[0007] In some embodiments, based on an estimation of a level of hemolysis, the system is configured to indicate a secondary clinical procedure to be performed. The secondary clinical procedure can comprise: delivery of saline or other fluid to the patient; delivery of a medication to the patient; or both. The secondary clinical procedure can be configured to limit hemolysis and / or the other side effect.Client Docket No. : ARG-011-PCT

[0008] In some embodiments, the system is configured to estimate a level of hemolysis generated for each delivery of energy.

[0009] In some embodiments, the system is configured to estimate a level of hemolysis generated by one or more energy deliveries, and the estimation is based on one, two, or more of the magnitude of the electric field delivered that exceeds a hemolytic threshold at a given frequency; the volume of blood exposed to an energy delivery electric field; and / or the total number of cycles delivered during an application of energy.

[0010] In some embodiments, the system is configured to track, record, calculate, predict, prognose, and / or otherwise monitor the amount of hemolysis that occurs during a clinical procedure. The system can be configured to provide a display of information relating to the tracked, recorded, calculated, predicted, prognosed, and / or otherwise monitored amount of hemolysis.

[0011] In some embodiments, the system is configured to determine and / or display one or more parameter values relating to hemolysis and / or other cumulative effects of the delivery of energy to the patient by the system. The system can be configured to display one or more icons and / or other graphical indicators related to the determined parameter values. The system can be configured to determine the one or more parameter values based on one or more system parameters and / or one or more patient parameters.

[0012] In some embodiments, the system is configured to determine and / or display one or more parameter values relating to total energy delivered during a clinical procedure.

[0013] In some embodiments, the system is configured to model peak electric fields generated during energy delivery, and to use the model to determine the volume of blood that were exposed to electric fields that were greater than a hemolytic threshold.

[0014] In some embodiments, the system is configured to determine an amount of hemolysis generated by each pulse of energy delivery and / or to determine a cumulative amount of hemolysis generated throughout a clinical procedure. The system can be further configured to determine a hemolytic potential for a series of pulses of energy delivery. The system can be configured to determine the cumulative amount of hemolysis generated by summing each hemolytic potential for each series of pulses of energy delivery. The system can be configured to determine the cumulative amount of hemolysis generated based on a set of system parameters; patient parameters; and / or hemolysis mitigation parameters. The system can comprise and / or can be configured to determine one or more hemolysis thresholdsClient Docket No. : ARG-011-PCTto which the determined cumulative amount of hemolysis generated can be compared. The one or more hemolysis thresholds can comprise a safety margin. The system can be configured to prevent additional energy from being delivered after the determined cumulative amount of hemolysis generated exceeds the one or more hemolysis thresholds. The system can comprise a clinician override function configured to allow additional energy delivery after the determined cumulative amount of hemolysis generated exceeds the one or more hemolysis thresholds. The system can comprise and / or can be configured to determine one or more hemolysis warning thresholds, and the system can be configured to provide an alert if the determined cumulative amount of hemolysis generated exceeds the one or more hemolysis warning thresholds. The one or more hemolysis thresholds can be dynamically determined by the system. The system can be configured to determine a number of energy deliveries that can be delivered before the one or more hemolysis thresholds are exceeded.

[0015] In some embodiments, the system comprises a user interface that is configured to provide a procedural planning function.

[0016] In some embodiments, the generator comprises a signal generator configured to generate the provided energy. The signal generator can be configured to provide the energy in an energy form selected from the group consisting of: radiofrequency energy; electroporation energy; ultrasound and / or other sound energy; laser and / or other light energy; chemical energy; mechanical energy; and combinations thereof. The signal generator can be configured to provide the energy in the form of an electroporation waveform, and the generator can further comprise a controller configured to provide signaling configured to cause the signal generator to generate the electroporation waveform. The electroporation waveform can comprise a plurality of energy pulses, and each energy pulse can be separated by an inter-pulse delay period. The system can further comprise one or more external electrodes, and the electroporation waveform can be configured to be delivered in a unipolar arrangement to the at least one energy delivery element and the one or more external electrodes. The electroporation waveform can be configured to be delivered in both a unipolar arrangement and a bipolar arrangement. The electroporation waveform can comprise a first signal comprising a first sine wave, a second signal comprising a second sine wave, and a third signal comprising a combined reference of the first sine wave and the second sine wave; and the first sine wave and the second sine wave comprise a phase offset; and the first signal can be configured to be provided to a first energy delivery element of the at least one energy delivery elements, the second signal can be configured to be provided to aClient Docket No. : ARG-011-PCTsecond energy delivery element of the at least one energy delivery elements, and the third signal can be configured to be provided to at least one electrode of the one or more external electrodes.

[0017] In some embodiments, the energy delivery device comprises a catheter.

[0018] In some embodiments, the generator comprises a signal generator configured to generate the provided energy. The signal generator can comprise one or more shared waveform generation hardware modules, one or more specialized waveform generation hardware modules, or both. Each of the one or more specialized waveform generation hardware modules can be configured for a specific waveform generation modality, and the system can be configured to selectively activate one of the specialized waveform generation hardware modules based on the desired energy delivery modality. At least one of the one or more shared waveform generation hardware modules can comprise one or more components configured to control the function of the signal generator. At least one of the one or more shared waveform generation hardware modules can comprise one or more components configured to provide power to the signal generator. The generator can be configured to operate in different modes independently. The generator can be configured to generate high frequency sine wave waveforms comprising a frequency of at least 250kHz. The generator can be configured to generate a waveform comprising PFA energy and RF energy simultaneously. The generator can be configured to generate a waveform comprising a hybrid of sine waves and square waves. The hybrid waveform can be generated by a partial filtering of the sine waves. The generator can comprise an RF generator, and the RF generator can be configured to generate both an RF waveform and a PFA waveform. The generator can comprise one or more interchangeable components.

[0019] In some embodiments, the system further includes an arbitrary waveform generation hardware module configured to deliver energy comprising one or more arbitrary waveforms. The arbitrary waveform generation hardware module can be configured to provide direct waveform synthesis without requiring filtering and / or without requiring a waveform transformation process. The arbitrary waveform generation hardware module can be configured to dynamically switch between two or more of the one or more arbitrary waveforms. The arbitrary waveform generation hardware module can be configured to produce waveforms with voltage capabilities of at least 2kV. The one or more arbitrary waveforms can be selected from the group consisting of: sine waves; square waves; singleClient Docket No. : ARG-011-PCTperiod sine wave snippets; custom pulse patterns; pulses without ramp-up characteristics; triangle; chirp; sawtooth; and combinations thereof.

[0020] In some embodiments, the generator is configured to generate sine waves and to provide an output comprising a sine wave, a square wave, or both.

[0021] In some embodiments, the generator is configured to generate square waves and to provide an output comprising a sine wave, a square wave, or both.

[0022] In some embodiments, the system is configured to perform harmonic filtering configured to convert square waves to sine waves.

[0023] In some embodiments, the system is configured to perform pulse modulation configured to convert square waves to sine waves.

[0024] In some embodiments, the system further comprises one or more waveform processing modules configured to convert sine waves to square waves. The one or more waveform processing modules can comprise a comparator and / or a pulse-shaping circuit.

[0025] In some embodiments, the system is configured to generate high voltage packet sequences, each sequence comprising a voltage of at least 2kV.

[0026] In some embodiments, the system is configured to control and / or mitigate electrical arcing of the energy delivery device.

[0027] In some embodiments, the energy delivery device comprises a catheter and wherein the system is configured to perform a catheter conditioning procedure on the catheter.

[0028] In some embodiments, the system comprises a microbubble power threshold, and the system can be configured to limit microbubble formation based on the microbubble power threshold.

[0029] In some embodiments, the system is configured to determine a number of ablations (e.g., a minimum number of ablations) to efficaciously treat a pulmonary vein target.

[0030] In some embodiments, the system is configured to prevent or at least reduce hemolysis during the delivery of ablative energy to cardiac tissue.

[0031] According to another aspect of the present inventive concepts, a method for bidirectional waveform conversion comprises: defining a desired sine wave frequency;Client Docket No. : ARG-011-PCTgenerating, via a signal generator, a biphasic square wave at a predetermined frequency; and performing a waveform manipulation configured to process the biphasic square wave into one, two, or more sine wave approximations. The output can comprise the desired sine wave frequency. The waveform manipulation can comprise full spectrum filtering and / or partial spectrum filtering. The waveform manipulation can achieve complete harmonic elimination and / or suppression. The waveform manipulation can achieve selective harmonic elimination and / or suppression. The waveform manipulation can be configured to switch between full spectrum filtering and partial spectrum filtering to produce different waveforms.

[0032] The technology described herein, along with the attributes and attendant advantages thereof, will best be appreciated and understood in view of the following detailed description taken in conjunction with the accompanying drawings in which representative embodiments are described by way of example.INCORPORATION BY REFERENCE

[0033] All publications, patents, and patent applications mentioned in this specification 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 content of all publications, patents, and patent applications mentioned in this specification are herein incorporated by reference in their entirety. It will be clearly understood that, if a prior art publication is referred to herein, this reference does not constitute an admission that the publication forms part of the common general knowledge in the art in any country.BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Fig. 1 illustrates a schematic example of a system comprising a catheter assembly and a generator for providing electroporation, consistent with the present inventive concepts.

[0035] Figs. 2A and 2B illustrate side views of the catheters of an embodiment of a catheter assembly, and perspective views of the distal portion of a catheter of the catheter assembly in various geometric configurations, respectively, consistent with the present inventive concepts.Client Docket No. : ARG-011-PCT

[0036] Fig. 3 illustrates a side view of an embodiment of a catheter assembly positioned relative to tissue and within blood, consistent with the present inventive concepts.

[0037] Fig. 4 illustrates an embodiment of the display of a user interface of a system for providing electrical energy to treat a patient, consistent with the present inventive concepts.

[0038] Figs. 5A through 5C illustrate various charts and graphs of data collected by the applicant during a human clinical study, respectively, consistent with the present inventive concepts.

[0039] Figs. 6, 7A, 7B, and 7C illustrate two graphs of lesion depth data and two images of tissue with PFA lesions, respectively, consistent with the present inventive concepts.

[0040] Fig. 8 illustrates a block diagram of on an embodiment of signal generator hardware architecture comprising both shared components modules and specialized components modules, consistent with the present inventive concepts.

[0041] Figs. 9A and 9B illustrate two flowcharts of embodiments of methods for bidirectional waveform conversion, consistent with the present inventive concepts.

[0042] Figs. 10A through 10F illustrate various embodiments of harmonic filtering demonstrations and waveform conversion examples, consistent with the present inventive concepts.

[0043] Fig. 11 illustrates a graph of an embodiment of a waveform produced by signal generator, consistent with the present inventive concepts.

[0044] Figs. 12A and 12B illustrate graphs of experimentally determined arcing voltage threshold data and catheter conditioning data, respectively, consistent with the present inventive concepts.

[0045] Figs. 13A through 13C illustrate a flowchart of an embodiment of a method for determining power delivered per burst window and two graphs of experimentally determined microbubble power threshold data at two delivery frequencies, respectively, consistent with the present inventive concepts.

[0046] Figs. 14A through 14C illustrate two tables of clinical durability data collected by applicant during a human clinical study and a cross-sectional diagram of overlapping energy deliveries to tissue, respectively, consistent with the present inventive concepts.Client Docket No. : ARG-011-PCT

[0047] Figs. 15A through 15D illustrate graphs and charts of experimentally determined clinical data correlating pre-procedural patient parameters and cumulative index values with hemolysis-related clinical outcomes, consistent with the present inventive concepts.

[0048] Fig. 16 illustrates a flowchart of an embodiment of a method for managing hemolysis risk for a patient based, at least in part, on one or more patient parameters, consistent with the present inventive concepts.DETAILED DESCRIPTION OF THE DRAWINGS

[0049] Reference will now be made in detail to the present embodiments of the technology, examples of which are illustrated in the accompanying drawings. Similar reference numbers may be used to refer to similar components. However, the description is not intended to limit the present disclosure to particular embodiments, and it should be construed as including various modifications, equivalents, and / or alternatives of the embodiments described herein.

[0050] It will be understood that the words "comprising" (and any form of comprising, such as "comprise" and "comprises"), "having" (and any form of having, such as "have" and "has"), "including" (and any form of including, such as "includes" and "include") or "containing" (and any form of containing, such as "contains" and "contain") when used herein, specify the presence of stated features, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof.

[0051] It will be further understood that, although the terms first, second, third, etc. may be used herein to describe various limitations, elements, components, regions, layers and / or sections, these limitations, elements, components, regions, layers, and / or sections should not be limited by these terms. These terms are only used to distinguish one limitation, element, component, region, layer or section from another limitation, element, component, region, layer, or section. Thus, a first limitation, element, component, region, layer, or section discussed below could be termed a second limitation, element, component, region, layer, or section without departing from the teachings of the present application.

[0052] It will be further understood that when an element is referred to as being "on", "attached", "connected" or "coupled" to another element, it can be directly on or above, or connected or coupled to, the other element, or one or more intervening elements can be present. In contrast, when an element is referred to as being "directly on", "directlyClient Docket No. : ARG-011-PCTattached", "directly connected" or "directly coupled" to another element, there are no intervening elements present. Other words used to describe the relationship between elements should be interpreted in a like fashion (e.g., "between" versus "directly between," "adjacent" versus "directly adjacent," etc.).

[0053] It will be further understood that when a first element is referred to as being "in", "on" and / or "within" a second element, the first element can be positioned: within an internal space of the second element, within a portion of the second element (e.g., within a wall of the second element); positioned on an external and / or internal surface of the second element; and combinations of one or more of these.

[0054] As used herein, the term “proximate”, when used to describe proximity of a first component or location to a second component or location, is to be taken to include one or more locations near to the second component or location, as well as locations in, on and / or within the second component or location. For example, a component positioned proximate an anatomical site (e.g., a target tissue location), shall include components positioned near to the anatomical site, as well as components positioned in, on and / or within the anatomical site.

[0055] Spatially relative terms, such as "beneath," "below," "lower," "above," "upper" and the like may be used to describe an element and / or feature's relationship to another element(s) and / or feature(s) as, for example, illustrated in the figures. It will be 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 depicted in the figures. For example, if the device in a figure is turned over, elements described as "below" and / or "beneath" other elements or features would then be oriented "above" the other elements or features. The device can be otherwise oriented (e.g., rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly.

[0056] The terms “reduce”, “reducing”, “reduction” and the like, where used herein, are to include a reduction in a quantity, including a reduction to zero. Reducing the likelihood of an occurrence shall include prevention of the occurrence. Correspondingly, the terms “prevent”, “preventing”, and “prevention” shall include the acts of “reduce”, “reducing”, and “reduction”, respectively.

[0057] The term "and / or" where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. For example "A and / or B" is to be taken as specific disclosure of each of (i) A, (ii) B and (iii) A and B, just as if each is set out individually herein.Client Docket No. : ARG-011-PCT

[0058] The term “one or more”, where used herein can mean one, two, three, four, five, six, seven, eight, nine, ten, or more, up to any number.

[0059] The terms “and combinations thereof’ and “and combinations of these” can each be used herein after a list of items that are to be included singly or collectively. For example, a component, process, and / or other item selected from the group consisting of: A; B; C; and combinations thereof, shall include a set of one or more components that comprise: 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.

[0060] In this specification, unless explicitly stated otherwise, “and” can mean “or”, and “or” can mean “and”. 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.

[0061] As used herein, when a quantifiable parameter is described as having a value “between” a first value X and a second value Y, it shall include the parameter having a value of: at least X, no more than Y, and / or at least X and no more than Y. For example, a length of between 1 and 10 shall include a length of at least 1 (including values greater than 10), a length of less than 10 (including values less than 1), and / or values greater than 1 and less than 10.

[0062] The expression “configured (or set) to” used in the present disclosure may be used interchangeably with, for example, the expressions “suitable for”, “having the capacity to”, “designed to”, “adapted to”, “made to” and “capable of’ according to a situation. The expression “configured (or set) to” does not mean only “specifically designed to” in hardware. Alternatively, in some situations, the expression “a device configured to” may mean that the device “can” operate together with another device or component.

[0063] As used herein, the term “threshold” refers to a maximum level, a minimum level, and / or range of values correlating to a desired or undesired state. 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, such as to cause a desired effect (e.g., efficacious therapy) and / or to prevent or otherwise reduce (hereinafter “prevent”) an undesired event (e.g., a device and / or clinical adverse event). In some embodiments, a system parameter is maintained above a first threshold (e.g., above a first temperature threshold to cause a desired therapeutic effect to tissue) and below a second threshold (e.g., below a second temperature threshold to preventClient Docket No. : ARG-011-PCTundesired tissue damage). In some embodiments, a threshold value is determined to include a safety margin, such as to account for patient variability, system variability, tolerances, and the like. As used herein, “exceeding a threshold” relates to a parameter going above a maximum threshold, below a minimum threshold, within a range of threshold values and / or outside of a range of threshold values.

[0064] The term “diameter” where used herein to describe a non-circular geometry is to be taken as the diameter of a hypothetical circle approximating the geometry being described. For example, when describing a cross section, such as the cross section of a component, the term “diameter” shall be taken to represent the diameter of a hypothetical circle with the same cross sectional area as the cross section of the component being described.

[0065] The terms “major axis” and “minor axis” of a component where used herein are the length and diameter, respectively, of the smallest volume hypothetical cylinder which can completely surround the component.

[0066] As used herein, the term “functional element” is to be taken to include one or more elements constructed and arranged to perform a function. A functional element can comprise a sensor and / or a transducer. In some embodiments, a functional element is configured to deliver energy and / or otherwise 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 comprising a sensor) can be configured to record one or more parameters, such as a patient physiologic parameter; a patient anatomical parameter (e.g., a tissue geometry parameter); a patient environment parameter; and / or a system parameter. In some embodiments, a sensor or other functional element is configured to perform a diagnostic function (e.g., to gather data used to perform a diagnosis). In some embodiments, a functional element is configured to perform a therapeutic function (e.g., to deliver therapeutic energy and / or a therapeutic agent). In some embodiments, a functional element comprises one or more elements constructed and arranged to perform a function selected from the group consisting of: deliver energy; extract energy (e.g., to cool a component); deliver a drug or other agent; manipulate a system component or patient tissue; record or otherwise sense a parameter such as a patient physiologic parameter or a system parameter; and combinations of one or more of these. A functional element can comprise a fluid and / or a fluid delivery system. A functional element can comprise a reservoir, such as an expandable balloon or other fluid-maintaining reservoir. A “functional assembly” can comprise an assembly constructed and arranged to perform a function, such as a diagnosticClient Docket No. : ARG-011-PCTand / or therapeutic function. A functional assembly can comprise an expandable assembly. A functional assembly can comprise one or more functional elements.

[0067] The term “transducer” where used herein is to be taken to include any component or combination of components that receives energy or any input, and produces an output. For example, a transducer can include an electrode that receives electrical energy, and distributes the electrical energy to tissue (e.g., based on the size of the electrode). In some configurations, a transducer converts an electrical signal into any output, such as: light (e.g., a transducer comprising a light emitting diode or light bulb), sound (e.g., a transducer comprising a piezo crystal configured to deliver ultrasound energy); pressure (e.g., an applied pressure or force); heat energy; cryogenic energy; chemical energy; mechanical energy (e.g., a transducer comprising a motor or a solenoid); magnetic energy; and / or a different electrical signal (e.g., different than the input signal to the transducer). Alternatively or additionally, a transducer can convert a physical quantity (e.g., variations in a physical quantity) into an electrical signal. A transducer can include any component that delivers energy and / or an agent to tissue, such as a transducer configured to deliver one or more of: electrical energy to tissue (e.g., a transducer comprising one or more electrodes); light energy to tissue (e.g., a transducer comprising a laser, light emitting diode and / or optical component such as a lens or prism); mechanical energy to tissue (e.g., a transducer comprising a tissue manipulating element); sound energy to tissue (e.g., a transducer comprising a piezo crystal); chemical energy; electromagnetic energy; magnetic energy; and combinations of one or more of these.

[0068] As used herein, the term “fluid” can refer to a liquid, gas, gel, or any flowable material, such as a material which can be propelled through a lumen and / or opening.

[0069] As used herein, the term “material” can refer to a single material, or a combination of two, three, four, or more materials.

[0070] It is appreciated that certain features of the inventive concepts, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the inventive concepts which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination. For example, it will be appreciated that all features set out in any of the claims (whether independent or dependent) can be combined in any given way.

[0071] It is to be understood that at least some of the figures and descriptions of the inventive concepts have been simplified to focus on elements that are relevant for a clearClient Docket No. : ARG-011-PCTunderstanding of the inventive concepts, while eliminating, for purposes of clarity, other elements that those of ordinary skill in the art will appreciate may also comprise a portion of the inventive concepts. However, because such elements are well known in the art, and because they do not necessarily facilitate a better understanding of the inventive concepts, a description of such elements is not provided herein.

[0072] Terms defined in the present disclosure are only used for describing specific embodiments of the present disclosure and are not intended to limit the scope of the present disclosure. Terms provided in singular forms are intended to include plural forms as well, unless the context clearly indicates otherwise. All of the terms used herein, including technical or scientific terms, have the same meanings as those generally understood by an ordinary person skilled in the related art, unless otherwise defined herein. Terms defined in a generally used dictionary should be interpreted as having meanings that are the same as or similar to the contextual meanings of the relevant technology and should not be interpreted as having ideal or exaggerated meanings, unless expressly so defined herein. In some cases, terms defined in the present disclosure should not be interpreted to exclude the embodiments of the present disclosure.

[0073] Tissue ablation is used in numerous medical procedures to treat one or more medical conditions of a patient. Ablation can be performed to remove or denature undesired tissue such as cardiac cells associated with an arrhythmia. The ablation can be performed by passing energy, such as electrical energy, through one or more electrodes and causing tissue death at locations proximate the electrodes (e.g., where heat generated by the delivery of energy is sufficient to cause cell death, and / or where the electric field generated is sufficient to irreversibly electroporate the tissue). Ablation procedures can be performed on heart tissue of patients with any form of cardiac arrhythmia, such as atrial fibrillation (AF).

[0074] Radiofrequency ablation (RFA) is a medical procedure in which tissue which is part of the electrical conduction system of the heart, tumor tissue, and / or other dysfunctional tissue is ablated using the heat generated from delivery of alternating current. Typical frequencies of the alternating current in this context may be considered to be from 350kHz to 500kHz.

[0075] Particularly, in these types of ablation procedures, an energy delivery device, such as a catheter or other probe with one or more electrodes, is inserted proximate target tissue to cause destruction of a target region of the cardiac tissue through the delivery of thermalClient Docket No. : ARG-011-PCTenergy. In fact, electrical induced thermal ablation, such as RFA, can be used to effectively and continuously locally ablate a tissue site as the energy delivery device is placed on the tissue surface. Although RFA can effectively ablate volumes of target tissue, there are limitations to this thermal technique. One often cited problem using this procedure during cardiac ablation involves heat sink, a process whereby one aspect can include blood flow whereas the heat generated on the ablation element will be removed / dissipated by the cooler blood flow over the element. This heat dissipation effect can change (e.g., undesirably reduce) both the shape and the maximum volume of the tissue being ablated.

[0076] More recently, to ablate heart and / or other organ tissue, Pulsed Electric Fields (PEF) have been used as an alternative to the above-mentioned RFA. Pulsed Electric Fields (PEF) refer to the delivery of intermittent, high-intensity electric fields for short periods of time (e.g., microseconds or nanoseconds), which results in cellular electroporation of tissue. Electroporation is a process whereby an applied electric field (i.e., PEF) results in the formation of pores in cell membranes. Pore formation leads to permeabilization, which can be reversible or irreversible, depending upon the parameters of the applied PEF.

[0077] In reversible electroporation, the electroporated cells remain viable. This approach underlies the basis of electrochemotherapy and gene electrotransfer. In contrast, with Irreversible Electroporation (IRE), cells and tissues are made non-viable because the technique induces programmed cell death cascade activation.

[0078] IRE is a well-established treatment for solid tumors, however, IRE may also be useful in cardiology, particularly for cardiac ablation, especially given the limitations of current thermal based approaches.

[0079] When used to ablate cardiac tissue, Irreversible Electroporation (IRE) involves the delivery of electrical pulses to targeted tissue for a duration in the range of microseconds to nanoseconds that can lead to non-thermally produced defects in the cell membrane that are nanoscale in size. These defects can lead to a disruption of homeostasis of the cell membrane, thereby causing irreversible cell membrane permeabilization which induces cell death, without significantly raising the temperature of the tissue ablation zone. In some embodiments, the systems, devices and methods of the present inventive concepts are configured to avoid raising the temperature of tissue proximate the tissue ablation zone to a maximum increase of no more than 13°C, such as no more than 10°C, 7°C, or 4°C, and / or toClient Docket No. : ARG-011-PCTavoid raising the temperature of tissue proximate the tissue ablation zone to a maximum of no more than 50°C, such as a maximum of no more than 47°C or 44°C.

[0080] The present application relates to providing electroporation waveforms, radiofrequency (RF) waveforms, and / or other waveform arrangements for treating tissue. In some embodiments, a console is configured to provide both electroporation waveforms and RF waveforms to a treatment device (e.g., a catheter-based treatment device).Electroporation waveforms can comprise a plurality of energy pulses each comprising sinewave signals, such as when the energy pulses are separated by inter-pulse delay periods. By providing for inter-pulse delay periods, as well as other delay periods described herein, it is possible to successfully cause targeted cell death, while avoiding undesirable heating at a target treatment site, while avoiding or at least reducing the formation of microbubbles, or both.

[0081] Referring now to Fig. 1, a schematic example of a system comprising a catheter assembly and a generator for providing electroporation is illustrated, consistent with the present inventive concepts. System 10 can include generator 100 comprising a controller 110 configured to control one or more signal generators, such as signal generator 120, each as shown. System 10 can include one or more power supplying assemblies, such as power source 130 of generator 100. Power source 130 can be configured to provide power to signal generator 120. Generator 100 can be configured to deliver electrical energy comprising one or more waveforms, such as waveform 200, described in detail herein. In some embodiments, waveform 200 comprises a waveform configured to electroporate target tissue (e.g., irreversibly electroporate target tissue), electroporation waveform 200E. In some embodiments, generator 100 (e.g., and signal generator 120) are configured to deliver one, two, or more forms of energy selected from the group consisting of: radiofrequency energy; electroporation energy; ultrasound and / or other sound energy; laser and / or other light energy; chemical energy; mechanical energy; and combinations of these. System 10 can include one or more energy delivery devices and / or patient treatment devices, such as catheter assembly 300 shown. Catheter assembly 300 can operably attach to generator 100 such that electroporation waveform 200 can be provided by generator 100 and delivered to the patient via catheter assembly 300, such as is described herein.Client Docket No. : ARG-011-PCT

[0082] Catheter assembly 300 can include one, two, or more discrete elongate assemblies, such as two or more elongate assemblies that are configured to slidingly receive and / or be slidingly received within each other, and / or couple and / or decouple from each other, as described herein. For example, catheter assembly 300 can include an inner assembly, inner catheter 310, and an outer assembly configured to slidingly receive inner catheter 310, outer catheter 350, each shown. In some embodiments, system 10 includes multiple configurations of inner catheter 310 and / or outer catheter 350, such as, for example, when a configuration of outer catheter 350 is configured to interchangeably slidingly receive various configurations of inner catheter 310, as described herein. As described herein, embodiments of outer catheter 350 comprise catheters that are constructed and arranged to slidingly receive other catheters, such as to slidingly receive one or more other inner catheters 310 within a lumen of a shaft of outer catheter 350. Embodiments of inner catheter 310 can comprise catheters that are constructed and arranged to be slidingly received within other catheters and / or catheters that are constructed and arranged to be inserted into a patient directly (e.g., not through a lumen of an outer catheter 350). Embodiments of either or both inner catheter 310 and outer catheter 350 can be configured to be used with or without an outer catheter 350 or inner catheter 310, respectively. As used herein, an embodiment of catheter assembly 300 comprising a single catheter (e.g., a catheter that is configured to be inserted directly into a patient, such as through an introducer device) will be described in reference to inner catheter 310. It should be understood that various components and / or arrangements of catheter assembly 300 described in reference to an embodiment of inner catheter 310 or outer catheter 350 can also be included in an embodiment of outer catheter 350 or inner catheter 310, respectively. It should also be understood that various components of catheter assembly 300 can be inserted into a patient via one or more access devices, such as vascular access devices, guide sheath catheters, and the like.

[0083] Catheter assembly 300 can include one or more arrays of electrode assemblies, such as array 320 of electrode assemblies 325. Each electrode assembly 325 can include one or more conductive portions, electrodes 3251. Each electrode assembly 325 can be operably connected to generator 100 such that each assembly is individually addressable by generator 100 for delivery of energy via the electrode assembly, as described herein. In some embodiments, array 320 comprises an array of other forms of energy delivery elements, such as when electrodes 3251 comprise one, two, or more elements configured to deliver energy inClient Docket No. : ARG-011-PCTthe form of: ultrasound and / or other sound energy; laser and / or other light energy; chemical energy; mechanical energy; and combinations of these.

[0084] Catheter assembly 300 can include one or more handle assemblies, handle 330 shown, such as a handle assembly including one or more user controls, as described herein. One or more catheters of catheter assembly 300 can be fixedly attached to a handle 330, and one or more catheters of catheter assembly 300 can be configured to removably attach to a handle 330 and / or be slidingly inserted through a portion of a handle 330 (e.g., inserted through handle 330 and slidingly received within a catheter that is fixedly attached to handle 330). For example, the proximal end of inner catheter 310 can be fixedly attached to handle 330. Outer catheter 350 can be configured to slidingly receive inner catheter 310, such that the proximal end of outer catheter 350 is positioned proximate handle 330 (e.g., such that outer catheter 350 can removably attach to a portion of handle 330). Alternatively, or additionally, the proximal end of outer catheter 350 can be fixedly attached to handle 330. Inner catheter 310 can be configured to be slidingly received, from the proximal end, through outer catheter 350 (e.g., through a portion of handle 330). In some embodiments, inner catheter 310 can removably attach to a portion of handle 330 when inserted into outer catheter 350. Handle 330 can include a catheter control assembly, control assembly 335. Control assembly 335 can include one or more user controls, such as one or more buttons, knobs, levers, switches, or other controls configured to enable a user to manipulate and / or otherwise control catheter assembly 300 (e.g., to steer a catheter and / or to initiate the delivery of a therapy that is provided via the catheter). Control assembly 335 can include one or more assemblies for steering a portion of catheter assembly 300, such as steering control assembly 336. In some embodiments, a steering control assembly 336 can be constructed and arranged to steer one or more segments of a catheter assembly 300 (e.g., to steer along multiple axes), and / or control assembly 335 can comprise multiple steering assemblies 336, such as an assembly for each axis of articulation of catheter assembly 300, as described herein.

[0085] In some embodiments, each of inner catheter 310 and outer catheter 350 comprise a handle 330, such as when a handle 330 of inner catheter 310 is configured to operably engage a handle 330 of outer catheter 350 when the two catheters slidingly receive each other, as described herein.Client Docket No. : ARG-011-PCT

[0086] Catheter assembly 300 can include one or more expandable assemblies, expandable assembly 360 shown. Expandable assembly 360 can be positioned on an embodiment of inner catheter 310 and / or an embodiment of outer catheter 350. In some embodiments, at least a portion of array 320 is positioned on expandable assembly 360, as described herein.

[0087] Catheter assembly 300 can include one or more elongated interconnects, cable 305. Cable 305 can include one or more mechanical, electrical, optical, fluid, and / or other interconnecting elements, such as one or more linkages, wires, flex circuits, optical fibers, or fluid tubes. Cable 305 can include one or more connector assemblies, such as connector 306, which can be configured to operably attach to a mating connector assembly, such as to create one or more mechanical, electrical, optical, fluid and / or other operable connections (“operable connections” herein) between catheter assembly 300 and another component of system 10, such as generator 100.

[0088] Catheter assembly 300 can include one or more connector assemblies, such as connector assembly 340 that is configured to operably connect an inner catheter 310 to an outer catheter 350. In some embodiments, connector assembly 340 is configured to fixedly attach inner catheter 310 to outer catheter 350, such as to maintain the longitudinal alignment of the catheters.

[0089] Delivery of electroporation waveform 200E to one or more electrodes 3251 can result in one or more electric fields, singly or collectively electric field 290, that is generated in tissue proximate the electrodes 3251 of catheter assembly 300 receiving electroporation waveform 200E. AS described herein, the parameters and method of delivery of electroporation waveform 200E can be configured such that tissue, within a portion of electric field 290 that is sufficient to electroporate the tissue, is effectively electroporated, such as is described herein. In some embodiments, one or more components of system described herein as integral to generator 100 may not be integral to generator 100 but rather may operably attach to generator 100. For example, an external power source can be used and, as such, power source 130 may not comprise an integral part of generator 100. In other examples, the signal generator 120 itself can also comprise power source 130 as opposed to the two components being provided power individually. In some examples, controller 110 can be powered by power source 130 while in other examples, controller 110 can be powered by other means.Client Docket No. : ARG-011-PCT

[0090] In some embodiments, when delivering electroporation waveform 200E, energy can be delivered between two or more adjacent and / or other endocardially-positioned electrodes, such as electrodes 3251 of catheter assembly 300, in a bipolar arrangement, as described herein. Additionally or alternatively, energy can be delivered between an endocardially-positioned electrode 3251, and one or more external patient return patches, such as external electrode 60 shown. Delivery of energy between an endocardially-positioned electrode (e.g., electrode 3251) and one or more external patch electrodes (e.g., external electrode 60) can be described as delivering energy in a unipolar arrangement. In some embodiments, for example, when system 10 utilizes pure sine waves, electroporation waveform 200E can be delivered by generator 100 in a phased-combination arrangement (i.e., a combination of bipolar and unipolar delivery), where these pure sine waves can be combined to interfere constructively, by varying the relative phase between sine waves applied to adjacent activated electrodes (e.g., electrodes 3251), and a reference voltage can be provided by generator 100 to external electrode 60 (e.g., one or more patch electrodes positioned on the skin of the patient), such as is described herein.

[0091] In some embodiments, electroporation waveform 200E is configured to provide, when delivered to tissue, coherent sine-burst electroporation (CSE). CSE comprises the delivery of high voltage (e.g., at least 100V, or 1500V), phased sine waves to ablate (e.g., irreversibly electroporate) tissue, as described herein. Alternatively, or additionally, waveform 200E can be configured to deliver other forms of energy, such as one, two, or more energy forms selected from the group consisting of: radiofrequency energy; ultrasound and / or other sound energy; laser and / or other light energy; chemical energy; mechanical energy; and combinations of these.

[0092] Generator 100 can include one or more isolation transformers. Sine waves are more compatible with isolation transformers than square waves because the energy of the sine wave can be concentrated at a single frequency in the passband of the isolation transformer. Isolation transformers are considered the “gold standard” for patient safety because these types of transformers allow the patient’s electrical potential to “float” relative to the potential in the generator 100, and all pulsed field ablation (PF A) energy must couple through the transformer’s magnetic field to reach the patient. Therefore, any electrical failure on the generator 100 primary side of the transformer does not propagate to the secondary side attached to catheter assembly 300, because of the isolation created by the transformer’s magnetic field. By generator 100 providing a sine wave and leveraging the voltage gainClient Docket No. : ARG-011-PCTmade possible by a properly selected isolation transformer, it is possible for generator 100 to generate much higher voltages and thus much higher electric fields in a sine wave-based generator configuration, which will result in greater depth propagation of irreversible PFA.

[0093] Additionally, pure sine waves can be easily combined by generator 100 to interfere constructively, by varying the relative phase between multiple sine waves applied to adjacent activated electrodes, as described herein. If an external electrode 60 is connected, and the sine waves of a given frequency applied to adjacent activated electrodes 3251 (e.g., electrodes positioned on the endocardial surface) have no phase shift, then a unipolar field is generated between the electrodes 3251 and external electrode 60 (e.g., comprising one or more patch electrodes). If the sine waves applied to adjacent activated electrodes 3251 are at the same frequency, but 180° out of phase, then the two waves constructively interfere and combine to create a bipolar sine wave of twice the amplitude of that applied to each individual electrode 3251. No external electrode 60 (e.g., no return patch electrodes) is needed in this configuration.

[0094] System 10 can use unipolar fields to create a deeper lesion for a given peak voltage than a bipolar lesion. This increased depth is due to the field being directed from the endocardial tissue surface contacted by electrodes 3251 outwards through the thickness of the heart 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 larger number of muscle groups that are located between the electrodes 3251 and external electrode 60. Depending on electrode 3251 spacing and other factors, unipolar lesions can also result in less uniform “fill” between adjacent electrodes 3251 and can include gaps. Bipolar fields maintain their fields locally because the endocardially-positioned electrodes 3251 act as both a source and sink, resulting in negligible neuromuscular stimulation and a higher uniformity of fill without gaps between electrodes. Although the more localized nature of a bipolar field leads to less tissue penetration for a given peak voltage, the voltage doubling by driving out of phase can compensate and thus bipolar fields are often preferred in applications like Atrial Fibrillation (AF) where the tissue to be ablated is frequently less than 5mm in thickness to the epicardial surface.

[0095] Finally, another advantage of sine wave based systems is that sine wave based PFA is more efficient than either biphasic or monophasic square wave based PFA. Unlike standard RF ablation which relies on the root-mean-square (RMS) of the AC current to causeClient Docket No. : ARG-011-PCTresistive heating, electroporation is a field effect which relies on the peak amplitude of the field being generated. For any given amplitude, sine waves have less power, hence less heat generated, than square waves of the same amplitude. Further, a portion of the spectral energy in a square wave which causes the heat is contained within the odd harmonics. These harmonics are at multiples of the fundamental frequency where electroporation is less effective due to the low pass nature of biological tissue. In short, to generate a field of equivalent amplitude to a sine-wave based system, square wave systems require more heat generating energy at frequencies where it will have minimal impact on lesion generation.

[0096] System 10 can be configured to provide electroporation at a treatment site of a patient via catheter assembly 300. In particular, the electroporation technique may comprise high-frequency irreversible electroporation, however, in some embodiments, system 10 can be configured to provide a different type of electroporation, such as low frequency nonthermal irreversible electroporation or reversible electroporation, and / or electrolytic electroporation, such as electrolytic electroporation comprising a combination of low and high frequency electroporation.

[0097] Unipolar energy delivery methods can be used to create a deeper lesion for a given peak voltage than for a lesion created using a bipolar method utilizing two or more endocardially-positioned electrodes (e.g., electrodes 3251), because the direction of the resultant field (e.g., electric field 290) can be oriented from the contacted endocardial tissue outwards through the thickness of the heart wall tissue and through the rest of the body toward the one or more patch electrodes (e.g., external electrode 60) on the patient’s skin. This unipolar energy delivery tends to result in a greater degree of neuromuscular stimulation due to the larger number of muscle groups that are located on the path to the associated patient return electrode (e.g., external electrode 60). In some embodiments, for example, depending on the configuration of catheter assembly 300 and electrode 3251 spacing as well as other factors, lesions created using a unipolar energy delivery can result in less uniform “fill” between adjacent electrodes 3251 and can possibly include gaps. Bipolar fields maintain their fields locally because the endocardially-positioned electrodes 3251 act as both a source and sink, resulting in negligible neuromuscular stimulation and a higher uniformity of fill, without any gaps between electrodes 3251.

[0098] 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 theClient Docket No. : ARG-011-PCTunipolar component created by pulling the field in a given direction toward the one or more patch electrodes that are activated. For example, if external electrode 60 comprises a patch electrode that is placed on the patient’s skin such that the substrate to be ablated is tissue located between the endocardially-positioned electrodes 3251 and the external electrode 60, the size of the created lesion will be enhanced (e.g., deeper depth is achieved and a transmural lesion is created). System 10 can be configured to ablate one or more locations in any chamber of the heart, such as when configured to allow a clinician to ablate any location in the left atrium and / or other heart chamber. In some embodiments, external electrode 60 comprises multiple patch electrodes that are positioned on the patient’s skin in various locations, with each electrode independently activatable (e.g., configured to be selected as a return electrode), such as to activate particular patch electrodes to direct the field in one or more of anterior, posterior, superior and / or inferior directions, such as to cause a transmural lesion to be created in the cardiac wall at the location of the associated electrode 3251.

[0099] Controller 110 can comprise a module (e.g., an electronics module) that can be configured to perform and / or facilitate one or more functions of system 10, such as one or more processes; energy deliveries, such as delivery of an electroporation waveform; data analyses; data transfers; signal processing; and / or other functions of system 10 (“functions of system 10” or “system 10 functions” herein). Controller 110 can comprise 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; rectification circuitry; filters and other signal conditioners; sensor interface circuitry; transducer interface circuitry; 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, such as processor 111 and memory 112, each shown. Memory 112 can be coupled to processor 111, and memory 112 can store instructions used by processor 111 to perform one or more algorithms of system 10. For example, system 10 can comprise one or more algorithms, algorithm 25 shown, that are performed by processor 111 and / or another similar arrangement of a processor and instructions stored in memory. Algorithm 25 can comprise one or more machine learning, neural net, and / or other artificial intelligence algorithms (“Al algorithm” herein). All or a portion of algorithm 25 can be integrated into (e.g., stored in the memory of) one, two, or more of the various components of system 10, such as a device or other component of system 10 comprising a processor and / or a console of system 10. Controller 110 can comprise aClient Docket No. : ARG-011-PCTmicroprocessor or other processing unit which enables it to receive input data and provide output signals based on the input data. In some embodiments, controller 110 is configured to receive inputs from a user input device and / or from an automated computing device. Inputs from a user input device may come directly to controller 110 and / or may be provided via one or more other electronic devices. The inputs received by controller 110 can relate to particular parameters that define an electroporation waveform. For example, the received parameters can comprise a desired frequency, intensity, duration, phase, cycle length or other parameter of the waveform. As an output, controller 110 can be configured to provide signaling which is configured to interact with signal generator 120 where the signaling is configured to cause signal generator 120 to generate a desired electroporation waveform.

[0100] In some embodiments, generator 100 and / or another component of system 10 can include a user interface, such as user interface 150 of generator 100 shown, such as a user interface configured to provide and / or receive information to and / or from an operator of system 10. User interface 150 can be integrated into generator 100 as shown. Alternatively or additionally, user interface 150 can comprise a component separate from generator 100, such as a display separate from, but operably attached to, generator 100. User interface 150 can include one, two, or more user input and / or user output components. For example, user interface 150 can comprise a joystick, keyboard, mouse, touchscreen, speaker, light, transducer, and / or another human interface device, user interface device 151 shown. In some embodiments, user interface 150 comprises a display (e.g., a touchscreen display), such as display 152, also shown. In some embodiments, processor 111 can provide a graphical user interface, GUI 153 shown, to be presented on and / or provided by display 152.Algorithm 25 can be configured to perform one or more software routines that enable user control of one or more functions of system 10. The one or more software routines performed by algorithm 25 can comprise a graphical user interface, such as GUI 153. User interface device 151 can include an input and / or output device selected from the group consisting of a speaker; an indicator light, such as an LED indicator; a haptic feedback device such as a device comprising a vibrational alert component; a foot pedal; a switch, such as a momentary switch; a microphone; a camera, for example, when processor 111 enables eye tracking and / or other input via image processing; and combinations of these. In some embodiments, catheter assembly 300 includes at least a portion of user interface 150, such as a user interface device 151, for example, when functional element 399 of catheter assembly 300 comprises a button or other interface device 151 of user interface 150. Additionally, orClient Docket No. : ARG-011-PCTalternatively, catheter assembly 300 can include a user interface device 151 including a user output device, such as a light or a speaker, for example, a light configured to indicate a readiness condition of system 10 (e.g., a light configured to indicate when system 10 is and / or is not ready to provide electroporation waveform 200E).

[0101] In some embodiments, system 10 includes a data storage and processing device, server 400. Server 400 can comprise an “off-site” server (e.g., outside of the clinical site in which 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 comprise a cloud-based server. Server 400 can include processing unit 410 shown, 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 comprise a memory (not shown), which can store instructions for performing algorithm 25. Server 400 can be configured to receive and store various forms of data, such as: treatment data, diagnostic data, planning data, and / or procedural outcome data collected by system 10, data 420. In some embodiments, data 420 can comprise data collected from multiple patients (e.g., multiple patients treated with system 10), such as data collected during and / or after clinical procedures where electroporation waveform 200E was delivered to the patient via system 10. In some embodiments, generator 100 and server 400 can communicate over a network, for example, a wide area network such as the Internet. Alternatively, or additionally, system 10 can include a virtual private network (VPN) through which various devices of system 10 transfer data.

[0102] As described herein, the one or more functions of system 10 performed by controller 110 and / or processing unit 410 can be performed by either or both devices. For example, in some embodiments, treatment data can be collected by controller 110 of generator 100. The treatment data can then be transferred to server 400, where the data is processed, for example, to identify one or more trends, such as one or more trends in the effectiveness of various parameters of electroporation waveform 200E described herein. The insight attained from data processing of server 400 can then be transferred back to generator 100, for example, to inform a decision-making process (e.g., a decision made by algorithm 25 and / or an operator of system 10) regarding one or more parameters of electroporation waveform 200E to be provided to treat a patient.Client Docket No. : ARG-011-PCT

[0103] In some embodiments, algorithm 25 is configured to adjust (e.g., automatically and / or semi-automatically adjust, such as an adjustment performed based on one or more biases included in algorithm 25, as described herein) one or more operational parameters of system 10, such as one or more of the parameters of electroporation waveform 200E described herein. In some embodiments, algorithm 25 is configured to adjust an operational parameter based on one or more sensor signals, such as a sensor signal provided by a sensorbased functional element of the present inventive concepts as described herein. Algorithm 25 can be configured to adjust (e.g., automatically adjust and / or recommend the adjustment of) an operational parameter selected from the group consisting of to which one or more electrodes of a set of electrodes to provide electroporation waveform 200E (e.g., one or more electrodes 3251 of array 320 and / or one or more external electrodes 60); with which energy modality to deliver energy; the phase angle between two or more signals of electroporation waveform 200E; to which tissue locations to deliver energy, such as locations determined by analyzing cardiac mapping data; to which external electrode 60 to provide electroporation waveform 200E such as to direct the generated electric field toward target tissue; and combinations of two or more of these.

[0104] In some embodiments, algorithm 25 is configured to determine one or more parameters of a stimulation waveform. In these embodiments, algorithm 25 can comprise one or more biases, such as a bias to create a stimulation waveform that tends toward: a particular frequency range; a particular ratio of bipolar-to-unipolar energy delivery; a particular phase difference between included sine waves; a particular voltage or range of voltages; a particular delay between energy deliveries such as a particular inter-pulse delay; and combinations of one or more of these.

[0105] It will be appreciated that the term “signaling” used herein refers to one or more signals provided by controller 110 that comprise information for interpretation by signal generator 120 or, optionally, by another component of system 10. Signaling can be provided by way of one or more wired connections and / or wireless modes of data communication. As mentioned above, the signaling can be provided to signal generator 120 as per the embodiment of Fig. 1, and / or it may be provided to a power source itself, the power source being configured to generate an electroporation waveform, as described herein.

[0106] In some embodiments, algorithm 25 can be configured to cause system 10 to perform a method, method 510 shown, the method 510 providing an electroporationClient Docket No. : ARG-011-PCTwaveform (e.g., electroporation waveform 200E described herein) to an ablation device, such as catheter assembly 300. Method 510 can comprise providing signaling from controller 110 to a signal generator 120. The signaling can be configured to cause the signal generator 120 to produce an electroporation waveform 200E, and the electroporation waveform can comprise a plurality of pulses, where each energy pulse is separated by an inter-pulse delay period, such as energy pulses separated by inter-pulse delay periods. In some embodiments, method 510 is of similar construction and arrangement as the methods described in applicant’s co-pending United States Patent Application Serial Number 19 / 115,161, filed March 25, 2025, entitled “Electroporation System”, the content of which is herein incorporated by reference in its entirety for all purposes.

[0107] In some embodiments, each energy pulse can comprise one or more distinct sinewave signals, as described herein. Method 510 can further comprise generating the electroporation waveform based on the signaling (e.g., signal generator 120 can generate electroporation waveform 200E based on the signaling from controller 110). Method 510 can include providing the electroporation waveform 200E from the signal generator to an electroporation catheter, such as catheter assembly 300, for the provision of the electroporation waveform 200E to a target area.

[0108] In some embodiments, algorithm 25 can be configured to cause system 10 to perform a method, method 520 shown, the method 520 providing an electroporation waveform and one or more compensation signals. In some embodiments, method 520 comprises providing signaling (e.g., signaling from controller 110) to cause the provision of an electroporation waveform 200E, where the electroporation waveform 200E comprises one or more sequentially provided energy pulses 210 where each energy pulse 210 is configured to cause electroporation. Method 520 can further comprise providing signaling from controller 110 to cause the signal generator 120 to provide one or more compensation signals where the one or more compensation signals are configured to reduce a build-up of charge at a treatment location of a patient, the built-up charge caused by one or more of the plurality of stimulation signals (e.g., the plurality of energy pulses 210). In some embodiments, the controller 110 may be configured to provide this signaling to a signal generator 120 to cause the signal generator 120 to provide the electroporation waveform 200E comprising the energy pulses and the charge-reducing compensation signals. In some embodiments, the compensation signals are added to the electroporation waveform 200E. In some embodiments, method 520 is of similar construction and arrangement as the methodsClient Docket No. : ARG-011-PCTdescribed in applicant’s co-pending United States Patent Application Serial Number 19 / 115,161, filed March 25, 2025, entitled “Electroporation System”, the content of which is herein incorporated by reference in its entirety for all purposes.

[0109] In some embodiments, algorithm 25 can be configured to cause system 10 to perform a method, method 530 shown. Method 530 can comprise providing first signaling configured to cause the application of a first potential difference between a first electrode and a second electrode (e.g., a first electrode 3251 and a second electrode 3251 of catheter assembly 300) where the second electrode is a non-neighboring (e.g., non-adjacent) electrode to the first electrode. Method 530 can further comprise providing second signaling configured to cause the application of a second potential difference between a third electrode and a fourth electrode (e.g., a third electrode 3251 and a fourth electrode 3251 of catheter assembly 300) where the third electrode is a neighboring electrode (e.g., an adjacent electrode) to the first electrode and the fourth electrode is a non-neighboring electrode to the third electrode. In some embodiments, the first potential difference is applied between the first electrode and the second electrode asynchronously from the application of the second potential difference between the third electrode and the fourth electrode. Method 530 can be applied throughout a plurality of electrodes and electrode pairs, resulting in a contiguous cellular ablation lesion. In some embodiments, method 530 is of similar construction and arrangement as the methods described in applicant’s co-pending United States Patent Application Serial Number 19 / 115,161, filed March 25, 2025, entitled “Electroporation System”, the content of which is herein incorporated by reference in its entirety for all purposes.

[0110] Signal generator 120 can comprise any suitable signal generator for generating the electroporation waveform which comprises an electric signal for energizing one or more of the electrodes 3251 of catheter assembly 300. That is, the electroporation waveform is configured to cause the application of voltage electric fields to biological tissue via electrodes 3251 of catheter assembly 300. In particular, signal generator 120 can comprise a sinewave generator that is configured to generate signals comprising one or more sinewaves. Power source 130 can comprise any suitable device for providing electrical power to at least signal generator 120.

[0111] In some embodiments, system 10 can be configured to generate multiple different arrangements of waveforms and frequencies (“waveform modalities” herein) from a “singleClient Docket No. : ARG-011-PCTsource” (e.g., a generator 100 comprising a single signal generator 120), where the single source can provide two or more waveform modalities used to deliver energy to treat various patient conditions and / or various tissue types. The two or more waveform modalities can comprise different frequencies (e.g., different frequencies within a single modality and / or between two or more modalities). In some embodiments, system 10 can be configured to switch between different two or more waveform modalities during a clinical procedure performed using system 10.

[0112] In some embodiments, signal generator 120 can be configured to generate one or more waveform modalities selected from the group consisting of but not limited to: “PF A sine wave waveforms” (one or more sine wave-based waveforms configured to perform PF A); “PFA biphasic square wave waveforms” (one or more biphasic square wave-based waveforms configured to perform PFA); “RF sine wave waveforms” (one or more sine wave-based waveforms configured to perform thermal radiofrequency ablation); one or more “charge-balanced” waveforms; one or more PFA and / or RF waveforms comprising triangle waveforms and / or sawtooth waveforms; one or more waveforms comprising high-amplitude, short impulse followed by a low-amplitude, long stimulus; one or more arbitrary waveforms; and combinations of these. In some embodiments, signal generator 120 is configured to at least generate PFA sine wave waveforms (e.g., for irreversible electroporation applications). In some embodiments signal generator 120 is configured to at least generate PFA biphasic square wave waveforms. Additionally, or alternatively, signal generator 120 can be configured to at least generate biphasic square wave waveforms (e.g., for pulse field ablation procedures). Additionally, or alternatively, signal generator 120 can be configured to at least generate RF sine wave waveforms (e.g., for radiofrequency ablation applications). In some embodiments, signal generator 120 can be configured to generate two or more of these waveforms such as from a single source (e.g., as described herein). The single source can comprise “shared hardware modules” (modules used to deliver at least one RF waveform and at least one PFA waveform) and / or “specialized hardware modules” (modules used to deliver one or more RF waveforms and / or one or more PFA waveforms).

[0113] In some embodiments, signal generator 120 can comprise a hardware module comprising one or more hardware modules, such as shared RF / PFA hardware 121 (as shown in reference to Fig. 8). In some embodiments, shared RF / PFA hardware 121 can be configured to provide a common function (e.g., one or more functions common to both RF delivery and PFA delivery) across multiple energy delivery modalities. Additionally, orClient Docket No. : ARG-011-PCTalternatively, signal generator 120 can comprise one or more specialized hardware modules such as: low frequency sine wave PFA hardware 122, high frequency sine wave PFA hardware 123, biphasic square wave PFA hardware 124, RF ablation sine wave hardware 125, arbitrary waveform hardware 126, and / or combinations of these, for example, as shown in Fig. and described herein. In some embodiments, generator 100 (e.g., signal generator 120) is constructed and arranged as described in reference to Figs. 8, 9A-B, and / or Figs. 10A-F.

[0114] In some embodiments, system 10 and / or one or more components of system 10 further comprise one or more functional elements (“functional element” herein) such as functional element 99, functional element 199 of generator 100, and / or functional element 399 of catheter assembly 300, each shown. Each functional element can comprise at least two functional elements. Each functional element can comprise one or more elements selected from the group consisting of: sensor; transducer; and combinations of these. Each functional element of system 10 can comprise a sensor configured to produce a signal. Each functional element can comprise a sensor selected from the group consisting of: a physiologic sensor; a pressure sensor; a strain gauge; a position sensor; a GPS sensor; an accelerometer; a temperature sensor; a magnetic sensor; a chemical sensor; a biochemical sensor; a protein sensor; a flow sensor such as an ultrasonic flow sensor; a gas detecting sensor such as an ultrasonic bubble detector; a sound sensor such as an ultrasound sensor; an impedance sensor; a charge sensor; and combinations of these. Each functional element can comprise a physiologic sensor selected from the group consisting of: a pressure sensor such as a blood pressure sensor; a blood gas sensor; a flow sensor such as a blood flow sensor; a temperature sensor such as a blood or other tissue temperature sensor; and combinations of these. In some embodiments, system 10 can further comprise one or more algorithms, such as algorithm 25 described herein, which can be configured to process the signal produced by a sensor-based functional element. Each functional element can comprise one or more transducers. Each functional element can comprise one or more transducers selected from the group consisting of: a heating element such as a heating element configured to deliver sufficient heat to ablate tissue; a cooling element such as a cooling element configured to deliver cryogenic energy to ablate tissue; a sound transducer such as an ultrasound transducer; a vibrational transducer; and combinations of these. In some embodiments, functional element 399 comprises one or more vacuum ports that are fluidly connected (e.g., via a lumen of catheter assembly 300) to a functional element 199 comprising a source ofClient Docket No. : ARG-011-PCTvacuum. In these embodiments, vacuum can be applied to functional element 399 by element 199, such that one or more portions of catheter assembly 300 (e.g., one or more portions including one or more electrodes 3251) are maintained in contact with tissue via the applied vacuum.

[0115] Referring now to Figs. 2A and 2B, side view of the catheters of an embodiment of a catheter assembly, and perspective views of the distal portion of a catheter of the catheter assembly in various geometric configurations are illustrated, respectively, consistent with the present inventive concepts. Catheter assembly 300 and / or other components of system 10 described in Figs. 2A and 2B can be of similar construction and arrangement as the similar components described in reference to Fig. 1 and otherwise herein. Fig. 2A shows side views of an embodiment of outer catheter 350, and two embodiments, of inner catheters 310 of catheter assembly 300, inner catheters 310a and 310b. Outer catheter 350 can include an elongated body, shaft 351. Shaft 351 can include one or more lumens, such as lumen 352 (not shown), extending through shaft 351 from the proximal end of the shaft to a distal portion of the shaft. In some embodiments, lumen 352 extends to the distal end of shaft 351 (e.g., such that an inner catheter 310 can be inserted through lumen 352 and extend through lumen 352 and beyond the distal end of shaft 351. Array 320 can be positioned on a distal portion of shaft 351, as shown. A first connector portion of connector assembly 340, connector 345, can be fixedly attached to a proximal portion of shaft 351.

[0116] Each inner catheter 310 can comprise an elongated body, shaft 311a and 311b shown. Each shaft 311 can extend distally from a handle 330, as shown. Each handle 330 can include a control assembly 335, as shown. Each handle 330 can include a portion of connector assembly 340, such as connector 341, that is configured to fixedly attach to connector 345 of outer catheter 350, as described herein. In some embodiments, shaft 311 of inner catheter 310 comprises a user manipulatable portion, articulatable portion 312.Various embodiments of inner catheter 310 can comprise articulatable portions 312 that are configured to be manipulated into different geometries. For example, as shown, inner catheter 310a can comprise articulatable portion 312a that is configured to be manipulated by the user (e.g., steered) with a single degree of freedom, such as to curl shaft 31 la in a single plane (e.g., in a single direction in a single plane, as shown, or in either direction in a single plane). Additionally, or alternatively, inner catheter 310b can comprise asClient Docket No. : ARG-011-PCTarticulatable portion 312b that is configured to be manipulated by the user with multiple degrees of freedom, for example, to form a loop that is perpendicular to the axis of shaft 31 lb, as shown. In some embodiments, for example, when an articulatable portion 312 comprises a multi-bend shape (e.g., such as articulatable portion 312b), one or more segments of the articulatable portion can comprise a non-linear set shape. In some embodiments, articulatable portion 312 comprises a non-linear set shape, and is configured to be straightened (e.g., manually straightened by the user) for insertion into lumen 352 of shaft 351. In some embodiments, articulatable portion 312 comprises a segment with non-linear set shape and a steerable segment (e.g., a segment configured to be steered in a plane that is not parallel to the axis of shaft 311). As described herein, an articulatable portion (e.g., articulatable portion 312 and / or 353 described herebelow) of a catheter can comprise a steerable portion configured to be manipulated by steering wires and / or other steering mechanisms described herein, can comprise a non-linear set shape configured to be straightened (e.g., when positioned within a non-articulatable portion of an outer catheter), and / or can comprise a flexible portion configured to follow the shape of another catheter (e.g., the shape of a steerable and / or non-linearly biased portion of a catheter positioned within and / or surrounding the articulatable portion).

[0117] Shaft 351 can also comprise a manipulatable portion, articulatable portion 353.Articulatable portion 353 can comprise a flexible portion of shaft 351 that is configured to conform to the shape of an articulatable portion 312 of an inner catheter 310 that has been inserted into outer catheter 350, such that articulatable portion 312 and articulatable portion 353 are longitudinally aligned, as described herein. In some embodiments, at least a portion of array 320 is positioned on articulatable portion 353. Fig. 2B shows various geometric configurations of articulatable portion 353 of shaft 351 that are set by the shape of an articulatable portion 312 of shaft 311 positioned within lumen 352. For example, Fig. 2B shows (left) articulatable portion 353 in a linear configuration, for example, with articulatable portion 312b of shaft 311 in a linear configuration within lumen 352. Fig. 2B also shows (middle) articulatable portion 353 in a curved geometry, for example, with articulatable portion 312a of shaft 311 in a matching curved geometry within lumen 352. Fig. 2B also shows (right) articulatable portion 353 in a complex curved geometry, for example, with articulatable portion 312b of shaft 31 lb in a matching geometry within lumen 352. In some embodiments, one or more segments of articulatable portion 353 are configured to be manipulated by the user independently of inner catheter 310, for example, when outerClient Docket No. : ARG-011-PCTcatheter 350 comprises steering wires or other elements for controlling the shape of articulatable portion 353.

[0118] In some embodiments, inner catheters 310a and 310b are configured to be interchanged within outer catheter 350 while shaft 351 is positioned within a patient (e.g., when outer catheter 350 has been advanced through the vasculature of the patient). By exchanging inner catheters 310a and 310b, outer catheter 350 can be used to perform ablation treatments with multiple configurations of articulatable portion 353, such that catheter assembly 300 comprises a single, multi-purpose catheter, outer catheter 350, with interchangeable stylet type catheters, inner catheters 310a and 310b. For example, catheter assembly 300 can be used to perform linear and / or focal ablations with articulatable portion 353 configured as shown in the left image of Fig. 2B, circular linear ablations with articulatable portion 353 configured as shown in the middle image of Fig. 2B, and / or circular (e.g., PVI) ablations with articulatable portion 353 configured as shown in the right image of Fig. 2B.

[0119] Each inner catheter 310 can include cable 305 extending from handle 330 and terminating with connector 306, as shown. In some embodiments, one or more conduits (e.g., wires) extend from connector 306 to connector 341 (e.g., one or more wires of cable 305 that extend through handle 330), such that one or more operable connections can be made between outer catheter 350 and connector 306, such as when connector 345 is operably connected to connector 341.

[0120] Referring now to Fig. 3, a side view of an embodiment of a catheter assembly positioned relative to tissue and within a pool of blood is illustrated, consistent with the present inventive concepts. Catheter assembly 300 and / or other components of system 10 described in reference to Fig. 3 can be of similar construction and arrangement as the similar components described in reference to Fig. 1 and otherwise herein. Fig. 3 shows outer catheter 350 of catheter assembly 300 positioned within a pool of blood (e.g., within a cardiac chamber) and oriented relative to tissue, such as in a position to deliver energy (e.g., radiofrequency, electroporation, and / or other electromagnetic energy; ultrasound energy and / or other sound energy; laser and / or other light energy; chemical energy; mechanical energy; and / or other energy) to ablate the tissue, as described herein.Client Docket No. : ARG-011-PCT

[0121] Outer catheter 300 can include array 320 of electrode assemblies 325, for example, an electrode assembly comprising a tip electrode assembly 325a, and ring electrode assemblies 325b-d shown. Outer catheter 300 can be positioned relative to tissue as shown, such that tip electrode assembly 325a is positioned in contact with the tissue.System 10 can be configured to generate an electrical field, such as a field configured to irreversibly electroporate tissue as described herein, for example, by delivering one or more waveforms 200 (e.g., electroporation or other energy form waveform) between two or more electrode assemblies. For example, electroporation waveforms 200E can be delivered between electrode assemblies 325a and 325b, and / or an electrode 325 and an external electrode, such as external electrode 60. Delivery of electroporation waveforms 200E from electrode assemblies 325 can generate electric fields or other forms of energy delivery within the pool of blood surrounding electrode assemblies 325. In some embodiments, at least a portion of electric fields created by delivery of electroporation waveforms can comprise “hemolytic electric fields” HF, such as fields HF1 and HF2 shown. Hemolytic electric fields can comprise a charge density that is sufficient to cause hemolysis of the blood within the electric field HF. For example, each delivery of energy (e.g., PFA energy, described herein) in the heart can cause an amount of electrical hemolysis (e.g., hemolysis related to delivery of electrical energy) that is related to (e.g., in proportion to) one two, or more of the following: the magnitude of the electric field (e.g., field HF) that is more than the hemolytic threshold at a given frequency; the volume of blood exposed to this field; and / or the total number of cycles delivered during a delivery of energy (e.g., PFA energy). In some embodiments, hemolysis monitored by system 10 is caused by delivery of energy in one or more forms selected from the group consisting of: radiofrequency energy; PFA energy; ultrasound energy and / or other sound energy; laser and / or other light energy; chemical energy; and / or mechanical energy, and / or other form of energy.

[0122] In some embodiments, during a single clinical procedure, one or more deliveries of ablation and / or other therapeutic energy (e.g., PFA energy) may be delivered to treat the patient. For example, depending on the underlying arrhythmia being targeted, multiple PFA energy deliveries may be needed to completely isolate targeted tissue substrates over the duration of a given procedure. During a clinical procedure, hemolyzed blood can continue to accumulate within the patient, and the excess hemoglobin is filtered by the kidneys which excrete it into the urine. If the total hemolysis that occurs during a clinical procedure is above a first threshold, the excess filtered hemoglobin can manifest as hemoglobinuria duringClient Docket No. : ARG-011-PCTurination with dark brown, purple, or otherwise discolored urine. In some cases, for example, if the hemolysis that occurs during a procedure is above a second threshold, hemoglobinuria can worsen and either or both kidneys can become blocked, leading to acute renal failure, such as renal failure that can require dialysis and present a serious risk to patient health. In some embodiments, various thresholds of the occurrence of hemolysis during a clinical procedure including delivery of energy (e.g., PFA energy) correlate to a probability of various side effects, such as hemoglobinuria and / or renal failure, rather than the certainty of various side effects (e.g., one or more adverse events). For example, hemolysis over a hemolysis threshold can correlate to a probability of one or more side effects over a probability threshold. In some embodiments, system 10 is configured to track, predict, and / or otherwise calculate the amount of hemolysis that occurs during a clinical procedure. System 10 can be configured to provide a display of information relating to the amount (e.g., a predicted amount) of hemolysis caused during a clinical procedure, for example, as described in reference to Fig. 4 and otherwise herein.

[0123] Referring now to Fig. 4, an embodiment of the display of a user interface of a system for providing electrical energy to treat a patient is illustrated, consistent with the present inventive concepts. Generator 100 and / or other components of system 10 described in Fig. 4 can be of similar construction and arrangement as the similar components described in reference to Fig. 1 and otherwise herein. Fig. 4 shows an example of GUI 153 of user interface 150 of generator 100. System 10 can be configured to determine one or more parameter values relating to hemolysis and / or other cumulative effects of the delivery of energy to the patient by system 10, such as Cumulative Index CI. System 10 can be configured to provide one or more icons and / or other graphical indicators related to the parameter cumulative index CI, such as the value of the index as shown in Fig. 4.Additionally, or alternatively, system 10 can determine one or more additional parameter index values, for example, an index related to the total energy delivered during a clinical procedure.

[0124] In some embodiments, system 10 is configured to calculate cumulative index CI (e.g., an index relating to the amount of hemolysis caused during a clinical procedure) based on one or more system 10 parameters and / or patient parameters. For example, for a given configuration of catheter assembly 300 (not shown but described herein), system 10 can beClient Docket No. : ARG-011-PCTconfigured to computationally model the peak electric fields generated by the application of voltage in the 3D volume around the array 320, and use this model to determine the volume of blood exposed to fields greater than a hemolytic threshold (e.g. approximately 4kV / cm at 50kHz). Based on these computational models, system 10 can calculate an estimated index of the hemolytic potential generated by a single pulse (e.g., a single pulse of a series of pulses of a delivered energy waveform, such as waveform 200 described herein). This value can be scaled by the number of pulses in the series of pulses to determine a hemolytic potential, hemolytic potential HP, for a given energy delivery (e.g., for a given electroporation waveform 200E). In some embodiments, system 10 is configured to deliver various arrangements of electroporation waveform 200E, such as waveforms with different number of pulses, different amplitudes, different frequencies, and / or other differing parameters of the waveform. Various arrangements of waveform 200 can each be configured to create differing treatment lesions, for example, lesions of differing depths, and / or each arrangement can be configured to be delivered using varying electrode arrangements, such as via focal and / or multi-electrode arrangements. System 10 can be configured to determine a hemolytic potential HP for one or more embodiments of waveform 200 (e.g., a hemolytic potential HP correlating to each embodiment of electroporation waveform 200E).

[0125] In some embodiments, system 10 is configured to determine a cumulative index CI (e.g., throughout a clinical procedure) by summing hemolytic potential HP values as electroporation waveforms 200E are delivered to the patient (e.g., delivered to irreversibly electroporate tissue). Alternatively, or additionally, an algorithm of system 10 (e.g., algorithm 25 described herein) can determine cumulative index CI based on a set of one or more system 10, procedure, patient, and / or hemolysis mitigation parameters (e.g., in addition to the parameters of a delivered waveform 200). Additionally, or alternatively, system 10 can comprise, and / or can be configured to determine, one or more thresholds to which cumulative index CI can be compared, such as a threshold comprising one or more safety margins thresholds configured to indicate to the clinician when certain levels of hemolysis have been reached, and / or one or more thresholds above which system 10 prevents additional energy from being delivered. In some embodiments, system 10 comprises, and / or is configured to determine and / or adjust, one or more thresholds based on a set of one or more system 10, procedure, and / or patient parameters, as described herein.

[0126] One or more system 10 parameters that are used by system 10 to determine cumulative index CI and / or one or more system 10 thresholds, can be selected from the groupClient Docket No. : ARG-011-PCTconsisting of: one or more parameters of each waveform delivered (as described herein); the configuration of catheter assembly 300; the configuration of array 320 and / or electrode assemblies 325; the surface area of one or more electrode assemblies 325 used to deliver the waveform; the number of electrodes 3251 that deliver energy; the configuration of the energy delivered by each electrode 3251 (e.g., a quantification of pulse delivery parameters and / or inter-pulse delays); the total energy delivered by each electrode 3251; the cumulative time each electrode 3251 delivers bipolar energy; the cumulative time each electrode delivers unipolar energy; the cumulative time each electrode delivers energy in a phased-combinations arrangement; the number of tissue ablations performed; a quantification of the contact level between each electrode 3251 and tissue (e.g., as determined by an impedance or other measurement); and combinations of these. One or more procedure parameters used to determine cumulative index CI and / or one or more system 10 thresholds can be selected from the group consisting of: position and / or orientation of array 320 relative to cardiac tissue during delivery of each waveform 200; time between deliveries of each waveform 200; parameters relating to additional devices present within the patient, such as additional treatment catheters, mapping catheters, guidewires, and / or sheaths; parameters relating to hemolytic mitigation performed during the procedure; time of saline delivery (e.g., cumulative time of saline delivery); hydration level of the patient; a heart rhythm parameter (e.g., a AF or flutter parameter); a heart failure level parameter; and combinations of these. One or more patient parameters used to determine cumulative index CI and / or one or more system 10 thresholds can comprise one or more parameters selected from the group consisting of: age; sex; weight; one or more physical characteristics; overall health of the patient; kidney health; one or more biological markers; glomerular filtration rate (GFR); serum creatinine; cystatin C; albuminuria; lactate dehydrogenase (LDH); reticulocyte count; haptoglobin; unconjugated bilirubin; and combinations of these. In some embodiments, one or more hemolysis mitigation steps can be performed to lower the likelihood of hemoglobinuria (or other undesired effects) caused by delivery of energy by system 10. For example, a hydration routine for the patient can be prescribed prior to, during, and / or following a clinical procedure to mitigate the effect of hemolysis that may occur during a procedure. One or more mitigation parameters used to determine cumulative index CI, and / or one or more system 10 thresholds can be selected from the group consisting of: one or more parameters related to hydration performed on the patient prior to and / or during theClient Docket No. : ARG-011-PCTprocedure; one or more pharmaceutical drugs administered to the patient prior to and / or during the procedure; and combinations of these.

[0127] As described herein, system 10 can comprise one or more thresholds, such as one or more thresholds to which cumulative index CI can be compared. For example, system 10 can comprise a first “warning” threshold, threshold TW, above which a warning can be provided to the clinician. Additionally, or alternatively, system 10 can comprise a second “critical” threshold, threshold TC, above which one or more functionalities of system 10 can be disabled and / or prevented without a clinician override. In some embodiments, one or more thresholds of system 10 can be dynamically computed (e.g., dynamically determined), as described herein, for example, based on one or more patient parameters. Alternatively, or additionally, the scale of cumulative index CI can be dynamically adjusted, such as based on one or more patient parameters, for example, to dynamically relate to one or more static thresholds. For example, system 10 can be configured to determine cumulative index on a fixed scale (e.g., 1 to 10), with threshold TW set at a first value (e.g., 8), and threshold TC set at a second value (e.g., 10). The incremental effect on cumulative index CI of each energy delivery can be scaled by system 10 to “fit” the fixed scale of the index. Alternatively, or additionally, the effect of an energy delivery on cumulative index CI can comprise a fixed scale (e.g., based on various parameters as described herein), and the thresholds can be dynamically computed based on various parameters, as described herein. For example, thresholds TW and / or TC may be higher for a first patient to be treated using system 10 (e.g., a larger patient with various mitigation performed), and lower for second patient to be treated using system 10 (e.g., a smaller patient with no mitigation performed), such that a higher cumulative index CI may be acceptable for the first patient. For a fixed index, the same waveform 200 can result in a smaller incremental increase in cumulative index CI for the first patient compared to the second patient.

[0128] In some embodiments, system 10 comprises a cumulative index threshold, threshold TCI, which can comprise a value of cumulative index CI at or above which the probability of a hemolysis-related adverse event (e.g., hemoglobinuria, acute renal injury) exceeds a predetermined level (e.g., reaches an undesirable state). In some embodiments, threshold TCI is determined by algorithm 25 based at least in part on one or more patient parameters (e.g., a pre-procedural or other patient parameter indicative of kidney function), as described herein. In some embodiments, threshold TCI is distinct from threshold TW and threshold TC. For example, threshold TW and / or threshold TC can comprise thresholds on aClient Docket No. : ARG-011-PCTcumulative index scale (e.g., a unitless scale from 1 to 10), while threshold TCI can comprise a threshold on a cumulative hemolytic index (e.g., a value computed from energy delivery parameters as described herein). Alternatively, or additionally, threshold TCI can comprise a patient-specific value of threshold TW and / or threshold TC, as described herein.

[0129] In some embodiments, system 10 is configured to provide information (e.g., to the clinician) related to the number of energy deliveries “possible” before one or more thresholds (e.g., threshold TW and / or TC) are reached. For example, when threshold TW is reached (e.g., cumulative index CI reaches a warning level), system 10 can display information via GUI 153 related to the total number of energy deliveries (and / or sets of like or dissimilar energy deliveries comprising various parameters) that can be performed before reaching threshold TC. System 10 can be configured to “count down” (e.g., audibly, visually, and / or haptically) as additional energy deliveries are performed. In some embodiments, system 10 is configured to provide an interface (e.g., via GUI 153) for procedural planning (e.g., a clinician can utilize a procedural planning function provided by system 10 via GUI 153). The planning interface can be provided prior to a procedure, during a procedure, or both. In some embodiments, the clinician can develop a treatment plan using the planning interface.System 10 can be configured to display information related to the treatment plan to the clinician (e.g., via GUI 153) during the clinical procedure. In some embodiments, cumulative index CI is estimated by algorithm 25 for each step of the treatment plan (e.g., while the plan is developed using the planning interface). System 10 can be configured to provide a warning if the predicted cumulative index CI is above a threshold. Alternatively, or additionally, system 10 can be configured to provide one or more suggested mitigations for one or more adverse events (e.g., excessive hemolysis) based on the treatment plan developed by the clinician using the planning interface. For example, system 10 can be configured to suggest a hydration routine for the patient prior to the planned clinical procedure to mitigate excess hemolysis predicted to occur during the procedure.

[0130] In some embodiments, system 10 can be configured to display a real-time representation of cumulative index CI to the clinician via GUI 153. In some embodiments, the display of cumulative index CI is updated after each energy delivery is performed during the clinical procedure. In some embodiments, the displayed information comprises the current value of cumulative index CI and one or more patient-specific thresholds (e.g., threshold TW, threshold TC, and / or threshold TCI, as determined at least in part on one or more patient parameters as described herein), such as when the two variables are displayedClient Docket No. : ARG-011-PCTsimultaneously. In some embodiments, the displayed information comprises a visual indicator selected from the group consisting of: a color-coded bar; a graphical gauge; a numerical display; an animated indicator; and combinations of these. The visual indicator can be configured to indicate a proximity of the current cumulative index CI value to the one or more patient-specific thresholds. In some embodiments, the displayed information is configured to change appearance (e.g., color change, increase in visual prominence, provide an audible and / or haptic alert) as cumulative index CI approaches one or more thresholds.

[0131] In addition to energy delivery and associated hemolysis, or alternatively, system 10 can be configured to track one or more other cumulative metrics of a clinical procedure performed using system 10. For example, system 10 can be configured to determine (e.g., to predict) the amount of myoglobin released by cardiac and / or other muscle tissue during ablation. An index, such as cumulative index CI, can relate to the probability of myoglobin related effects on the patient following a clinical procedure, for example, the probability of rhabdomyolysis or hemoglobinuria.

[0132] Referring now to Figs. 5A through 5C, various charts and graphs of data collected by the applicant during a human clinical study are illustrated, respectively, consistent with the present inventive concepts. Applicant has performed human clinical studies using the devices and methods of System 10 described herein. Based on information gathered during these studies, applicant has been able to correlate energy delivered during each procedure to the rate of hemoglobinuria and acute renal failure. Applicant has developed a preliminary scale for an exemplary cumulative index CI of hemolysis caused by the delivery of electroporation waveforms 200E (e.g., electroporation and / or other energy delivery form waveform) during these procedures. Fig. 5 A shows a table of data including the index range calculated of each of a set of patients, the complication rate for the patients within each range, and the corresponding percentage of the complication rate. Fig. 5B shows a graph of the data of Fig. 5 A. Fig. 5C shows a chart of patient data, indicating the date of the study procedure, procedural details, the post-procedure calculated index value, and the associated complications.

[0133] Applicant has developed a preliminary scale for cumulative index CI of cumulative hemolysis caused by the delivery of electroporation and / or other form of energy (e.g., energy delivery by the devices of system 10, described herein). The preliminary scaleClient Docket No. : ARG-011-PCTranges from 0 to 500 (e.g., an example quantitative range only) and is based on the number of pulses per energy delivery, the amplitude of the pulses, and the total number of energy deliveries performed during the procedure. As shown (using this 0 to 500 range), patients with a cumulative index CI of between 250 and 450 had a 100% occurrence of hemoglobinuria following the procedure. The only patient with a cumulative index CI of greater than 450 (462.8) had acute renal failure following the procedure. Based on the example scale shown, Fig. 5B illustrates a graph of cumulative hemolytic index value including multiple (e.g., three as shown) exemplary thresholds used by system 10, such as thresholds for warnings (e.g., thresholds TW), and / or lockouts (e.g., thresholds TC) of system 10. System 10 can be configured to provide a first warning to the clinician when the cumulative hemolytic index exceeds a first threshold, TW1 (e.g., a threshold of 200 as shown), to provide a second warning when the index exceeds a second threshold, TW2 (e.g., a threshold of 250 as shown), and / or to provide a third warning and / or initiate a lockout (e.g., prevent further energy delivery) when the cumulative index exceeds a third threshold TCI (e.g., a threshold of 450 as shown). In some embodiments, similar thresholds on a different quantitative scale can be proportionally based to these thresholds associated with the 0 to 500 scale described herein.

[0134] Referring now to Figs. 6, 7A, 7B, and 7C, two graphs of lesion depth data and two images of tissue with PFA lesions are illustrated, respectively, consistent with the present inventive concepts. The data shown and the lesions shown in the images represent lesions created using the devices and methods described in reference to system 10 herein. As described herein, generator 100 can be constructed and arranged to provide energy to be delivered, via catheter assembly 300, to tissue. The energy delivered can be configured to generate an electric field which causes irreversible electroporation of target tissue within the electric field.

[0135] As described herein, system 10 can be configured to deliver energy in a unipolar arrangement, a bipolar arrangement, and / or in a combination arrangement (e.g., a phased-combination arrangement), as described herein. Additionally, or alternatively, console 100 can be configured to provide energy with varying output levels, such as low, medium, and high output levels, such as levels described in the table herebelow. As shown in Fig. 6, a combination of energy delivery settings of system 10 can be selected to adjust the depth ofClient Docket No. : ARG-011-PCTlesions created by the delivery of energy. As described herein, system 10 can be configured to deliver energy in a focal arrangement and / or a linear arrangement. As shown in the righthand portion of the graph of Fig. 6, bipolar focal energy delivery can generate lesions with a greater depth than bipolar linear energy delivery.

[0136] As shown in Fig. 6 and described herein, system 10 can be configured to deliver energy using varying modalities and / or different energy parameters to achieve different lesion depths. The data collected by applicant and displayed in Fig. 6 represents lesions created using the following modes and energy delivery parameters:

[0137] In some embodiments, system 10 is configured to deliver high frequency PFA energy, as described herein. For example, system 10 can deliver PFA energy with a frequency of at least 240kHz or at least 480kHz. Fig. 7A shows a graph of lesion depth data also represented by the images shown in Figs. 7B and 7C. Applicant has conducted porcine studies demonstrating that system 10 can successfully create lesions using high frequency PFA. Lesions generated using bipolar, high frequency (e.g., a frequency of at least 240kHz) energy delivery settings can achieve lesions with a depth of approximately 13.2mm. Lesions generated using unipolar, high frequency (e.g., a frequency of at least 480kHz) energy delivery settings can achieve lesions with a depth of approximately 9.9mm. In some embodiments, system 10 is configured to minimize the creation of microbubbles that areClient Docket No. : ARG-011-PCTcreated by the delivery of energy (e.g., high frequency energy or otherwise) to the tissue. Additionally, or alternatively, energy delivered (e.g., high frequency energy or otherwise) by system 10 can be provided such as to limit muscular contractions caused by the delivery of energy to the tissue. The lesion data and images collected by applicant and displayed in Figs.7A through 7C represent lesions created using the following modes and energy delivery parameters:As described herein, system 10 can be configured to deliver energy comprising varying combinations of one or more energy delivery parameters, such as parameters selected from the group consisting of: frequency; voltage; phase angle; delivery time; number of bursts of energy delivered; number of energy deliveries performed (e.g., for the creation of a single lesion); and combinations of these. For example, system 10 can be configured to deliver energy with a frequency of at least 5MHz, at least 240kHz, and / or at least 480kHz. System 10 can be configured to deliver energy with a target voltage of at least 5,500V, at least 6,500V, or at least 12,000V. Energy can be delivered with a phase angle between 0° and 180°. Application time can comprise a duration of at least 5sec, such as at least lOsec, 15sec, or 20sec, and / or a duration of no more than 50sec, such as no more than 45sec, 40sec, or 35sec. System 10 can perform energy deliveries comprising multiple bursts of energy delivered over a delivery period, such as at least 4 bursts, 6 bursts, 8 bursts, 10 bursts, 12 bursts, 14 bursts, 16 bursts, 18 bursts, or 20 bursts. In some embodiments, system 10 is configured to deliver no more than 40 bursts during a single energy delivery, such as no more than 38 bursts, 36 bursts, 34 bursts, 32 bursts, or 30 bursts.

[0138] Referring now to Fig. 8, a block diagram of an embodiment of signal generator hardware architecture comprising both shared modules and specialized modules is illustrated,Client Docket No. : ARG-011-PCTconsistent with the present inventive concepts. Signal generator 120 and / or other components of system 10 described in Fig. 8 can be of similar construction and arrangement as the similar components described in reference to Fig. 1 and otherwise herein. Fig. 8 shows signal generator 120 comprising both shared RF / PFA waveform generation hardware 121, as well as one or more specialized hardware modules configured for specific waveform generation modalities, where each module can be selectively activated based on the desired energy delivery modality.

[0139] In some embodiments, shared RF / PFA waveform generation hardware 121 can be configured to provide one or more common functions across multiple energy delivery modalities. In some embodiments, the shared RF / PFA waveform generation hardware 121 can be configured to operably couple to one or more specialized hardware modules, for example, as described herein. The shared RF / PFA waveform generation hardware 121 can comprise one or more components selected from the group consisting of: H-bridge; power supply; energy storage (e.g., capacitor); isolation transformer; active electrode sensing mechanisms (e.g., relays); pulse timing generator (e.g., PLDs); and combinations of these. Additionally, or alternatively, shared RF / PFA waveform generation hardware 121 can be configured to provide uniform power delivery across different waveform modalities, where each specialized hardware module can access the shared resources without interfering with the operation of the other specialized hardware modules. System 10 can include one or more sets of hardware modules configured for enhanced (e.g., optimized) specific waveform delivery and / or otherwise configured for delivering a specific waveform modality. One or more of these modules can be operably coupled to shared RF / PFA waveform generation hardware 121, and / or to other modules of signal generator 120, such as to provide these waveforms. In some embodiments, the shared waveform generation hardware 121 comprises one or more components configured to control the function of signal generator 120, for example, shared waveform generation hardware 121 can comprise one or more components of controller 110. In some embodiments, the shared waveform generation hardware 121 comprises one or more components configured to provide and / or route power to signal generator 120, for example, shared waveform generation hardware 121 can comprise and / or be operably attached to one or more components of power source 130.

[0140] In some embodiments, one or more specialized hardware modules can be configured to operate independently of each other while sharing “common resources.” from shared RF / PFA hardware 121. Common resources can include one or more resources selectedClient Docket No. : ARG-011-PCTfrom the group consisting of: alarms; voltage (e.g., output voltage) measurement circuitry; current measurement circuitry; impedance measurement circuitry; system communication circuitry; configuration circuitry; control circuitry; user interface; temperature measurement circuitry; frequency selection circuitry; and combinations of these. In some embodiments system 10 can include a set of hardware modules configured for delivering low frequency PF A, low frequency sine wave PFA hardware 122. In some embodiments, low frequency PFA hardware 122 can be operably coupled to shared RF / PFA waveform generation hardware 121. In some embodiments, low frequency sine wave PFA hardware 122 can be configured to generate one or more sine wave waveforms at a predetermined frequency, Fl.In some embodiments, Fl comprises a frequency of at least 20kHz, such as at least 30kHz, 40kHz, and / or 50kHz. In some embodiments, Fl comprises a frequency of no more than 100kHz, such as no more than 90kHz, 80kHz, 70kHz, 60kHz, and / or 50kHz. In some embodiments low frequency sine wave PFA hardware 122 can be configured to provide coherent sine burst irreversible electroporation energy (e.g., such as for atrial fibrillation treatments). In some embodiments, generator 100 is configured to operate in different modes independently.

[0141] In some embodiments, system 10 can include a set of hardware modules configured for delivery of high frequency PFA, high frequency sine wave PFA hardware 123. In some embodiments, high frequency sine wave PFA hardware 123 can be operably coupled to shared RF / PFA waveform generation hardware 121 and configured to generate sine wave waveforms at a predetermined frequency, F2. In some embodiments, F2 comprises a frequency of at least 250kHz, such as at least 300kHz, 400kHz, 500kHz, 600kHz, 700kHz, 800kHz and / or 900 kHz. In some embodiments, F2 comprises a frequency of no more than 1MHz, such as no more than 900 kHz, 800 kHz, 700 kHz, 600 kHz, and / or 500 kHz. In some embodiments, F2 comprises a frequency of up to at least 5 MHz, such as up to at least 1MHz, 2MHz, 3MHz, and / or 4MHz. In some embodiments high frequency sine wave PFA hardware 123 can be configured to provide coherent sine burst irreversible electroporation energy (e.g., such as when used to achieve deep tissue penetration for ventricular tachycardia treatments).

[0142] High frequency sine wave PFA hardware 123 can be configured to utilize a combination of amplitude control and duty cycle control to deliver PFA energy and RF energy simultaneously. In some embodiments, system 10 is configured to heat target tissue prior to and / or during the delivery of PFA (e.g., to heat the tissue via RF energy delivery), such as to lower the threshold for PFA vulnerability in cardiac cells.Client Docket No. : ARG-011-PCT

[0143] In some embodiments, system 10 can include a set of hardware modules configured for delivering biphasic square wave energy (e.g., for PFA energy delivery), biphasic square wave PFA hardware 124. In some embodiments, biphasic square wave PFA hardware 124 can be operably coupled to shared RF / PFA waveform generation hardware 121 and configured to generate biphasic square wave waveforms at a predetermined frequency, F3. In some embodiments, F3 comprises a frequency of at least 50kHz, such as at least 150kHz, 250kHz, 350kHz, 450kHz, 550kHz, 650kHz, 750kHz, 850kHz, 950kHz, and / or 1MHz. In some embodiments, F3 comprises a frequency of no more than 5MHz, such as no more than 4MHz, 3MHz, 2MHz, and / or 1MHz. In some embodiments, F3 comprises a frequency of up to at least 5MHz. In some embodiments, biphasic square wave PFA hardware 124 can be configured to provide pulsed field ablation energy (e.g., such as for atrial fibrillation and / or ventricular tachycardia treatment applications, rapid energy delivery, and / or protocols requiring square wave characteristics).

[0144] Biphasic square wave PFA hardware 124 can be configured to deliver biphasic square wave waveforms selected from the group consisting of: waveforms comprising symmetric phase amplitudes; waveforms comprising asymmetric phase amplitudes; waveforms comprising variable delays between phases; charge balanced waveforms; and combinations of these. In some embodiments, generator 100 is configured to generate a hybrid waveform comprising sine waves and square waves. In some embodiments, the hybrid waveform is generated by a partial filtering of the sine waves.

[0145] In some embodiments, system 10 can include a set of hardware modules configured for delivering radio frequency ablation energy comprising sine waves, RF ablation sine wave hardware 125. In some embodiments, RF ablation sine wave hardware 125 can be operably coupled to shared RF / PFA waveform generation hardware 121 and configured to generate RF sine wave waveforms at a predetermined frequency, F4. In some embodiments, F4 comprises a frequency of at least 100kHz, such as at least 200kHz, 300kHz, 400kHz, 500kHz, 600kHz, 700kHz, 800kHz, 900kHz, and / or 1MHz. In some embodiments, F4 comprises a frequency of no more than 5MHz, such as no more than 4MHz, 3MHz, 2MHz, and / or 1MHz. In some embodiments, F3 comprises a frequency of up to at least 5MHz . In some embodiments, RF ablation sine wave hardware 125 can be configured to provide radiofrequency ablation energy (e.g., such as for performing thermal tissue ablation, cardiac arrhythmia treatments, conventional RF ablation procedures, and / or continuous wave RF applications). RF ablation sine wave hardware 125 can be configured to adjust the deliveryClient Docket No. : ARG-011-PCTof RF ablation energy to match specific output values (e.g., to match the output parameters of third-party generators). Matching of specific output values can provide a regulatory advantage for companies that require approval (e.g., regulatory approval) of new and / or updated generators and / or catheters.

[0146] In some embodiments, generator 100 comprises an RF generator configured to generate both an RF waveform and a PFA waveform.

[0147] In some embodiments, generator 100 comprises one or more interchangeable components and / or modules, such as one or more components configured to be replaced at a clinical site.

[0148] In some embodiments, system 10 can include a set of hardware modules configured for delivering the energy comprising one or more “arbitrary waveforms”, arbitrary waveform generation hardware 126. In some embodiments, arbitrary waveform generation hardware 126 can comprise components configured to deliver a broad range of waveform modalities (e.g., PFA waveforms, RF waveforms, and / or other waveforms). In some embodiments, one or more sets of specialized hardware modules can be configured to provide one, two, three, or more waveform modalities. In some embodiments, arbitrary waveform generation hardware 126 can be operably coupled to shared RF / PFA waveform generation hardware 121 and configured to directly generate customizable waveforms at one or more frequencies (e.g., predetermined frequencies and / or user-prescribed frequencies), F5. In some embodiments, F5 comprises a waveform at a frequency of at least 10kHz, such as at least 25kHz, 50kHz, 100kHz, 200kHz, 240kHz, 250kHz, 300kHz, 400kHz, 480kHz, 500kHz, 600kHz, 700kHz, 800kHz, 800kHz, 1MHz, 2MHz, and / or 5MHz. In some embodiments, F5 comprises a waveform at a frequency of no more than 10MHz, such as no more than 9MHz, 8MHz, 7MHz, 6MHz, 5MHz, 4MHz, 3MHz, 2MHz and / or 1MHz. In some embodiments, F5 can comprise a waveform at a frequency of up to at least 10MHz. In some embodiments, arbitrary waveform generation hardware 126 can be configured to provide direct waveform synthesis without requiring filtering (e.g., harmonic filtering) and / or without waveform transformation processes (e.g., peak width modulation, peak density modulation, and / or summation of waves). In some embodiments, arbitrary waveform generation hardware 126 can be configured to produce precise waveforms with high voltage capabilities, such as waveforms comprising a peak voltage of up to at least 2kV, such as up to at least 3kV, 4kV, 6kV, 8kV, and / or lOkV. In some embodiments arbitrary waveform generation hardware 126Client Docket No. : ARG-011-PCTcan be configured to provide fast rise and fall times, such as a time period TP1, for high voltage transitions (e.g., such as transitions between -lOkV to +10kV). In some embodiments, TP1 comprises a time period of at least 10ns, such as at least 25ns, 50ns, 75ns, 100ns, 200ns, 500ns, Ips, 2ps, 5ps, and / or 8ps. In some embodiments, TP1 comprises a time period of no more than lOps, such as no more than 8ps, 5ps, 2ps, Ips, 500ns, 200ns, 100ns, 50ns, and / or 25ns. In some embodiments, TP1 can comprise a time period of up to at least lOps. In some embodiments, the arbitrary waveform generation hardware 126 is configured to provide high voltage transitions at high current delivery, such as current delivery Cl. In some embodiments, Cl comprises deliveries of current of at least 10A, such as at least 25 A, 50A, 75A, 100A, 125A, 150A, 167, 175A, and / or 190A. In some embodiments, Cl comprises deliveries of current of no more than 200A, such as no more than 190A, 175A, 167A, 150A, 125A, 100A, 75A, 50A, and / or 25A. In some embodiments, the high voltage transitions comprise transitions between -lOkV to +10kV (e.g., transitions from negative voltages to positive voltages, bipolar voltage transitions, and / or voltage reversals). In some embodiments, arbitrary waveform generation hardware 126 can be configured to generate one or more waveforms selected from the group consisting of sine waves; square waves; triangle waves; chirp waves; sawtooth waves; single period sine wave snippets; custom pulse patterns; pulses without ramp-up characteristics; other unspecified waveform modalities; and combinations of these. In some embodiments, arbitrary waveform generator hardware 126 is configured to generate waveforms for one or more applications selected from the group consisting of cardiac ablation; tumor ablation; reversible PFA applications (e.g., drug delivery); and combinations of these.

[0149] Referring now to Fig. 9A and 9B, two flowcharts of embodiments of methods for bidirectional waveform conversion are illustrated, consistent with the present inventive concepts. Signal generator 120 and / or other components of system 10 described in Figs. 9A and 9B can be of similar construction and arrangement as the similar components described in reference to Fig. 1 and otherwise herein. Fig. 9A shows a flowchart of an embodiment of Method 1000 for generating sine waves from square wave inputs. Fig. 9B shows a flowchart of an embodiment of Method 2000 for generating square waves from sine wave inputs. In some embodiments, the bidirectional waveform conversion methods can be configured to provide flexible waveform generation of multiple energy delivery modalities. For example, square wave signals can be converted to sinusoidal waveforms and / or sine wave signals canClient Docket No. : ARG-011-PCTbe converted to square wave approximations. In some embodiments, system 10 can comprise one or more waveform processing modules and / or components configured to perform harmonic filtering, waveform manipulation, signal processing techniques and / or bidirectional waveform conversion (e.g., for pulse field ablation applications, radiofrequency ablation procedures, and / or cardiac tissue treatment)

[0150] Referring specifically to Fig. 9A, a flowchart of an embodiment of Method 1000 for generating RF and / or PFA sine waves from biphasic square waves is illustrated. Method 1000 can be performed by one or more components of system 10 described herein, such as generator 100, algorithm 25, and / or signal generator 120. Method 1000 begins with Step 1010, in which system 10 defines the desired sine wave frequency. In some embodiments, one or more parameters of a biphasic square wave, such as those related to fundamental frequency of the square wave, can be established. For example, square waves generated by system 10 can comprise one or more parameters selected from the group consisting of: a pulse width of at least 10ns and / or no more than lOps; an amplitude of at least 2kV and / or no more than lOkv; a pulse delay of at least up to Ips; an inter pulse delay of at least 100ns and / or no more than 20ms; and combinations of these. In Step 1020, signal generator 120 generates a biphasic square wave at a predetermined frequency. In some embodiments, the biphasic square wave signals can be produced at the defined fundamental frequency which can be enhanced (e.g., optimized) for subsequent waveform manipulation. In Step 1030, system 10 performs waveform manipulation (e.g., harmonic filtering, pulse width modulation, and / or pulse density modulation), in which square wave inputs can be processed to generate sine wave approximations. In Step 1040, system 10 outputs a sine wave at a predetermined fundamental frequency. In some embodiments, the processed RF sine wave and / or PFA sine wave outputs can be provided as energy for applications such as radiofrequency ablation, pulse field ablation, and / or electroporation energy delivery to target tissue.

[0151] In some embodiments, waveform manipulation comprises full spectrum filtering and / or partial spectrum filtering. Waveform manipulation can achieve complete harmonic elimination and / or suppression. Additionally, or alternatively, manipulation can achieve selective harmonic elimination and / or suppression. In some embodiments, waveform manipulation is configured to switch between full spectrum filtering and partial spectrum filtering, such as to produce different waveforms interprocedurally.Client Docket No. : ARG-011-PCT

[0152] Referring specifically to Fig. 9B, a flowchart of an embodiment of Method 2000 for generating square waves from sine waves is illustrated. Method 2000 can be performed by one or more components of system 10 described herein, such as generator 100, algorithm 25, and / or signal generator 120. Method 2000 begins with Step 2010, in which system 10 is used to define the desired square wave frequency. For example, one or more frequency parameters, such as those related to fundamental frequency can be established for sine wave generation. In some embodiments, the system is configured to generate sine waves with a predetermined frequency, F6. In some embodiments, F6 comprises a frequency of at least 50kHz, such as at least 100kHz, 200kHz, 500kHz, 1MHz, 2MHz, 3MHz, and / or 4MHz. In some embodiments, F6 comprises a frequency of no more than 5MHz, such as no more than 4MHz, 3MHz, 2MHz, 1MHz, 500kHz, 200kHz, and / or 100kHz. In some embodiments, F6 comprises a frequency of up to at least 5MHz. In Step 2020, signal generator 120 generates a sine wave, in which the sine wave signal can be produced at an enhanced (e.g., optimized) frequency for subsequent waveform processing. In Step 2030, system 10 performs waveform manipulation (e.g., high voltage comparator, and / or summation of waves), in which sine wave inputs can be processed to generate square wave approximations. In Step 2040, system 10 outputs a square wave at a predetermined frequency. In some embodiments, the processed square wave approximation can be provided for one or more applications, such as pulsed field ablation, electroporation energy delivery and / or other applications requiring square wave characteristics.

[0153] In some embodiments, generator 100 is configured to generate sine waves and provide an output comprising a sine wave, a square wave, or both.

[0154] In some embodiments, generator 100 is configured to generate square waves and provide an output comprising a sine wave, a square wave, or both.

[0155] In some embodiments, system 10 is further configured to perform harmonic filtering configured to convert square waves to sine waves.

[0156] In some embodiments, system 10 is further configured to perform a pulse modulation configured to convert square waves to sine waves.

[0157] In some embodiments, system 10 further comprises one or more waveform processing modules and / or components configured to convert sine waves to square waves. The one or more waveform processing modules and / or components can comprise a comparator and / or pulse-shaping circuit.Client Docket No. : ARG-011-PCT

[0158] Referring now to Figs. 10A through 10F, various embodiments of harmonic filtering demonstrations and waveform conversion examples are illustrated, consistent with the present inventive concepts. Signal generator 120 and / or other components of system 10 described in Figs. 10A through 10F can be of similar construction and arrangement as the similar components described in reference to Fig. 1 and otherwise herein. Fig. 10A shows an example of an embodiment of harmonic filtering processes demonstrating elimination of harmonics (e.g., complete and / or nearly complete elimination of harmonics) from biphasic square wave-based waveforms (also referred to as “square wave waveforms”) to sine wavebased waveforms (also referred to as “sine wave waveforms”). Fig. 10B shows an example of an embodiment of harmonic filtering processes demonstrating partial harmonic filtering. Fig.10C shows an embodiment of an example of square wave reference signals for emulation targets. Fig. 10D shows an embodiment of an example of simulated output waveforms attempting to replicate the square wave characteristics shown in Fig. 10C. Fig. 10E shows an embodiment of an example of high voltage square wave pulse generation. Fig. 10F shows square wave packet formation with coordinated pulse sequences. In some embodiments, system 10 can comprise one or more harmonic filters, harmonic filter 1205, which can be configured to generate RF sine wave approximations, PFA sine wave approximations, or both, from biphasic square wave sources. Additionally, or alternatively, harmonic filter 1205 can be configured to generate square wave approximations from sine wave sources. In some embodiments, harmonic filter 1205 can be configured for complete harmonic filtering, in which harmonic content can be substantially reduced and / or eliminated to provide “clean” sinusoidal output for ablation (e.g., radiofrequency ablation). Alternatively, or additionally, harmonic filter 1205 can be configured for partial harmonic filtering, in which one or more predetermined ranges of harmonics may be specifically suppressed. In some embodiments, harmonic filter 1205 can comprise variable filtering levels, adaptive harmonic suppression, and / or configurable waveform shaping to optimize energy delivery characteristics for specific treatment protocols.

[0159] Fig. 10A illustrates an example of an embodiment of a method of complete harmonic filtering of a square wave-based waveform to a sine wave-based waveform, using harmonic filter 1205. The left panel shows the generated square wave waveform including the fundamental sine wave as well as additional harmonic frequencies illustrated on a logarithmic plot. As shown in Fig. 10A, the fundamental sine wave frequency occurs atClient Docket No. : ARG-011-PCTapproximately 50kHz as the strongest normalized magnitude peak and the harmonic frequencies extend across frequency ranges from approximately 100kHz to approximately 10MHz, in which the harmonic amplitudes can be significantly present but steadily decreasing in amplitude. As shown in Fig. 10A, the shaded portion comprises an example of the harmonic frequencies above the fundamental intended to be eliminated or at least substantially reduced (“eliminated” or “reduced” herein) by harmonic filter 1205. The middle panel shows the resulting sinusoidal waveform after complete harmonic filtering by harmonic filter 1205 has been performed, in which only the fundamental frequency at 50kHz remains with all other harmonic frequencies removed by harmonic filter 1205, demonstrating clean frequency response with predominant fundamental frequency content. The right panel shows the resulting filtered sine wave pulsed over time with normalized amplitude traces from approximately Ops to 250ps, in which sinusoidal pulse characteristics demonstrate smooth waveform transitions and controlled pulse duration suitable for RF ablation and / or PFA applications.

[0160] Fig. 10B illustrates an example of an embodiment of a method of partial harmonic filtering of a square wave-based waveform to a sine wave-based waveform, using harmonic filter 1205. The left panel shows the generated square wave-based waveform including the fundamental sine wave as well as additional harmonic frequencies illustrated on a logarithmic plot. As shown in Fig. 10B, the fundamental sine wave frequency occurs at approximately 50kHz as the strongest normalized magnitude peak and the harmonic frequencies extend across frequency ranges from approximately 100kHz to approximately 10MHz, in which the harmonic amplitudes can be significantly present but steadily decreasing in amplitude. As shown in Fig. 10B, the shaded portion comprises an example of the selected harmonic frequencies above the fundamental selectively reduced by harmonic filter 1205 while maintaining controlled harmonic content. The middle panel shows the resulting partially filtered sinusoidal waveform after partial harmonic filtering by harmonic filter 1205 has been performed, in which the fundamental frequency at 50kHz remains as the dominant component with selected harmonic frequencies reduced (e.g., such as harmonic frequencies above approximately 1MHz as shown in Fig. 10B) and some harmonic content preserved (e.g., such as harmonic frequencies between 100kHz and 1MHz as shown in Fig. 10B), by harmonic filter 1205. The right panel shows the resulting partially filtered waveform pulsed over time with repetitive pulse patterns and controlled amplitude characteristics, in which the waveform characteristics demonstrate intermediate filtering results between full square waveClient Docket No. : ARG-011-PCTand pure sinusoidal output, such as for square wave applications requiring transformer compatibility and retaining a generally biphasic square wave shape.

[0161] Fig. 10C illustrates square wave reference signals that system 10 can be configured to emulate. Fig. 10C shows the assumed 2kV square-wave reference comprising six sequential pulses with high voltage amplitude characteristics. The square wave reference can be configured with one or more waveform parameters selected from the group consisting of: amplitude; pulse-to-pulse delay; starting phase; and combinations of these. Fig. 10D illustrates the simulated output waveform generated by system 10 in replicating the square wave characteristics shown in Fig. 10C. Fig. 10C shows identical 2kV square waves from a modified sine wave generator, such as signal generator 120. The simulated waveforms can be generated using one or more waveform generation methods, for example, as described herein. Fig. 10E illustrates high voltage square wave pulse generation at approximately 2.12kV amplitudes. In some embodiments, system 10 is configured to generate high voltage pulses with a predetermined peak voltage, VI, into a load. In some embodiments, VI comprises a peak voltage of at least 2kV, such as at least 2.5kV, 3kV, 3.5kV, 4kV, and / or 4.5kV. In some embodiments, VI comprises a peak voltage of no more than 5kV, such as no more than 4.5kV, 4kV, 3.5kV, 3kV, and / or 2.5kV. In some embodiments, VI comprises a peak voltage of up to at least 5kV into a load. In some embodiments, system 10 can be configured to provide voltage control from approximately IkV to 4kV, where pulse amplitude can be adjusted based on one or more factors including: tissue impedance characteristics, treatment requirements, and / or safety protocols. In some embodiments, the high voltage pulse generation can be configured with controlled rise times, fall times, pulse durations, and amplitude stability for pulsed field ablation, irreversible electroporation, and / or other waveform applications. In some embodiments, system 10 is configured to generate pulses with a rise time, RT1. In some embodiments, RT1 comprises a rise time of at least 20ns, such as at least 50ns, 100ns, 200ns, 500ns, Ips, and / or 1.5 s. In some embodiments, RT1 comprises a rise time of no more than 2ps, such as no more than 1.5ps, I s, 500ns, 400ns, 200ns, 100ns, and / or 50ns. In some embodiments, RT1 comprises a rise time of up to at least 2ps. In some embodiments, the system is configured to generate pulses with a fall time, FT1. In some embodiments FT1 comprises a fall time of at least 20ns, such as at least 50ns, 100ns, 200ns, 400ns, 500ns, Ips, and / or 1.5ps. In some embodiments, FT1 comprises a fall time of no more than 2ps, such as no more than 1.5ps, Ips, 500ns, 400ns, 200ns, 100ns, and / or 50ns. In some embodiments, FT1 comprises a fall time of up to at least 2ps. In some embodiments,Client Docket No. : ARG-011-PCTsystem 10 is configured to generate pulses with a predetermined pulse duration, PD1. In some embodiments, PD1 comprises a pulse duration of at least 200ns±Vp, such as at least 500ns±Vp, lps±Vp, 2ps±Vp, 2.5ps±Vp, 5ps±Vp, 7.5ps±Vp and / or 9ps±Vp. In some embodiments, PD1 comprises a pulse duration of no more than 10ps±Vp, such as no more than 9ps±Vp, 7.5ps±Vp, 5ps±Vp, 2.5ps±Vp, 2ps±Vp, lps±Vp, and / or 500ns±Vp. In some embodiments, PD1 comprises a pulse duration of up to at least 10ps±Vp.

[0162] Fig. 10F illustrates square wave packet formation comprising coordinated pulse sequences, showing square-wave packet generation with multiple sequential pulses. In some embodiments, and as shown in Fig. 10F, system 10 can be configured to generate high voltage packet sequences with a predetermined peak voltage, V2 into a load. In some embodiments, V2 comprises a peak voltage of at least 2kV, such as at least 2.5kV, 3KV, 3.5kV, 4kV, and / or 4.5kV. In some embodiments, V2 comprises a peak voltage of no more than 5kV, such as no more than 4.5kV, 4kV, 3.5kV, 3kV, and / or 2kV. In some embodiments, V2 comprises a peak voltage of up to at least 5kV into a load. In some embodiments, system 10 can be configured to control inter-pulse intervals (e.g., approximately lOps delay between pulses), and / or other parameters such as: packet duration, pulse counts per package (e.g., 6 packets per burst), and / or burst timing characteristics. In some embodiments, the square wave can be configured for one or more applications including pulsed field ablation protocols and / or tissue treatment applications requiring coordinated energy delivery services.

[0163] Referring now to Fig. 11, a graph of an embodiment of a waveform produced by signal generator is illustrated, consistent with the present inventive concepts. Signal generator 120 and / or other components of system 10 described in Fig. 11 can be of similar construction and arrangement as the similar components described in reference to Fig. 1 and otherwise herein. Fig. 11 shows and example of a square wave waveform comprising a zerodifferential signal portion, as described herein.

[0164] In some embodiments, signal generator 120 is configured to produce an initial square wave waveform, and signal generator 120 can be configured to filter this initial waveform to generate a sine wave. Signal generator 120 can be configured to produce the initial square wave waveform comprising one or more characteristics and / or using one or more methods or hardware modules that produce a square wave that is specifically configured to be filtered to produce a sine wave. In some embodiments, the initial squareClient Docket No. : ARG-011-PCTwave waveform can be generated using an H-bridge or other circuit constructed and arranged to generate the initial waveform. Signal generator 120 can comprise an H-bridge and / or other circuit comprising a multi-state circuit configured to produce the initial square wave waveform. In some embodiments, the multi-state circuit can comprise a two-state circuit, such as a circuit configured to produce a square wave comprising positive and negative segments (e.g., a square wave with a 50% duty cycle). Alternatively, or additionally, the multi-state circuit can comprise a circuit with more than two states, such as three or more states. For example, a multi-state circuit for creating a square wave waveform can comprise a three-state circuit configured to produce a square wave comprising positive, negative, and zero-differential segments (e.g., a “brake” state), for example, as shown in Fig. 11. In some embodiments, signal generator 120 comprises a three-state circuit (e.g., a three-state H-bridge) configured to operate with a duty cycle, such as a 2 / 3 duty cycle shown. In some embodiments, the brake state comprises a state where the circuit drives a near zero differential (e.g., the output of the circuit is shorted). In some embodiments, for example, when signal generator 120 comprises an H-bridge circuit comprising one or more switches (e.g., FETs) for controlling the flow of current through the circuit, the brake state can comprise a state where two or more switches are activated simultaneously to drive the near zero-differential state.

[0165] A square wave waveform comprising a three-state configuration as shown in Fig.11 can provide a better approximation of a desired sine wave than a two-state square wave waveform (e.g., a waveform that is easier to filter into a sine wave waveform). In some embodiments, signal generator 120 is configured to produce a square wave waveform that does not comprise one or more harmonic and / or other signal artifacts (e.g., signal artifacts typical of a hardware generated square wave waveform) For example, signal generator 120 can be configure to produce a square wave waveform that does not comprise a third-harmonic artifact (e.g., such as the waveform shown in Fig. 11).

[0166] Referring now to Figs. 12A and 12B, graphs of experimentally determined arcing voltage threshold data and catheter conditioning data are illustrated, respectively, consistent with the present inventive concepts. Signal generator 120 and / or other components of system 10 described in reference to Figs. 12A and 12B can be of similar construction and arrangement as the similar components described in reference to Fig. 1 andClient Docket No. : ARG-011-PCTotherwise herein. Fig. 12A shows a graph of a relationship between a number of cycles per burst and an arcing voltage threshold for energy delivered by system 10. Fig. 12B shows a graph of an initial arcing voltage threshold and a conditioned arcing voltage threshold for a plurality of catheters (e.g., catheter assembly 300), before and after a “catheter conditioning procedure” has been performed, as described herein.

[0167] In some embodiments, system 10 can be configured to control and / or mitigate electrical arcing during energy delivery (e.g., during pulsed field ablation energy delivery) to tissue. Electrical arcing can occur when a voltage applied across one or more electrodes (e.g., electrodes 3251 of catheter assembly 300) exceeds a dielectric breakdown voltage of the medium between the one or more electrodes 3251 (e.g., a medium comprising blood, saline, and / or other biological fluids or tissue). In some embodiments, the minimum voltage at which electrical arcing occurs comprises an arcing voltage threshold, AVT1. In some embodiments, AVT1 is dependent on one or more factors including the medium between the one or more electrodes 3251, the energy delivery parameters, and / or the condition of catheter assembly 300 (e.g., the electromechanical state of catheter assembly 300 after a catheter conditioning procedure has been performed). Electrical arcing can damage tissue, damage one or more components of catheter assembly 300, and / or produce undesirable clinical effects. In some embodiments, system 10 is configured to reduce and / or eliminate arcing events by setting and / or adjusting one or more energy delivery parameters.

[0168] In some embodiments, system 10 can be configured to set the number of cycles per burst, such as to control AVT1 of the energy delivery. As shown in Fig. 12A, decreasing the number of cycles per burst can increase AVT1. Increasing AVT1 can allow system 10 to deliver higher voltage energy without triggering an arcing event. An increase in temperature at or near the one or more electrodes 3251 during energy delivery can alter dielectric properties of the medium between the one or more electrodes 3251. Increasing the number of cycles per burst can cause an increase in the temperature at or near the one or more electrodes 3251 during the energy delivery. Additionally, or alternatively, reducing the number of cycles per burst can reduce the increase in temperature.

[0169] In some embodiments, system 10 is configured to deliver energy comprising one or more bursts of energy, as described herein. Each burst can comprise one or more cycles of a waveform (e.g., a sine wave waveform and / or a square wave waveform). In some embodiments, the one or more cycles of each burst is delivered within a ’’burst window”.Client Docket No. : ARG-011-PCTThe burst window can comprise a time period BW1, over which the cycles of a burst are delivered. In some embodiments, BW1 comprises a time period of at least 50ms, at least 100ms, at least 150ms, at least 200ms, at least 250ms, at least 300ms, at least 400ms, and / or at least 500ms. In some embodiments, BW 1 comprises a time period of no more than 1000ms, no more than 750ms, no more than 500ms, no more than 400ms, no more than 300ms, no more than 250ms, no more than 200ms, and / or no more than 100ms. In some embodiments, BW1 comprises a time period of approximately 250ms.

[0170] In some embodiments, system 10 is configured to deliver energy comprising a number of cycles per burst, cycles CB1. In some embodiments, CB1 comprises at least 3 cycles, at least 5 cycles, at least 8 cycles, at least 10 cycles, at least 11 cycles, at least 13 cycles, at least 15 cycles, and / or at least 20 cycles. In some embodiments, CB1 comprises no more than 25 cycles, no more than 20 cycles, no more than 15 cycles, no more than 11 cycles, no more than 10 cycles, no more than 8 cycles, and / or no more than 5 cycles.

[0171] As shown in Fig. 12 A, testing performed by the applicant has shown, in some scenarios, that when CB1 comprises approximately 8 cycles delivered within a BW1 of approximately 250ms, AVT1 can comprise approximately 4720V. When CB1 comprises approximately 10 cycles that are delivered within a BW1 of approximately 250ms, AVT1 can comprise approximately 4560V. When CB1 comprises approximately 11 cycles that are delivered within a BW1 of approximately 250ms, AVT1 can comprise approximately 4440V. When CB1 comprises approximately 13 cycles that are delivered within a BW1 of approximately 250ms, AVT1 can comprise approximately 3800V.

[0172] In some embodiments, reducing the number of cycles per burst can increase AVT1 by at least 50V, at least 100V, at least 200V, at least 300V, at least 500V, at least 700V, and / or at least 900V. In some embodiments, reducing CB1 from approximately 13 cycles to approximately 8 cycles within a BW 1 of approximately 250ms can increase AVT1 by approximately 920V (e.g., from approximately 3800V to approximately 4720V). In some embodiments, system 10 can be configured to select a CB1 such that AVT1 is maintained above a target voltage for the energy delivery. Additionally, or alternatively, system 10 can be configured to select a target voltage below AVT1 for a desired CB1 and / or BW1 (e.g., to prevent an arcing event when energy delivery parameters are selected based on a desired burst window duration and / or number of cycles).Client Docket No. : ARG-011-PCT

[0173] In some embodiments, AVT1 comprises a voltage of at least 3500V, at least 3800V, at least 4000V, at least 4440V, at least 4560V, at least 4720V, at least 5000V, at least 5500V, and / or at least 6000V. In some embodiments, system 10 is configured to deliver energy at a voltage EVI, that is below AVT1. In some embodiments, voltage EVI comprises a voltage of at least 1000V, at least 1500V, at least 2000V, at least 2500V, at least 3000V, at least 3500V, at least 4000V, at least 4500V, at least 5000V, at least 5500V, and / or at least 6000V. In some embodiments, EVI comprises a voltage of no more than 7000V, no more than 6500V, no more than 6000V, no more than 5500V, no more than 5000V, no more than 4500V, no more than 4000V, and / or no more than 3500V.

[0174] In some embodiments, system 10 can be configured to deliver higher frequency pulsed field ablation energy at higher voltages without arcing (e.g., as compared to low frequency pulsed field ablation energy). In some embodiments, when delivering energy at a high frequency, AVT1 can comprise a higher voltage than when delivering energy at a low frequency. In some embodiments, the high frequency can comprise a frequency of at least 240kHz, such as approximately 480kHz. In some embodiments, the low frequency can comprise a frequency of no more than 100kHz, such as approximately 50kHz. In some embodiments, AVT1 at a high frequency can comprise at least 5000V, at least 5500V, at least 6000V, and / or at least 6500V. In some embodiments, when delivering energy at a frequency of approximately 480kHz in a unipolar configuration, AVT1 can comprise approximately 6029V. In some embodiments, when delivering energy at a frequency of approximately 50kHz in a bipolar configuration, AVT1 can comprise approximately 4040V. In some embodiments, when delivering energy at a frequency of approximately 50kHz in a unipolar configuration, AVT1 can comprise approximately 2636V. In some embodiments, system 10 can be configured to select a delivery frequency based at least in part on a target voltage, AVT1, and / or based on a desired lesion depth.

[0175] System 10 can be configured to deliver energy in a unipolar configuration, a bipolar configuration, or both. In some embodiments, AVT1 can be dependent at least in part on the energy delivery configuration. For example, a unipolar delivery configuration at a high frequency (e.g., a frequency of at least 240kHz) can result in AVT1 comprising a higher voltage than a bipolar delivery configuration at a lower frequency (e.g., a frequency of less than 100kHz). In some embodiments, system 10 is configured to select the delivery configuration (e.g., unipolar and / or bipolar) based at least in part on one or more factors selected from the group consisting of: the target voltage; the arcing voltage threshold (e.g.,Client Docket No. : ARG-011-PCTAVT1); the energy delivery frequency; the target tissue type; the catheter configuration; and combinations of these.

[0176] In some embodiments, system 10 can be configured to perform a “catheter conditioning procedure” prior to therapeutic energy delivery. For example, a catheter conditioning procedure can comprise delivering “conditioning energy” to catheter assembly 300, such as energy configured to modify one or more electrical properties of the cathetertissue interface. In some embodiments, the one or more electrodes 3251 of catheter assembly 300 can comprise one or more undesired surface conditions (e.g., manufacturing variations, contaminants, and / or other imperfections) that can reduce AVT1. In some embodiments, the conditioning energy can be configured to reduce, modify, and / or eliminate the one or more undesired surface conditions on the one or more electrodes 3251. In some embodiments, reducing, modifying, and / or eliminating the one or more undesired surface conditions can increase AVT1.

[0177] In some embodiments, the catheter conditioning procedure can comprise delivering conditioning energy that is at a level that is at or above an initial value of AVT1 of catheter assembly 300. In some embodiments, the conditioning energy can be configured to modify the one or more electrodes 3251 of catheter assembly 300, such as to increase AVT1. In some embodiments, the catheter conditioning procedure can comprise one or more steps selected from the group consisting of: incrementally increasing the voltage applied to catheter assembly 300 to determine and initial value of AVT1; delivering conditioning energy (e.g., at or above the initial value of AVT1) to modify the one or more electrodes 3251; incrementally increasing the voltage applied to catheter assembly 300 to determine a conditioned value of AVT1; and combinations of these. In some embodiments, the conditioned value of AVT1 is greater than the initial value of AVT1. A catheter conditioning procedure can be performed prior to a clinical procedure, for example, during a manufacturing process of catheter assembly 300. In some embodiments, system 10 comprises multiple catheter assemblies 300, such as a first catheter assembly 300a and a second catheter assembly 300b. In these embodiments, system 10 can be configured to utilize multiple different catheter conditioning procedures (e.g., procedures that utilize different voltages, different durations of energy delivery, and / or other differences), such as a first catheter conditioning procedure configured to condition catheter assembly 300a and a second catheter conditioning procedure configured to condition catheter assembly 300b.Client Docket No. : ARG-011-PCT

[0178] As shown in Fig. 12B, catheter conditioning procedure can be configured to increase the arcing voltage threshold AVT1, an increase which can be represented by a percentage, CPI. In some embodiments, CPI comprises an increase of at least 0.5%, at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 6%, and / or at least 7%. In some embodiments, CPI comprises an increase of no more than 15%, no more than 12%, no more than 10%, no more than 8%, no more than 7%, no more than 5%, and / or no more than 3%. In some embodiments, CPI comprises an increase of approximately 2.8%, approximately 4.8%, approximately 7.2%, and / or approximately 0.6%. In some embodiments, catheter conditioning can increase AVT1 by at least 40V, at least 100V, at least 150V, at least 200V, at least 300V, and / or at least 400V.

[0179] In some embodiments, the conditioning energy used in a catheter conditioning procedure comprises one or more energy types selected from the group consisting of high-power pulsed field ablation energy; high-frequency pulsed field ablation energy; radiofrequency ablation energy; combined pulsed field ablation and radiofrequency ablation energy (e.g., combined CSE and RF energy); and combinations of these. In some embodiments, catheter assembly 300 can be conditioned using combined pulsed field ablation and radiofrequency ablation energy that is delivered prior to therapeutic PFA energy delivery.

[0180] In some embodiments, system 10 can be configured to automatically perform a catheter conditioning procedure prior to therapeutic energy delivery. In some embodiments, system 10 can be configured to assess whether a catheter conditioning procedure is beneficial (e.g., has caused a desired change in catheter assembly 300) based on one or more factors selected from the group consisting of an initial value of AVT1; a target voltage; a delivery frequency; a catheter type; and combinations of these. In some embodiments, controller 110 is configured to recommend a catheter conditioning procedure to a user (e.g., to a clinician or other user, via GUI 153) when an initial value of AVT1 is below a predetermined safety margin above the target voltage to be used.

[0181] In some embodiments, the catheter conditioning procedure can be performed during a clinical procedure (e.g., after catheter assembly 300 is positioned within the patient and prior to therapeutic energy delivery). In some embodiments, a catheter conditioning procedure performed during the clinical procedure comprises delivering one or more sub-therapeutic conditioning pulses via one or more electrodes 3251 of catheter assembly 300, such as to assess whether a target therapeutic voltage is within an acceptable range relative toClient Docket No. : ARG-011-PCTAVT1. One or more sub-therapeutic conditioning pulses can comprise pulses at a voltage below the target therapeutic voltage. In some embodiments, system 10 can be configured to incrementally increase the voltage of the conditioning pulses to determine AVT1 for the specific catheter-tissue interface. In some embodiments, system 10 is configured to limit the conditioning energy to a level that avoids clinically significant hemolysis occurring during the assessment.

[0182] In some embodiments, the catheter conditioning procedure can be performed during a manufacturing process of catheter assembly 300 (e.g., prior to sterilization and / or prior to packaging of catheter assembly 300). A catheter conditioning procedure performed during the manufacturing process can comprise determining an initial value of AVT1 specific to an individual catheter assembly 300. In some embodiments, the catheter conditioning procedure performed during the manufacturing process is performed in a “conditioning medium”, such as a medium selected from the group consisting of a saline solution; a gel medium; a tissue-simulating phantom; a controlled-impedance test fixture; and combinations of these. In some embodiments, the conditioning medium is configured to approximate one or more electrical properties of a medium within a patient, such as a medium comprising blood, saline, and / or other biological fluids (e.g., an impedance, a dielectric constant, and / or a conductivity of the medium).

[0183] In some embodiments, the initial value of AVT1 determined during the manufacturing process (e.g., during a conditioning step of the manufacturing process) can be stored (e.g., in memory) and be associated with the individual catheter assembly 300. In some embodiments, the initial value of AVT1 is stored in a memory device of catheter assembly 300 (e.g., a memory device integrated into connector assembly 610, such as a memory chip positioned on catheter assembly 300, for example, an RFID tag). In some embodiments, the initial value of AVT1 is stored in a database indexed by a serial number or other unique identifier of catheter assembly 300. In some embodiments, the initial value of AVT1 is stored in a barcode, a QR code, and / or another machine-readable identifier associated with catheter assembly 300. In some embodiments, when catheter assembly 300 is connected to generator 100 (e.g., via connector assembly 610), controller 110 can read the stored initial value of AVT1 and use the stored initial value as an input parameter for energy delivery planning and / or other use. In some embodiments, when the stored initial value of AVT1 is above a predetermined safety margin relative to a target therapeutic voltage, a catheterClient Docket No. : ARG-011-PCTconditioning procedure to be performed during the clinical procedure can be simplified and / or eliminated.

[0184] In some embodiments, system 10 can be configured to adjust one or more energy delivery parameters based at least in part on one or more “arcing control factors” selected from the group consisting of: the number of cycles per burst; the delivery frequency; the burst window duration (e.g., BW1); the delivery configuration (e.g., unipolar, bipolar, or both); a catheter conditioning status (e.g., performed or not performed); the arcing voltage threshold (e.g., an initial value of AVT1, a conditioned value of AVT1, or both); and combinations of these. In some embodiments, controller 110 and / or algorithm 25 can be configured to dynamically adjust CB1 during a clinical procedure based on monitoring of arcing events and / or AVT1 changes.

[0185] Referring now to Figs. 13A through 13C, a flowchart of a power analysis method and two graphs of experimentally determined microbubble power threshold data are illustrated, respectively, consistent with the present inventive concepts. Signal generator 120 and / or other components of system 10 described in reference to Figs. 13A through 13C can be of similar construction and arrangement as the similar components described in reference to Fig. 1 and otherwise herein. Fig. 13 A shows a flowchart of an embodiment of Method 3000 for determining power delivered per burst window from waveform parameters, as well as for adjusting waveform parameters in a closed loop manner. Fig. 13B shows a graph of a relationship between a power delivered per burst window and the occurrence of microbubbles at a first delivery frequency. Fig. 13C shows a graph of a relationship between a power delivered per burst window and the occurrence of microbubbles at a second delivery frequency.

[0186] In some embodiments, system 10 can be configured to deliver pulsed field ablation energy to tissue via one or more electrodes 3251 of catheter assembly 300, as described herein. In some embodiments, the delivery of pulsed field ablation energy can result in the formation of microbubbles in the medium proximate the one or more electrodes 3251 (e.g., a medium comprising blood, saline, and / or other biological fluids). In some embodiments, the formation of microbubbles can be associated with a thermal energy accumulation at or near the one or more electrodes 3251 during energy delivery. In some embodiments, microbubbles can be detected using an imaging modality, such as intracardiacClient Docket No. : ARG-011-PCTechocardiography (e.g., ICE). The formation of microbubbles during energy delivery can be undesirable.

[0187] In some embodiments, system 10 can be configured to monitor and / or reduce the formation of microbubbles during energy delivery to tissue. In some embodiments, the energy delivered by system 10 within a burst window (e.g., BW1) comprises a power per burst window, PB1. In some embodiments, the power above which microbubble formation occurs comprises a microbubble power threshold, MPT1. In some embodiments, system 10 can be configured to maintain PB 1 below MPT1. In some embodiments, maintaining PB 1 below MPT1 can reduce and / or eliminate the formation of microbubbles during energy delivery.

[0188] Method 3000 can be performed by system 10 (e.g., performed by controller 110 by executing algorithm 25) to determine PB 1 from one or more waveform parameters of the energy to be delivered by system 10. Method 3000 can be configured to prevent or at least reduce formation of bubbles (e.g., microbubbles or other bubbles) during delivery of energy by system 10 (e.g., delivery of ablation energy to form efficacious lesions in cardiac tissue). Method 3000 can begin with Step 3010. In Step 3010, system 10 can determine a proposed voltage and / or current of a signal (e.g., a sinusoidal signal) to be delivered by signal generator 120 to the tissue. In Step 3020, system 10 can determine a root mean square (RMS) voltage and a root mean square current of the proposed signal. In some embodiments, the RMS voltage can be determined by dividing the peak sinusoidal voltage by the square root of two. In some embodiments, the RMS current can be determined by dividing the peak sinusoidal current by the square root of two. In Step 3030, system 10 can determine an instantaneous power of the proposed signal from the RMS voltage and the RMS current. In some embodiments, the instantaneous power can be determined from a product of the RMS voltage and the RMS current. In Step 3040, system 10 can determine an energy per cycle from the instantaneous power and a cycle period of the proposed signal. In some embodiments, the energy per cycle can be determined from the product of the instantaneous power and a time duration of one cycle of the energy delivery waveform. In Step 3050, system 10 can determine an energy per burst from the energy per cycle and the number of cycles per burst (e.g., CB1). In some embodiments, the energy per burst can be determined from a product of the energy per cycle and the number of cycles per burst. In Step 3060, system 10 can determine PB1 from the energy per burst and the burst window (e.g., BW1). In someClient Docket No. : ARG-011-PCTembodiments, PB 1 can be determined by dividing the energy per burst by the burst window duration.

[0189] In some embodiments, PB1 is dependent on one or more factors selected from the group consisting of: a voltage of the delivered energy; a current of the delivered energy; a frequency of the delivered energy; the number of cycles per burst (e.g., CB1); the burst window duration (e.g., BW1); and combinations of these. In some embodiments, increasing the voltage of the delivered energy increases PB1. In some embodiments, increasing CB1 increases PB 1.

[0190] In some embodiments, the occurrence of microbubble formation correlates to a threshold being exceeded. As shown in Fig. 13B, when PB1 is below MPT1, microbubble formation can be absent and / or undetectable (e.g., via ICE). As shown in Fig. 13B, when PB1 is at or above MPT1, microbubble formation can occur (e.g., and can be detectable, such as via ICE). In some embodiments, the transition between no microbubble formation and microbubble formation comprises a sigmoid relationship with PB1.

[0191] In some embodiments, MPT1 is dependent on one or more factors selected from the group consisting of: a catheter design (e.g., a configuration of catheter assembly 300 and / or one or more electrodes 3251); a frequency of delivered energy; a waveform type of delivered energy (e.g., sinusoidal, square wave, or both); and combinations of these.

[0192] As shown in Figs. 13B and 13C, MPT1 can be dependent on the delivery frequency. For example, MPT1 at a first frequency can comprise a different value than MPT1 at a second frequency. In some embodiments, MPT1 at a higher delivery frequency comprises a lower power value than MPT1 at a lower delivery frequency. In some embodiments, MPT1 comprises a power of at least 25W, at least 50W, at least 60W, at least 70W, at least 75W, at least 80W, at least 90W, at least 96W, at least 100W, at least HOW, and / or at least 125W. In some embodiments, MPT1 comprises a power of no more than 200W, no more than 175W, no more than 150W, no more than 125W, no more than HOW, no more than 100W, no more than 96W, no more than 80W, and / or no more than 75W. As shown in Fig. 13B, when the delivery frequency comprises approximately 240kHz, MPT1 can comprise approximately 96.5W. As shown in Fig. 13C, when the delivery frequency comprises approximately 480kHz, MPT1 can comprise approximately 75.11W.

[0193] In some embodiments, system 10 can be configured to maintain PB1 below MPT1, such as by adjusting one or more energy delivery parameters. For example, when theClient Docket No. : ARG-011-PCTvoltage of the delivered energy is increased, the number of cycles per burst (e.g., CB1) can be decreased to maintain PB 1 below MPT1. In some embodiments, when the voltage of the delivered energy is decreased, CB1 can be increased while maintaining PB1 below MPT1. In some embodiments, system 10 can be configured to select CB1 (e.g., select a value for CB1) based at least in part on a target voltage and MPT1.

[0194] In some embodiments, controller 110 and / or algorithm 25 can be configured to determine MPT1 based on at least one or more factors selected from the group consisting of: the energy delivery frequency; the catheter design; the energy delivery waveform type; preclinical and / or clinical data (e.g., of the patient); and combinations of these. In some embodiments, controller 110 and / or algorithm 25 can be configured to calculate PB1 in real time or near real time (“real time” herein) and / or prior to energy delivery based on the one or more waveform parameters.

[0195] In some embodiments, following Step 3060, Method 3000 continues to Step 3070 where PB1 is compared to MPT1. Following Step 3070, if PB1 is less than MPT1, Method 3000 can continue to Step 3090, where the energy (e.g., the currently configured energy) can be delivered to the patient. Following Step 3070, if PB1 is greater than MPT1, Method 3000 can continue to Step 3080. In Step 3080, system 10 can adjust one or more parameters of the proposed energy delivery signal, such as the signal power and / or the number of cycles (e.g., CB1). In some embodiments, when PB1 is greater than MPT1, system 10 can decrease CB1 to reduce PB1 below MPT1. In some embodiments, when PB1 is greater than or equal to MPT1, system 10 can decrease the voltage of the energy to be delivered to reduce PB1 to a level below MPT1. Following Step 3080, Method 3000 can return to Step 3010.

[0196] In some embodiments, system 10 can be configured to select CB1 based at least in part on a target voltage and MPT1. In some embodiments, when the voltage of the delivered energy is increased, the number of cycles per burst (e.g., CB1) can be decreased to maintain PB1 below MPT1. In some embodiments, when the voltage of the delivered energy is increased, CB1 can be increased while maintaining MPT1. In some embodiments, system 10 can adjust the one or more parameters of the proposed signal to additionally maintain the delivered voltage below the arcing voltage threshold (e.g., AVT1).

[0197] In some embodiments, system 10 can be configured to calculate PB1 in real time and / or prior to energy delivery based on the one or more waveform parameters. In some embodiments, system 10 can be configured to dynamically adjust CB1 during a procedure toClient Docket No. : ARG-011-PCTmaintain PB 1 below MPT1. In some embodiments, when a user adjusts the target voltage, system 10 can be configured to automatically adjust CB1 to maintain PB1 below MPT1. In some embodiments, system 10 is configured to provide a notification to the user (e.g., a visual and / or audible alert, such as via GUI 153) when PB1 approaches and / or exceeds MPT1.

[0198] Referring now to Figs. 14A through 14C, two tables of clinical durability data and a diagram of overlapping energy deliveries are illustrated, respectively, consistent with the present inventive concepts. Signal generator 120 and / or other components of system 10 described in reference to Figs. 14A through 14C can be of similar construction and arrangement as the similar components described in reference to Fig. 1 and otherwise herein. Fig. 14A shows a table of pulmonary vein isolation (PVI) durability data for a plurality of human patients across multiple study cohorts. Fig. 14B shows a table of PVI durability data for an optimized treatment cohort. Fig. 14C shows a cross-sectional diagram of overlapping energy deliveries to tissue using sequential electrode subsets of catheter assembly 300.

[0199] Applicant has performed human clinical studies using the devices and methods of system 10 described herein. Based on information gathered during these studies, applicant has been able to correlate a number of energy deliveries performed using system 10 at each pulmonary vein target (e.g., target comprising cardiac tissue surrounding the pulmonary vein ostium) to a durability rate of pulmonary vein isolation. As shown in Fig. 14A, applicant has collected durability data across a plurality of study cohorts comprising both persistent and paroxysmal atrial fibrillation patients. The data of Fig. 14A comprises pulmonary vein isolation durability rates grouped by the number of energy deliveries (also referred to as “ablations” herein) performed at each pulmonary vein target. In some embodiments, a durable pulmonary vein isolation comprises an electrical isolation that persists at a follow-up assessment (e.g., an assessment performed at least 30 days, at least 60 days, at least 90 days, or more following performance of the ablation procedure).

[0200] As shown in Fig. 14 A, PVI durability can be correlated to the number of energy deliveries performed at each pulmonary vein target. In some embodiments, the number of energy deliveries delivered by system 10 per pulmonary vein target comprises a number of ablations, AB1. In some embodiments, AB1 comprises at least 3 ablations, at least 4 ablations, at least 5 ablations, at least 6 ablations, at least 7 ablations, at least 8 ablations,Client Docket No. : ARG-011-PCTand / or at least 9 ablations. In some embodiments, AB1 comprises no more than 15 ablations, no more than 12 ablations, no more than 10 ablations, no more than 9 ablations, no more than 8 ablations, no more than 7 ablations, or no more than 6 ablations. As shown in Fig. 14A, when AB1 comprises no more than 5 ablations per pulmonary vein target, patients treated using system 10 exhibited an aggregate durability of approximately 57.8%. Patients treated using system 10 and having an AB1 of at least 6 ablations per pulmonary vein target exhibited an aggregate durability of approximately 97.2%. The data of Fig. 14A demonstrates a durability inflection associated with a minimum number of ablations performed using system 10 per pulmonary vein target.

[0201] In some embodiments, durability increases as the number of ablations AB1 increases. As shown in Fig. 14A, when AB1 comprises approximately 6 ablations, durability comprises approximately 95.5%. When AB1 comprises approximately 7 ablations, durability comprises approximately 98.0%. When AB1 comprises approximately 8 ablations, durability comprises approximately 100.0%. When AB 1 comprises 9 or more ablations, durability comprises approximately 100.0%.

[0202] In some embodiments, system 10, and the methods of the present inventive concepts, can be configured to perform an “optimized” treatment protocol, such as an optimized treatment protocol that is based on the clinical results observed by the applicant. In some embodiments, the optimized treatment protocol comprises performing a set of ablations with an AB 1 of at least 5 ablations, at least 6 ablations, or at least 7 ablations per each pulmonary vein target. As shown in Fig. 14B, applicant has collected durability data from a treatment cohort in which the optimized treatment protocol was enforced. As shown in Fig. 14B, when the optimized treatment protocol comprises AB1 of at least 6 ablations per pulmonary vein target, PVI durability comprises approximately 95.5%. Also as shown in Fig. 14B, when the optimized treatment protocol comprises AB1 of at least 7 ablations per pulmonary vein target, PVI durability comprises approximately 98.8%.

[0203] In some embodiments, PVI durability under the optimized treatment protocol increases as AB1 increases. As shown in Fig. 14B, when AB1 comprises approximately 6 ablations, PVI durability comprises approximately 98.3%. When AB1 comprises approximately 7 ablations, PVI durability comprises approximately 98.8%. When AB 1 comprises approximately 8 ablations, PVI durability comprises approximately 100.0%.When AB1 comprises 9 or more ablations, PVI durability comprises approximately 100.0%.Client Docket No. : ARG-011-PCT

[0204] The data of Fig. 14A and 14B demonstrates that enforcement of a minimum number of ablations per pulmonary vein target (e.g., at least 6 ablations) can reduce and / or eliminate a failure mode (e.g., an insufficient efficacy level) associated with insufficient energy delivery. In some embodiments, system 10 can be configured to enforce (e.g., require) a minimum number of ablations per pulmonary vein target during an ablation procedure. In some embodiments, controller 110 and / or algorithm 25 can be configured to track the number of energy deliveries performed at each pulmonary vein target during a procedure (e.g., and alert a user if an insufficient number of energy deliveries has been performed at a target).

[0205] In some embodiments, system 10 is configured to provide one or more notifications (e.g., via GUI 153) when the number of energy deliveries at a pulmonary vein target is below a minimum threshold. In some embodiments, the minimum threshold comprises at least 5 ablations, at least 6 ablations, and / or at least 7 ablations. In some embodiments, system 10 is configured to prevent and / or at least warn the clinician before delivering energy to a subsequent pulmonary vein target until the minimum threshold is satisfied at the current vein target. Additionally, or alternatively, system 10 can be configured to provide a recommendation (e.g., via GUI 153) to the clinician to perform additional energy deliveries at the current pulmonary vein target.

[0206] In some embodiments, system 10 comprises one or more suggested treatment protocols (e.g., recommended sets of treatment steps) for performing pulmonary vein isolation. In some embodiments, the suggested treatment comprises a predetermined number of ablations to be performed at each pulmonary vein target. The predetermined number of ablations can vary by pulmonary vein target based on one or more factors, such as one or more factors selected from the group consisting of: pulmonary vein anatomy; pulmonary vein size; pulmonary vein type; pulmonary vein location; electrode-tissue contact quality; desired overlap coverage; and combinations of these.

[0207] In some embodiments, a suggested treatment protocol for PVI comprises a number of ablations at each of the one or more pulmonary vein targets to be treated. In some embodiments, a left superior pulmonary vein (LSPV) target protocol comprises at least 5 ablations, at least 6 ablations, and / or at least 7 ablations. In some embodiments, the LSPV target protocol comprises approximately 6 ablations. In some embodiments, a left inferior pulmonary vein (LIPV) target protocol comprises at least 5 ablations, at least 6 ablations,Client Docket No. : ARG-011-PCTand / or at least 7 ablations. In some embodiments, the LIPV target protocol comprises approximately 6 ablations. In some embodiments, a right inferior pulmonary vein (RIPV) target protocol comprises at least 5 ablations, at least 6 ablations, at least 7 ablations, and / or at least 8 ablations. In some embodiments, the RIPV target protocol comprises approximately 7 ablations. In some embodiments, a right superior pulmonary vein (RSPV) target protocol comprises at least 5 ablations, at least 6 ablations, at least 7 ablations, and / or at least 8 ablations. In some embodiments, the RSPV target protocol comprises approximately 7 ablations.

[0208] In some embodiments, the recommended treatment protocol for PVI comprises delivering energy from a first set of electrodes 3251 of catheter assembly 300 positioned at a first location relative to tissue to be treated. The recommended treatment protocol can further comprise overlapping energy deliveries, for example, by repositioning catheter assembly 300 between sequential energy deliveries such that one or more electrodes 3251 contact a tissue region that was contacted during a prior energy delivery. In some embodiments, the overlapping energy deliveries comprise at least 3 energy deliveries with overlapping electrode contact in each aspect of the pulmonary vein target, such as at least 3 energy deliveries, and / or at least 4 energy deliveries.

[0209] In some embodiments, system 10 can be configured to deliver energy using various electrode configurations and / or various other configurations of catheter assembly 300. In some embodiments, each configuration comprises an electrode selection parameter and a power level parameter. The electrode selection parameter can define a number of electrodes 3251 of catheter assembly 300 that will deliver energy during an energy delivery (e.g., two electrodes, four electrodes, eight electrodes). The power level parameter can define an energy intensity for the energy delivery (e.g., a low power level, a standard power level, and / or a maximum power level). In some embodiments, the electrode selection parameter and the power level parameter are independently selectable. For example, electrode configurations (e.g., which electrodes 3251 of catheter assembly 300 are used to deliver energy) can be selected from the group consisting of: an eight-electrode standard configuration (“8E Standard”); a four-electrode standard configuration (“4E Standard”); a four-electrode maximum configuration (“4E Max”); a four-electrode maximum phased configuration (“4E Max-Phased”); a two-electrode standard configuration (“2E Standard”); a two-electrode maximum configuration (“2E Max”); and combinations of these.Client Docket No. : ARG-011-PCT

[0210] In some embodiments, the 8E Standard configuration comprises activating all eight electrodes 3251 of array 320 at a standard power level. In some embodiments, a 4E Standard configuration comprises activating any four adjacent electrodes 3251 of array 320 at a standard power level. In some embodiments, a 4E Max configuration comprises activating any four adjacent electrodes 3251 of array 320 at a maximum power level. In some embodiments, a 4E Max-Phased configuration comprises activating any four adjacent electrodes 3251 of array 320 at a maximum power level with a phased delivery arrangement. In some embodiments, a 2E Standard configuration comprises activating two distal electrodes 3251 of array 320 at a standard power level. In some embodiments, a 2E Max configuration comprises activating two distal electrodes 3251 of array 320 at a maximum power level.

[0211] In some embodiments, the one or more electrode configurations can be selected via GUI 153. In some embodiments, selecting an electrode configuration comprises selecting a number of active electrodes and a power level. In some embodiments, selecting the number of active electrodes comprises selecting a subset of electrodes 3251 from GUI 153. In some embodiments, the subset of electrodes 3251 can be selected from the group consisting of all 8 electrodes, any adjacent 4 electrodes, any non-adjacent 4 electrodes; any alternating 4 electrodes; any adjacent 2 electrodes; any 2 distal electrodes; any non-adjacent 2 electrodes; any single electrode; and combinations of these. In some embodiments, selecting the power level comprises selecting one or more power levels, such as a low power level, a standard power level, and / or a maximum power level. In some embodiments, selecting the 4E Max-Phased configuration further comprises selecting a phased delivery option from a user interface element within GUI 153.

[0212] Fig. 14C shows an embodiment of the overlapping energy delivery method described above. As shown in Fig. 14C, a first energy delivery and a second energy delivery can be performed sequentially using, for example, a four-electrode configuration (e.g., a 4E Max configuration). As shown in Fig. 14C, array 320 can comprise eight electrodes 3251 (e.g., labeled El through E8 in Fig. 14C).

[0213] The first energy delivery can comprise activating a first subset of electrodes 3251 (e.g., electrodes El through E4). The first energy delivery can create a first lesion region in the tissue. In some embodiments, the second energy delivery comprises activating a second subset of electrodes 3251 (e.g., electrodes E5 through E8). The second energy delivery can create a second lesion region in the tissue. In some embodiments, the first lesion region andClient Docket No. : ARG-011-PCTthe second lesion region comprise an overlap region where the first lesion region and the second lesion region intersect (e.g., comprise one or more common volumes of tissue that received ablative energy). Alternatively, or additionally, catheter assembly 300 can be repositioned, such that the second energy delivery is delivered using the same electrodes 3251 as the first energy delivery (e.g., with or without delivering to an overlapping region), as described herebelow.

[0214] In some embodiments, the overlap region assures that there is continuous ablated tissue between the first energy delivery and the second energy delivery. In some embodiments, creating overlapping energy deliveries can reduce and / or eliminate gaps between adjacent lesion regions. Reducing and / or eliminating gaps can improve the durability and / or completeness of the “lines of block” (as defined herein) created by system 10.

[0215] In some embodiments, catheter assembly 300 can be repositioned between energy deliveries such that one or more electrodes 3251 from the first energy delivery overlap with one or more electrodes 3251 from the second energy delivery. In some embodiments, the overlap comprises at least 1 electrode, at least 2 electrodes, at least 3 electrodes, and / or at least 4 electrodes. In some embodiments, catheter assembly 300 is advanced along a treatment path such that sequential energy deliveries create a continuous line of ablated tissue (e.g. a line of block comprising a linear or other portion of ablated tissue). In some embodiments, system 10 can be configured to create one or more lines of block in cardiac tissue (e.g., portions of ablated tissue configured to block electrical conduction through the tissue). The one or more lines of block can be created at one or more cardiac treatment locations selected from the group consisting of a posterior wall superior line of block; a posterior wall inferior line of block; a cavo-tri cuspid isthmus (CTI) line of block; and combinations of these. “Line of block” and “line” are used interchangeably herein.

[0216] In some embodiments, a posterior wall superior line can be created using one or more energy delivery sequences. In some embodiments, the posterior wall superior line comprises at least 2 energy deliveries, at least 3 energy deliveries, at least 4 energy deliveries, and / or at least 5 energy deliveries. In some embodiments, the posterior wall superior line comprises approximately 3 energy deliveries using a 4E Max configuration. Alternatively, or additionally, the posterior wall superior line can comprise approximately 2 energy deliveries using a 4E Max configuration and approximately 2 to 3 energy deliveries using a 2E MaxClient Docket No. : ARG-011-PCTconfiguration. In some embodiments, creating a posterior wall superior line comprises anchoring a distal portion of catheter assembly 300 in a first pulmonary vein (e.g., a left superior pulmonary vein) and delivering energy with a proximal portion of catheter assembly 300 in contact with the posterior wall. In some embodiments, creating the posterior wall superior line further comprises anchoring the distal portion of catheter assembly 300 in a second pulmonary vein (e.g., a right superior pulmonary vein) and delivering energy with the proximal portion in contact with the posterior wall such that the resulting “lesion lines” intersect (e.g., resulting linear or other portions of ablated tissue intersect).

[0217] In some embodiments, a posterior wall inferior line can be created using one or more energy delivery sequences. For example, the posterior wall inferior line can comprise (e.g., can be created using) at least 2 energy deliveries, at least 4 energy deliveries, at least 6 energy deliveries, at least 8 energy deliveries, at least 10 energy deliveries, and / or at least 11 energy deliveries. In some embodiments, the posterior wall inferior line comprises approximately 1 energy delivery using a 4E Max configuration and approximately 5 to 10 energy deliveries using a 2E Standard configuration. In some embodiments, creating the posterior wall inferior line comprises anchoring a distal portion of catheter assembly 300 in a left inferior pulmonary vein and delivering energy with a proximal portion of catheter assembly 300 in contact with the posterior wall floor. Creating the posterior wall inferior line can further comprise performing additional energy deliveries using a 2E Standard configuration, such as to extend the line toward a right inferior pulmonary vein.

[0218] In some embodiments, a CTI line can be created using one or more energy delivery sequences. In some embodiments, the CTI line comprises a number of energy deliveries that is dependent on patient anatomy. In some embodiments, a CTI line can comprise approximately 1 energy delivery using a 4E Max configuration and approximately 5 to 9 energy deliveries using a 2E Max configuration. Alternatively, or additionally, the CTI line can comprise approximately 2 energy deliveries using a 4E Max configuration and approximately 4 to 7 energy deliveries using a 2E Max configuration.

[0219] In some embodiments, system 10 is configured to model lesion depth for the one or more electrode configurations based at least in part on in vivo data (e.g., in vivo data collected by system 10 on the current patient and / or previous patients treated using system 10). The one or more electrode configurations can produce a lesion with a lesion depth, LD1.Lesion depth LD1 can vary based on the electrode configuration and the power level used inClient Docket No. : ARG-011-PCTdelivering energy. In some embodiments, LD1 comprises a depth of at least 4mm, at least 5mm, at least 5.5mm, at least 6mm, at least 7mm, and / or at least 8mm. In some embodiments, LD1 comprises a depth of no more than 10mm, no more than 9mm, no more than 8mm, no more than 7mm, no more than 6mm, or no more than 5mm.

[0220] In some embodiments, the 4E Max configuration and the 4E Max-Phased configuration can produce a greater value of LD1 than one or more other electrode configurations (e.g., such as those described herein). In some embodiments, system 10 can be configured to recommend an electrode configuration based at least in part on: a desired value of LD1, a target tissue thickness, a target treatment location, and / or combinations of these.

[0221] Referring now to Figs. 15A through 15D, graphs and charts of experimentally determined hemolysis-related clinical data are illustrated, consistent with the present inventive concepts. Various components of system 10 described in reference to Figs. 15A through 15D can be of similar construction and arrangement as the similar components described in reference to Fig. 1 and otherwise herein. Fig. 15A shows a bar chart illustrating a relationship between a pre-procedural (e.g., baseline) patient parameter and a hemolysis-related clinical outcome for a plurality of clinical procedures performed using system 10. Fig. 15B shows a heat map of a relationship between the pre-procedural patient parameter and a cumulative index value for a plurality of clinical procedures performed using system 10. Fig. 15C shows a scatter plot of individual clinical procedure data points plotted against the pre-procedural patient parameter and the cumulative index value, with threshold-defined quadrant rates. Fig. 15D shows two scatter plots illustrating a patient-specific threshold shifting capability of system 10.

[0222] System 10 can be configured to set and / or determine one or more thresholds (e.g., threshold TW, threshold TC, and / or a cumulative index threshold TCI) based at least in part on one or more patient parameters. In some embodiments, the one or more patient parameters comprise a pre-procedural patient parameter (e.g., a baseline) indicative of a patient’s renal function. For example, the pre-procedural patient parameter can comprise an estimated glomerular filtration rate (eGFR). The estimated glomerular filtration rate (eGFR) can comprise a measure of kidney filtration capacity, expressed in units of mL / min / 1.73m2. In some embodiments, the baseline eGFR comprises a pre-procedural baseline valueClient Docket No. : ARG-011-PCTmeasured prior to a clinical procedure performed using system 10. System 10 can be configured to receive the baseline eGFR value (e.g., via user interface 150, such as via GUI 153) as an input to algorithm 25.

[0223] As shown in Fig. 15 A, applicant has shown from human clinical procedures performed using system 10 that a lower baseline eGFR (e.g., worse kidney function) is associated with a higher probability of hemoglobinuria to be caused by a cardiac ablation procedure. Fig. 15A shows a hemoglobinuria rate (y-axis) as a function of baseline eGFR (x-axis) for a plurality of patients (e.g., at least 150 patients) treated. The data of Fig. 15 A is grouped into a plurality of eGFR ranges. As shown, a first eGFR range comprising patients with an eGFR value of less than approximately 50 mL / min / 1.73m2was associated with a hemoglobinuria rate of approximately 67% A second eGFR range comprising patients with an eGFR value between approximately 50 mL / min / 1.73m2and approximately 70 mL / min / 1.73m2was associated with a hemoglobinuria rate of approximately 19%. A third eGFR range comprising patients with an eGFR value between approximately 70 mL / min / 1.73m2and 90 mL / min / 1.73m2was associated with a hemoglobinuria rate of approximately 10%. Finally, a fourth eGFR range comprising patients with an eGFR value of greater than approximately 90 mL / min / 1.73m2is associated with a hemoglobinuria rate of approximately 7%.

[0224] In some embodiments, system 10 can be configured to apply a patient parameter threshold TPP, that is selected to stratify patients based on a pre-procedural patient parameter (e.g., the baseline eGFR value). For example, a threshold at an eGFR value of approximately 70 mL / min / 1.73m2can divide a patient population into two groups with meaningfully different hemoglobinuria rates. The data collected by applicant shows the aggregate hemoglobinuria rate for patients with an eGFR below TPP of 70 was approximately 20.9%. The aggregate hemoglobinuria rate for patients with an eGFR at or above TPP of 70 was approximately 9.6%. In some embodiments, TPP comprises an eGFR value of at least 50 mL / min / 1.73m2, at least 55 mL / min / 1.73m2, at least 60 mL / min / 1.73m2, at least 65 mL / min / 1.73m2, at least 70 mL / min / 1.73m2, at least 75 mL / min / 1.73m2, and / or least 80 mL / min / 1.73m2. In some embodiments, TPP comprises an eGFR value of no more than 100 mL / min / 1.73m2, no more than 90 mL / min / 1.73m2, no more than 85 mL / min / 1.73m2, no more than 80 mL / min / 1.73m2, no more than 75 mL / min / 1.73m2, no more than 70 mL / min / 1.73m2, and / or no more than 65 mL / min / 1.73m2.Client Docket No. : ARG-011-PCT

[0225] As shown in Fig. 15B, applicant has determined from human clinical procedures performed using system 10 that a combination of baseline eGFR and cumulative index CI can be associated with a probability of occurrence of hemoglobinuria (e.g., a cumulative index calculated by system 10 as described herein). Fig. 15B shows a heat map comprising a grid of cells, where each cell represents a combination of a baseline eGFR range (y-axis) and a cumulative index CI range (x-axis, labeled “Hemolytic Index” in Fig. 15B). Each cell is color-coded to indicate the observed hemoglobinuria rate for patients within the corresponding eGFR and a cumulative index CI range, where a first color (e.g., green) indicates a low hemoglobinuria rate and a second color (e.g., red) indicates a high hemoglobinuria rate. The y-axis of Fig. 15B comprises a plurality of eGFR groupings corresponding to kidney function severity categories, such as a normal kidney function category (e.g., eGFR of at least 90 mL / min / 1.73m2), a mild impairment category (e.g., eGFR between approximately 60 mL / min / 1.73m2and approximately 79 mL / min / 1.73m2), and a moderate-to-severe impairment category (e.g., eGFR of less than approximately 59 mL / min / 1.73 m2).

[0226] In some embodiments, the highest observed hemoglobinuria rates occur when an increased value of cumulative index CI overlaps with a reduced eGFR. In some embodiments, neither the pre-procedural patient parameter (e.g., eGFR) nor the cumulative index CI alone fully predicts the probability of hemoglobinuria. The combination of the pre-procedural patient parameter and the cumulative index CI can provide a more accurate prediction of the hemoglobinuria probability than either parameter alone. In Fig. 15B, a horizontal threshold line at the patient parameter threshold TPP (e.g., at an eGFR of approximately 70 mL / min / 1.73m2) and a vertical threshold line at a cumulative index threshold TCI (e.g., at a cumulative index CI of approximately 190) divide the heat map into regions with different hemoglobinuria rates. The data shows the hemoglobinuria rate for patients with an eGFR below TPP was approximately 2.2 times higher than the hemoglobinuria rate for patients with an eGFR at or above TPP (e.g., approximately 20.9% compared to approximately 9.6%). The hemoglobinuria rate for patients with a cumulative index CI above TCI was approximately 1.6 times higher than the hemoglobinuria rate for patients with a hemolytic index at or below TCI (e.g., approximately 18% compared to approximately 11.2%).

[0227] In some embodiments, the cumulative index threshold TCI comprises a CI value of at least 150, at least 160, at least 170, at least 175, at least 180, at least 190, at least 200, atClient Docket No. : ARG-011-PCTleast 210, and / or at least 215. In some embodiments, TCI comprises a CI value of no more than 250, no more than 230, no more than 215, no more than 200, no more than 190, no more than 180, no more than 175, and / or no more than 160.

[0228] In some embodiments, the patient parameter threshold TPP and the cumulative index threshold TCI can partition a patient population it two or more segments, such as quadrants shown in Fig. 15B. For example, as shown, TPP can comprise an eGFR of approximately 80 mL / min / 1.73m2and TCI comprises a cumulative index CI value of approximately 175, and these thresholds can partition the patient population into quadrants (e.g., above and below TPP and above and below TCI). In the data collected by the applicant, the first quadrant (e.g., eGFR at or above approximately 80 mL / min / 1.73m2and cumulative index CI at or below approximately 175) is associated with a hemoglobinuria rate of approximately 3.6%; the second quadrant (e.g., eGFR at or above approximately 80 mL / min / 1.73m2and cumulative index CI of above approximately 175) is associated with a hemoglobinuria rate of approximately 12.5%; the third quadrant (e.g., eGFR below approximately 80 mL / min / 1.73m2and cumulative index CI at or below approximately 175) is associated with a hemoglobinuria rate of approximately 18.2%; and the fourth quadrant (e.g., eGFR below approximately 80 mL / min / 1.73m2and cumulative index CI above 175) is associated with a hemoglobinuria rate of approximately 25%. The data of Fig. 15B demonstrates a clear interaction effect between the pre-procedural patient parameter and the cumulative index CI, where the hemoglobinuria risk is lowest when the lowest when the patient has nominal kidney function and a low cumulative index CI. Data collected by the applicant shows that the hemoglobinuria risk was highest for the study cohort when a high cumulative index CI coincided with reduced renal function.

[0229] Fig. 15C shows individual patient data points from clinical procedures performed using system 10 plotted on a scatter plot with baseline eGFR (y-axis) and cumulative index CI (x-axis). Each data point represents a single clinical procedure performed by system 10. Data points associated with a hemoglobinuria outcome are indicated by a first indicator (e.g., a first color such as red), and data points not associated with a hemoglobinuria outcome are indicated by a second indicator (e.g., a second color such as blue). Fig. 15C shows threshold lines at a patient parameter threshold TPP (e.g., at eGFR at approximately 70 mL / min / 1.73m2) and a cumulative index threshold TCI (e.g., at a cumulative index CI value of approximately 190) that divide the scatter plot into four quadrants.Client Docket No. : ARG-011-PCT

[0230] The thresholds TPP and TCI shown in Fig. 15C were selected as the values that produced the largest increase in hemoglobinuria rate between adjacent quadrants based on the applicant study data. In some embodiments, algorithm 25 can be configured to determine optimal threshold placement for TPP and / or TCI based at least in part on clinical procedure data (e.g., data collected by system 10 from multiple patients that is updated over time). In some embodiments, the threshold placement is determined to maximize the sensitivity of the threshold-based classification, a specificity of the threshold-based classification, or both. As shown in Fig. 15C, each quadrant is associated with a hemoglobinuria rate that was observed in the applicant’s studies. As shown, a first quadrant comprising patients with an eGFR below TPP and a cumulative index CI above TCI (e.g., a highest risk quadrant) is associated with a hemoglobinuria rate of approximately 25%. A second quadrant comprising patients with an eGFR below TPP and a cumulative index CI at or below TCI is associated with a hemoglobinuria rate of approximately 18.5%. A third quadrant comprising patients with an eGFR at or above TPP and a cumulative index CI above TCI is associated with a hemoglobinuria rate of approximately 14.8%. A fourth quadrant comprising patients with an eGFR at or above TPP and a cumulative index CI at or below TCI (e.g., a lowest risk quadrant) is associated with a hemoglobinuria rate of approximately 8%.

[0231] In some embodiments, algorithm 25 of system 10 can be configured to partition the patient population into one or more risk categories based at least in part on the placement of TPP and TCI. In some embodiments, each risk category is associated with one or more corresponding clinical actions, such as: a standard ablation procedure using standard thresholds for energy delivery or other procedural parameters; an ablation procedure with adjusted (e.g., more conservative) thresholds; an ablation procedure with one or more additional conditions being monitored; a procedure with one or more additional clinical treatments (e.g., drug treatments and / or other clinical treatments); a recommendation to defer the procedure; and combinations of these. In some embodiments, system 10 can be configured to display the risk category and / or the one or more corresponding clinical actions associated with the particular patient to a clinician (e.g., via GUI 153).

[0232] As shown in Fig. 15D, system 10 can be configured to receive a patient parameter value PPV (e.g., a baseline eGFR) for a given patient, and to determine a corresponding cumulative index threshold TCI for that patient based at least in part on the received patientspecific value PPV. Fig. 15D shows two scatter plots of the same clinical procedure. The left panel of Fig. 15D shows the data with a first patient-specific eGFR value (e.g., an eGFRClient Docket No. : ARG-011-PCTof approximately 90 mL / min / 1.73m2, corresponding to normal kidney function) entered as an input to algorithm 25. The right panel of Fig. 15D shows the data with a second patientspecific eGFR value (e.g., an eGFR of approximately 60 mL / min / 1.73m2, corresponding to mild kidney impairment) entered as an input to algorithm 25. In each panel, a horizontal line indicates the entered baseline eGFR value, and a vertical line indicates the algorithmically determined cumulative index threshold TCI.

[0233] In some embodiments, when the patient-specific eGFR value comprises a higher value (e.g., approximately 90 mL / min / 1.73m2, correlating to better kidney function), algorithm 25 can determine a higher cumulative index threshold TCI (e.g., a cumulative index CI value of approximately 215). Additionally, or alternatively, when the patientspecific eGFR value comprises a lower value (e.g., approximately 60 mL / min / 1.73m2), algorithm 25 can determine a lower cumulative index threshold TCI (e.g., a cumulative index CI value of approximately 175). In some embodiments, the relationship between the patientspecific eGFR value and the corresponding TCI comprises a direct relationship. For example, a lower eGFR value results in a more conservative (e.g., lower) cumulative index threshold TCI. A higher eGFR can result in a higher cumulative index threshold TCI. In some embodiments, the more conservative TCI for patients with reduced renal function can correlate to a reduction in the total energy delivered by system 10 during the clinical procedure. In some embodiments, reducing the total energy delivered can reduce the possibility of hemoglobinuria and / or other hemolysis-related adverse events.

[0234] In some embodiments, system 10 can be configured to determine the cumulative index threshold TCI based at least in part on the patient-specific eGFR value using one or more approaches. In some embodiments algorithm 25 can be configured to compute a patient-specific scale for cumulative index CI. The incremental effect of each energy delivery on cumulative index CI can be scaled based at least in part on the patient-specific eGFR value. The thresholds (e.g., threshold TW and / or threshold TC) can comprise fixed values, and the scale of cumulative index CI can be adjusted per patient. Alternatively, or additionally, algorithm 25 can be configured to compute a patient-specific ceiling for cumulative index CI (e.g., patient-specific values of threshold TW and / or threshold TC). The scale of cumulative index CI can comprise a universal scale (e.g., the same scale for all patients), and the thresholds can be adjusted based at least in part on the patient-specific eGFR value.Client Docket No. : ARG-011-PCT

[0235] In some embodiments, the cumulative index threshold TCI determined by algorithm 25 based on a patient-specific eGFR value comprises a cumulative index CI value of at least 150, at least 160, at least 170, at least 175, at least 180, at least 190, at least 200, at least 210, at least 215, and / or at least 220. In some embodiments, TCI comprises a cumulative index CI value of no more than 250, no more than 230, no more than 220, no more than 215, no more than 210, no more than 200, no more than 190, no more than 180, no more than 175, and / or no more than 160. For example, for a patient with an eGFR of approximately 60 mL / min / 1.73m2, TCI can comprise a threshold of approximately 175. For a patient with an eGFR of approximately 70 mL / min / 1.73m2, TCI can comprise a threshold of approximately 190.

[0236] In some embodiments, algorithm 25 comprises a machine learning and / or other artificial intelligence algorithm (e.g., an Al algorithm, as described herein), such as an Al algorithm that is configured to determine and / or modify one or more thresholds of system 10 (e.g., threshold TW, threshold TC, threshold TCI, and / or patient parameter threshold TPP) based at least in part on a clinical outcome database, database DB1 (e.g., DB1 comprising data 420 described herein). In some embodiments, the clinical outcome database DB1 comprises data from a plurality of prior clinical procedures performed using system 10 (e.g., on the same patient, and / or one or more different patients), and / or other clinical data (e.g., data collected from various patients treated with one or more systems other than and / or in addition to system 10). The clinical outcome database DB1 can be stored in memory 112 of generator 100, on server 400, or both. In some embodiments, the clinical outcome database DB1 comprises, for each of the plurality of prior clinical procedures (e.g., performed on the same patient, and / or one or more different patients), data selected from the group consisting of one or more cumulative index CI values; one or more patient parameters (e.g., preprocedural eGFR values, patient weight, patient age, comorbidity status); one or more energy delivery parameters (e.g., waveform parameters, electrode configurations, number of energy deliveries); one or more clinical outcomes (e.g., hemoglobinuria occurrence, acute renal injury occurrence, post-procedure hemolysis levels); and combinations of these.

[0237] In some embodiments, algorithm 25 is configured to compute an upper boundary safety limit for cumulative index CI (e.g., threshold TCI) based at least in part on the data of clinical outcome database DB1. In some embodiments, the upper boundary safety limit comprises a maximum cumulative index CI value above which the probability of an adverse clinical outcome (e.g., hemoglobinuria, acute renal injury) exceeds a threshold (e.g., aClient Docket No. : ARG-011-PCTclinician determined acceptable probability). In some embodiments, the upper boundary safety limit is determined by an algorithm 25 comprising an Al algorithm (e.g., a machine learning model) based on correlations between cumulative index values and clinical outcomes across the plurality of prior clinical procedures. In some embodiments, system 10 can be configured to display the upper boundary safety limit to the clinician (e.g., via GUI 153), for example, as a visual indicator positioned proximate a display of the current value of cumulative index CI.

[0238] In some embodiments, system 10 is configured to iteratively “refine” (e.g., modify) the machine learning model as new clinical procedure data is added to the clinical outcome database DB1 (e.g., the model can be retrained using updated datasets from database DB1). For example, after each clinical procedure performed using system 10, one or more of: procedure data; patient parameters; and / or clinical outcomes, can be transmitted to server 400 and added to the clinical outcome database DB 1. In some embodiments, the machine learning model of algorithm 25 can be re-trained and / or updated based on the expanded clinical outcome database DB1. In some embodiments, the updated model can be transmitted to generator 100 (e.g., via the network connection between generator 100 and server 400, as described herein) and / or otherwise integrated into system 10, such as for use during a clinical procedure (e.g., as described herein, algorithm 25 can be performed “locally” via controller 110 of generator 100, and / or remotely via processing unit 410 of server 400). In some embodiments, iterative refinement of the machine learning model of algorithm 25 can improve the accuracy (e.g., effectiveness) of the one or more thresholds as additional clinical procedure data is accumulated.

[0239] In some embodiments, system 10 is configured to provide a physician-facing alert and / or recommendation based at least in part on an output of the processing performed by system 10 using algorithm 25 (e.g., the output of the machine learning model). In some embodiments, the alert and / or recommendation comprises information including but not limited to: a warning threshold TW and / or critical threshold TC, as described herein. For example, system 10 can be configured to provide a patient-specific risk assessment (e.g., a predicted probability of hemoglobinuria based on the patient’s eGFR value and the current cumulative index CI value) to the clinician via GUI 153. In some embodiments, system 10 is configured to provide a recommendation for one or more procedural adjustments (e.g., a recommendation to use a different electrode configuration, a recommendation to limit additional energy deliveries, and / or a recommendation to increase a saline irrigation rate)Client Docket No. : ARG-011-PCTbased at least in part on the patient-specific risk assessment performed by algorithm 25. In some embodiments, GUI 153 is configured to display the patient-specific cumulative index threshold TCI (e.g., as determined by algorithm 25 based on the patient’s eGFR value) alongside a current value of cumulative index CI. In some embodiments, GUI 153 displays the patient-specific cumulative index threshold TCI as a visual indicator (e.g., a progress bar, a numerical comparison, a color-coded region, and / or a boundary marker) relative to the current cumulative index CI value. In some embodiments, the visual indicator is configured to be updated in real time as cumulative index CI changes during the clinical procedure.

[0240] In some embodiments, one or more patient parameters received by system 10 (e.g., via user interface 150) comprise patient parameters selected from the group consisting of an eGFR value; a diabetes status (e.g., presence or absence of diabetes mellitus, and / or the type or severity level of diabetes present in the patient); a hypertension status (e.g., presence or absence of hypertension and / or a blood pressure measurement); a body mass index; a patient age; a patient weight; a hydration level; a renal disease level; a history of cardiac surgery; a current medication regimen; and combinations of these. In some embodiments, algorithm 25 can be configured to modify one or more thresholds (e.g., TPP, TCI, TW, and / or TC) based at least in part on two or more of the one or more of the patient parameters (e.g., based on eGFR and at least one or more other patient parameter). For example, the presence of diabetes (e.g., a significant level of diabetes) can result in a more conservative (e.g., lower) cumulative index threshold TCI than would be determined based on eGFR alone.

[0241] In some embodiments, system 10 can be configured to receive intra-procedural monitoring data indicative of a hemolysis-related condition during a clinical procedure (e.g., during a procedure where therapy is provided by system 10). In some embodiments, the intra-procedural monitoring data comprises a urine-based hemolysis evaluation. For example, system 10 can be configured to receive data from a urine monitoring device (e.g., a Foley catheter comprising one or more sensors, an external urine collection device, a urine dipstick, and / or combinations of these), such as when functional element 99 comprises a urine monitoring device. In some embodiments, the one or more sensors of the urine monitoring device comprise one or more sensor types selected from the group consisting of an optical sensor, such as an optical sensor configured to detect a color change in the urine (e.g., a color change indicative of free hemoglobin); a colorimetric sensor; a chemical sensor, such as a chemical sensor configured to detect one or more hemolysis-related biomarkers;Client Docket No. : ARG-011-PCTand combinations of these. In some embodiments, a functional element 99 comprising a urine monitoring device can be configured to detect free hemoglobin in the urine. The presence of free hemoglobin can be indicative of hemoglobinuria.

[0242] In some embodiments, system 10 can be configured to establish a baseline urine parameter value prior to the clinical procedure and to monitor for changes relative to the baseline during the clinical procedure. In some embodiments, a change in the urine parameter value relative to the baseline (e.g., a delta value) that exceeds a threshold can be indicative of a hemolysis-related adverse event. In some embodiments, algorithm 25 can be configured to receive intra-procedural urine monitoring data as a real-time input and to modify one or more thresholds (e.g., TCI, TW, TC) and / or to provide an alert to the clinician based at least in part on the received intra-procedural data.

[0243] In some embodiments, system 10 is configured to determine a post-procedure protocol based at least in part on the patient’s pre-procedural patient parameters, based at least in part on a final value of cumulative index CI at the completion of the clinical procedure, or both. In some embodiments, the post-procedure protocol comprises a hydration protocol. In some embodiments, the hydration protocol is set based on the patient’s renal function (e.g., based on the baseline eGFR value), based on the final cumulative index CI value, or both. For example, a patient with a lower eGFR and a higher final cumulative CI value can receive a more aggressive hydration protocol than a patient with a higher eGFR and a lower final cumulative index CI value.

[0244] In some embodiments, system 10 is configured to capture post-procedure clinical outcome data (e.g., post-procedure hemolysis blood test results, hemoglobinuria occurrence, and / or acute renal function changes) and to transmit the post-procedure clinical outcome data to the clinical outcome database DB1 (e.g., stored in server 400). In some embodiments, the post-procedure clinical outcome data is associated with the corresponding pre-procedural patient parameters and / or the procedural energy delivery data for the same clinical procedure. Capturing the post-procedure clinical outcome data and adding it to the clinical outcome database DB1 can create an adaptive learning loop of system 10 (e.g., where one or more algorithms of system 10 are iteratively improved based on additional data gathered by system 10, as described herein). In some embodiments, the machine learning model of algorithm 25 is refined (e.g., iteratively refined) based on the complete procedure-to-outcome data.Client Docket No. : ARG-011-PCT

[0245] Referring now to Fig. 16, a flowchart of an embodiment of a method for managing hemolysis risk for a patient is illustrated, consistent with the present inventive concepts. Various components of system 10 described in reference to Fig. 16 can be of similar construction and arrangement as the similar components described in reference to Fig.1 and otherwise herein. Fig. 16 depicts an embodiment of Method 4000. Method 4000 can be performed by and / or performed using one or more components of system 10 (e.g., performed by controller 110 by executing algorithm 25 and / or by a clinician using the components of system 10 described herein). Method 4000 can be performed (e.g., started) prior to a clinical procedure (e.g., an ablation procedure) performed using system 10. In some embodiments, Method 4000 can be performed to determine one or more patient-specific thresholds for the clinical procedure based at least in part on one or more patient parameters.

[0246] Method 4000 can begin with Step 4010. In Step 4010, system 10 can receive one or more patient parameter values. In some embodiments, the one or more patient parameter values are received via user interface 150 (e.g., via GUI 153). The one or more patient parameter values can be determined by performing one or more pre-procedural tests and / or assessments. In some embodiments, the one or more pre-procedural tests comprise one or more tests selected from the group consisting of: a blood test (e.g., a serum creatinine test, a cystatin C test, a blood urea nitrogen test); a urine test; a renal function panel; an imaging procedure; a point-of-care diagnostic test; and combinations of these. In some embodiments, system 10 is configured to perform and / or facilitate the one or more pre-procedural tests (e.g., by providing a testing protocol via GUI 153, by providing and / or interfacing with a diagnostic device, such as a functional element 99 comprising a diagnostic device, and / or by receiving test results from an external laboratory system). In some embodiments, the one or more patient parameter values comprise a pre-procedural patient parameter value indicative of a patient’s renal function (e.g., an estimated glomerular filtration rate, and / or an eGFR, as described herein). In some embodiments, the one or more patient parameter values further comprise one or more additional values selected from the group consisting of: a diabetes status; a hypertension status; a body mass index; a patient age; a patient weight; a hydration status; a history of renal disease; a current medication regimen; and combinations of these.

[0247] Following Step 4010, Method 4000 can proceed to Step 4020. In Step 4020, system 10 (e.g., via algorithm 25) can determine one or more thresholds, for example, one or more patient-specific thresholds based at least in part on the one or more patient parameter values received in Step 4010. System 10 can determine one or more patient parameterClient Docket No. : ARG-011-PCTthresholds TPP, such as TPP1 and TPP2 comprising first and second threshold values, respectively, for assessing the patient parameter values from Step 4010. In some embodiments, algorithm 25 determines the one or more patient-specific thresholds using a machine learning model trained on a clinical outcome database DB1, as described herein.

[0248] Following Step 4020, Method 4000 can continue to Step 4030. In Step 4030, system 10 can determine whether the one or more patient parameter values received in Step 4010 are acceptable for proceeding by comparing the one or more values to the first threshold TPP1. For example, TPP1 can comprise a threshold value at or above which the patient’s renal function is acceptable for a standard clinical procedure (e.g., an eGFR of approximately 70 mL / min / 1.73m2or above as described herein). Following Step 4030, if the one or more patient parameter values meet the first patient parameter threshold TPP1, Method 4000 can continue to Step 4040.

[0249] In Step 4040, one or more standard clinical procedure settings can be established for a procedure to be performed using system 10 to treat the patient. Following Step 4040, Method 4000 can continue to Step 4090, described herein.

[0250] Following Step 4030, if the one or more patient parameter values are not acceptable (e.g., do not meet the first patient parameter threshold), Method 4000 can continue to Step 4050. In Step 4050, system 10 can determine whether the one or more patient parameter values received in Step 4010 are acceptable for proceeding with one or more patient-specific procedural settings, as described herein, for example, by comparing the one or more values to the second threshold TPP2. Threshold TPP2 can comprise a value that is higher and / or lower than the value of TPP 1 (e.g., lower when a lower patient parameter value indicates a “less” healthy patient, and vice versa). For example, TPP2 can comprise a lower value than TPP1 when assessing eGFR patient parameter values. Threshold TPP2 can comprise a value above which the patient parameter value is acceptable for proceeding to Step 4060 (e.g., a value between TPP1 and TPP2), and below which Method 4000 continues to Step 4070. Alternatively, or additionally, a threshold value TPP2 can comprise a value below which the patient parameter value is acceptable (e.g., a value between TPP1 and TPP2), and above which the value is unacceptable.

[0251] Following Step 4050, if the one or more patient parameters are between TPP2 and TPP1, Method 4000 can continue to Step 4060. In Step 4060, one or more patient-specific and / or otherwise adjusted clinical procedure settings can be established for a procedure to beClient Docket No. : ARG-011-PCTperformed using system 10. For example, one or more thresholds and / or other parameter values used by system 10 during a clinical procedure can be adjusted based on the preprocedural health of the patient based on the comparison of the one or more patient parameter values to TPP1 and TPP2. In some embodiments, the adjusted thresholds comprise a more conservative cumulative index threshold TCI (e.g., a lower value of TCI than would be applied for a patient meeting the first patient parameter threshold TPP1). In some embodiments, the adjusted thresholds comprise adjusted values of threshold TW and / or threshold TC. In some embodiments, system 10 is configured to operate under one or more “special” conditions established in Step 4060. For example, the one or more special conditions can comprise one or more conditions selected from the group consisting of: an additional monitoring condition (e.g., intra-procedural urine monitoring as described herein); a reduced maximum energy delivery limit; an increased saline irrigation rate; a modified electrode configuration; and combinations of these. Following Step 4060, Method 4000 can proceed to Step 4090.

[0252] Following Step 4050, if the one or more patient parameters are not acceptable for continuing to Step 4060 (e.g., the patient is not indicated for undergoing a clinical procedure where treatment is provided by system 10 based on the current health of the patient), for example, if the patient’s eGFR is below TPP2, Method 4000 can continue to Step 4070. In Step 4070, system 10 can provide a recommendation for an intervention (e.g., a preprocedure intervention). In some embodiments, the intervention comprises one or more interventions selected from the group consisting of: a hydration regimen; administration of one or more pharmaceutical agents; a lifestyle modification; a delay of the clinical procedure; and combinations of these. In some embodiments, a hydration regimen can increase the patient’s eGFR by at least 5 mL / min / 1.73m2, at least 10 mL / min / 1.73m2, and / or at least 15 mL / min / 1.73m2.

[0253] Following Step 4070, Method 4000 can continue to Step 4080. In Step 4080, system 10 can receive a re-assessed value of the one or more patient parameters (e.g., an updated post-intervention eGFR measurement). In some embodiments, the re-assessed value is received via user interface 150 (e.g., via GUI 153). Following Step 4080, Method 4000 can return to Step 4030 (e.g., the re-assessed patient parameter is compared to the first threshold and the second threshold as described herein).Client Docket No. : ARG-011-PCT

[0254] In Step 4090, system 10 can be used to perform the clinical procedure using the one or more system parameters determined via Method 4000. In some embodiments, the one or more patient-specific thresholds applied during the clinical procedure of Step 4090 comprise the thresholds determined at Step 4040 and / or the adjusted thresholds determined at Step 4060. In some embodiments, during the clinical procedure of Step 4090, system 10 can monitor cumulative index CI and compare the cumulative index CI to the one or more patient-specific thresholds in real time, as described herein. In some embodiments, GUI 153 is configured to display the cumulative index CI and / or to update the displayed cumulative index CI after each energy delivery performed during the clinical procedure. In some embodiments, during and / or following the clinical procedure of Step 4090, system 10 can capture clinical outcome data from the procedure. In some embodiments, the clinical outcome data comprises data selected from the group consisting of: a final value of cumulative index CI; one or more energy delivery parameters (e.g., waveform parameters, electrode configurations, number of energy deliveries); one or more intra-procedural measurements (e.g., impedance measurements, temperature measurements); a hemoglobinuria occurrence; a post-procedure hemolysis level; a post-procedure renal function measurement (e.g., a post-procedure eGFR value); an acute renal injury occurrence; and combinations of these. In some embodiments, the clinical outcome data are stored in a clinical outcome database DB1 (e.g., stored in memory 112 of generator 100, on server 400, or both). In some embodiments, the clinical outcome data stored in the clinical outcome databases (e.g., database DB1) are used by algorithm 25 to refine the machine learning model described herein. In some embodiments, the machine learning model is progressively refined as additional clinical outcome data from subsequent clinical procedures are added to the clinical outcome database.

[0255] In some embodiments, when the one or more patient parameters do not meet the second patient parameter threshold (e.g., eGFR is below TPP2) following a pre-procedure intervention (e.g., when the re-assessed patient parameter of Step 4080 returns to Step 4030 and still does not meet the first patient parameter threshold TPP1 or the second patient parameter threshold TPP2), system 10 can be configured to provide a notification to the clinician. In some embodiments, the notification comprises an indication that the clinical procedure may present an elevated risk of a hemolysis-related adverse event (e.g., hemoglobinuria, acute renal injury). In some embodiments, the notification comprises a recommendation to defer the clinical procedure. In some embodiments, the patient and / orClient Docket No. : ARG-011-PCTclinician can elect to forego the clinical procedure based at least in part on the notification. In some embodiments, the clinical procedure comprises an elective procedure (e.g., an ablation procedure for atrial fibrillation), such as an elective procedure that can be avoided or at least postponed.

[0256] In some embodiments, Method 4000 can be performed in conjunction with a “threshold shifting”, such as the threshold shifting illustrated in Fig. 15D. In some embodiments, the one or more patient-specific thresholds determined at Step 4020 correspond to the cumulative index threshold TCI shown in the left panel (e.g., for a patient with an eGFR of approximately 90 mL / min / 1.73m2) or the right panel (e.g., for a patient with an eGFR of approximately 60 mL / min / 1.73m2) of Fig. 15D. In some embodiments, the decision tree of Method 4000 determines which path (e.g., standard thresholds at Step 4040, adjusted thresholds at Step 4060, or post-intervention thresholds following Step 4070 and 4080) is to be applied for a given patient based at least in part on the patient’s pre-procedural patient parameter value relative to TPP1 and TPP2.

[0257] The above-described embodiments should be understood to serve only as illustrative examples; further embodiments are envisaged. Any feature described herein in relation to any one embodiment may be used alone, or in combination with other features described, and may also be used in combination with one or more features of any other of the embodiments, or any combination of any other of the embodiments. Furthermore, equivalents and modifications not described above may also be employed without departing from the scope of the inventive concepts, which is defined in the accompanying claims.

Claims

Client Docket No. : ARG-011-PCTWHAT IS CLAIMED IS:

1. A system for delivering energy to a patient, comprising:a generator configured to provide energy; andan energy delivery device comprising at least one energy delivery element configured to deliver energy to tissue and / or other material of the patient,wherein the system is configured to:track the energy delivered by the energy delivery device; andbased on the energy delivered, estimate, monitor, record, and / or prognose hemolysis and / or other side effect.

2. The system according to claim 1 and / or any one or more other claims herein, wherein based on an estimation of the hemolysis level, the system is further configured to estimate, monitor, record, and / or prognose at least a second side effect.

3. The system according to claim 1 and / or any one or more other claims herein, wherein based on an estimation of a level of hemolysis, the system is configured to indicate a secondary clinical procedure to be performed.

4. The system according to claim 3 and / or any one or more other claims herein, wherein the secondary clinical procedure comprises: delivery of saline or other fluid to the patient; delivery of a medication to the patient; or both.

5. The system according to claim 3 and / or any one or more other claims herein, wherein the secondary clinical procedure is configured to limit hemolysis and / or the other side effect.

6. The system according to claim 1 and / or any one or more other claims herein, wherein the system is configured to estimate a level of hemolysis generated for each delivery of energy.

7. The system according to claim 1 and / or any one or more other claims herein, wherein the system is configured to estimate a level of hemolysis generated by oneClient Docket No. : ARG-011-PCTor more energy deliveries, and wherein the estimation is based on one, two, or more of: the magnitude of the electric field delivered that exceeds a hemolytic threshold at a given frequency; the volume of blood exposed to an energy delivery electric field; and / or the total number of cycles delivered during an application of energy.

8. The system according to claim 1 and / or any one or more other claims herein, wherein the system is configured to track, record, calculate, predict, prognose, and / or otherwise monitor the amount of hemolysis that occurs during a clinical procedure.

9. The system according to claim 8 and / or any one or more other claims herein, wherein the system is configured to provide a display of information relating to the tracked, recorded, calculated, predicted, prognosed, and / or otherwise monitored amount of hemolysis.

10. The system according to claim 1 and / or any one or more other claims herein, wherein the system is configured to determine and / or display one or more parameter values relating to hemolysis and / or other cumulative effects of the delivery of energy to the patient by the system.

11. The system according to claim 10 and / or any one or more other claims herein, wherein the system is configured to display one or more icons and / or other graphical indicators related to the determined parameter values.

12. The system according to claim 10 and / or any one or more other claims herein, wherein the system is configured to determine the one or more parameter values based on one or more system parameters and / or one or more patient parameters.

13. The system according to claim 1 and / or any one or more other claims herein, wherein the system is configured to determine and / or display one or more parameter values relating to total energy delivered during a clinical procedure.

14. The system according to claim 1 and / or any one or more other claims herein, wherein the system is configured to model peak electric fields generated duringClient Docket No. : ARG-011-PCTenergy delivery, and to use the model to determine the volume of blood that were exposed to electric fields that were greater than a hemolytic threshold.

15. The system according to claim 1 and / or any one or more other claims herein, wherein the system is configured to determine an amount of hemolysis generated by each pulse of energy delivery and / or to determine a cumulative amount of hemolysis generated throughout a clinical procedure.

16. The system according to claim 15 and / or any one or more other claims herein, wherein the system is further configured to determine a hemolytic potential for a series of pulses of energy delivery.

17. The system according to claim 16 and / or any one or more other claims herein, wherein the system is configured to determine the cumulative amount of hemolysis generated by summing each hemolytic potential for each series of pulses of energy delivery.

18. The system according to claim 15 and / or any one or more other claims herein, wherein the system is configured to determine the cumulative amount of hemolysis generated based on a set of system parameters; patient parameters; and / or hemolysis mitigation parameters.

19. The system according to claim 15 and / or any one or more other claims herein, wherein the system comprises and / or is configured to determine one or more hemolysis thresholds to which the determined cumulative amount of hemolysis generated is compared.

20. The system according to claim 19 and / or any one or more other claims herein, wherein the one or more hemolysis thresholds comprise a safety margin.

21. The system according to claim 19 and / or any one or more other claims herein, wherein the system is configured to prevent additional energy from being delivered after the determined cumulative amountClient Docket No. : ARG-011-PCTof hemolysis generated exceeds the one or more hemolysis thresholds.

22. The system according to claim 21 and / or any one or more other claims herein, wherein the system comprises a clinician override function configured to allow additional energy delivery after the determined cumulative amount of hemolysis generated exceeds the one or more hemolysis thresholds.

23. The system according to claim 19 and / or any one or more other claims herein, wherein the system comprises and / or is configured to determine one or more hemolysis warning thresholds, and wherein the system is configured to provide an alert if the determined cumulative amount of hemolysis generated exceeds the one or more hemolysis warning thresholds.

24. The system according to claim 19 and / or any one or more other claims herein, wherein the one or more hemolysis thresholds are dynamically determined by the system.

25. The system according to claim 19 and / or any one or more other claims herein, wherein the system is configured to determine a number of energy deliveries that can be delivered before the one or more hemolysis thresholds are exceeded.

26. The system according to claim 1 and / or any one or more other claims herein, wherein the system comprises a user interface that is configured to provide a procedural planning function.

27. The system according to claim 1 and / or any one or more other claims herein, wherein the generator comprises:a signal generator configured to generate the provided energy.

28. The system according to claim 27 and / or any one or more other claims herein, wherein the signal generator is configured to provide the energy in anClient Docket No. : ARG-011-PCTenergy form selected from the group consisting of: radiofrequency energy; electroporation energy; ultrasound and / or other sound energy; laser and / or other light energy; chemical energy; mechanical energy; and combinations thereof.

29. The system according to claim 27 and / or any one or more other claims herein, wherein the signal generator is configured to provide the energy in the form of an electroporation waveform, and wherein the generator further comprises a controller configured to provide signaling configured to cause the signal generator to generate the electroporation waveform.

30. The system according to claim 29 and / or any one or more other claims herein, wherein the electroporation waveform comprises a plurality of energy pulses, and wherein each energy pulse is separated by an inter-pulse delay period.

31. The system according to claim 29 and / or any one or more other claims herein, further comprising one or more external electrodes, wherein the electroporation waveform is configured to be delivered in a unipolar arrangement to the at least one energy delivery element and the one or more external electrodes.

32. The system according to claim 31 and / or any one or more other claims herein, wherein the electroporation waveform is configured to be delivered in both a unipolar arrangement and a bipolar arrangement.

33. The system according to claim 32 and / or any one or more other claims herein,wherein the electroporation waveform comprises a first signal comprising a first sine wave, a second signal comprising a second sine wave, and a third signal comprising a combined reference of the first sine wave and the second sine wave;Client Docket No. : ARG-011-PCTwherein the first sine wave and the second sine wave comprise a phase offset; andwherein the first signal is configured to be provided to a first energy delivery element of the at least one energy delivery elements, the second signal is configured to be provided to a second energy delivery element of the at least one energy delivery elements, and the third signal is configured to be provided to at least one electrode of the one or more external electrodes.

34. The system according to claim 1 and / or any one or more other claims herein, wherein the energy delivery device comprises a catheter.

35. The system according to claim 1 and / or any one or more other claims herein, wherein the generator comprises a signal generator configured to generate the provided energy.

36. The system according to claim 35 and / or any one or more other claims herein, wherein the signal generator comprises one or more shared waveform generation hardware modules, one or more specialized waveform generation hardware modules, or both.

37. The system according to claim 36 and / or any one or more other claims herein, wherein each of the one or more specialized waveform generation hardware modules is configured for a specific waveform generation modality, and wherein the system is configured to selectively activate one of the specialized waveform generation hardware modules based on the desired energy delivery modality.

38. The system according to claim 36, wherein at least one of the one or more shared waveform generation hardware modules comprises one or more components configured to control the function of the signal generator.Client Docket No. : ARG-011-PCT39. The system according to claim 36, wherein at least one of the one or more shared waveform generation hardware modules comprises one or more components configured to provide power to the signal generator.

40. The system according to claim 35 and / or any one or more other claims herein, wherein the generator is configured to operate in different modes independently.

41. The system according to claim 35 and / or any one or more other claims herein, wherein the generator is configured to generate high frequency sine wave waveforms comprising a frequency of at least 250kHz.

42. The system according to claim 35 and / or any one or more other claims herein, wherein the generator is configured to generate a waveform comprising PFA energy and RF energy simultaneously.

43. The system according to claim 35 and / or any one or more other claims herein, wherein the generator is configured to generate a waveform comprising a hybrid of sine waves and square waves.

44. The system according to claim 43 and / or any one or more other claims herein, wherein the hybrid waveform is generated by a partial filtering of the sine waves.

45. The system according to claim 35 and / or any one or more other claims herein, wherein the generator comprises an RF generator, and wherein the RF generator is configured to generate both an RF waveform and a PFA waveform.

46. The system according to claim 35 and / or any one or more other claims herein, wherein the generator comprises one or more interchangeable components.Client Docket No. : ARG-011-PCT47. The system according to claim 1 and / or any one or more other claims herein, wherein the system further includes an arbitrary waveform generation hardware module configured to deliver energy comprising one or more arbitrary waveforms.

48. The system according to claim 47 and / or any one or more other claims herein, wherein the arbitrary waveform generation hardware module is configured to provide direct waveform synthesis without requiring filtering and / or without requiring a waveform transformation process.

49. The system according to claim 47 and / or any one or more other claims herein, wherein the arbitrary waveform generation hardware module is configured to dynamically switch between two or more of the one or more arbitrary waveforms.

50. The system according to claim 47 and / or any one or more other claims herein, wherein the arbitrary waveform generation hardware module is configured to produce waveforms with voltage capabilities of at least 2kV.

51. The system according to claim 47 and / or any one or more other claims herein, wherein the one or more arbitrary waveforms are selected from the group consisting of: sine waves; square waves; single period sine wave snippets; custom pulse patterns; pulses without ramp-up characteristics; triangle; chirp; sawtooth; and combinations thereof.

52. The system according to claim 1 and / or any one or more other claims herein, wherein the generator is configured to generate sine waves and to provide an output comprising a sine wave, a square wave, or both.

53. The system according to claim 1 and / or any one or more other claims herein, wherein the generator is configured to generate square waves and to provide an output comprising a sine wave, a square wave, or both.

54. The system according to claim 1 and / or any one or more other claims herein, wherein the system is configured to perform harmonic filtering configured to convert square waves to sine waves.Client Docket No. : ARG-011-PCT55. The system according to claim 1 and / or any one or more other claims herein, wherein the system is configured to perform pulse modulation configured to convert square waves to sine waves.

56. The system according to claim 1 and / or any one or more other claims herein, wherein the system further comprises one or more waveform processing modules configured to convert sine waves to square waves.

57. The system according to claim 56 and / or any one or more other claims herein, wherein the one or more waveform processing modules comprises a comparator and / or a pulse-shaping circuit.

58. The system according to claim 1 and / or any one or more other claims herein, wherein the system is configured to generate high voltage packet sequences, each sequence comprising a voltage of at least 2kV.

59. A method for bidirectional waveform conversion, comprising:defining a desired sine wave frequency;generating, via a signal generator, a biphasic square wave at a predetermined frequency; andperforming a waveform manipulation configured to process the biphasic square wave into one, two, or more sine wave approximations,wherein the output comprises the desired sine wave frequency.

60. The method according to claim 59 and / or any one or more other claims herein, wherein the waveform manipulation comprises full spectrum filtering and / or partial spectrum filtering.

61. The method according to claim 60 and / or any one or more other claims herein, wherein the waveform manipulation achieves complete harmonic elimination and / or suppression.Client Docket No. : ARG-011-PCT62. The method according to claim 60 and / or any one or more other claims herein, wherein the waveform manipulation achieves selective harmonic elimination and / or suppression.

63. The method according to claim 59 and / or any one or more other claims herein, wherein the waveform manipulation is configured to switch between full spectrum filtering and partial spectrum filtering to produce different waveforms.

64. The system according to claim 1 and / or any one or more other claims herein, wherein the system is configured to control and / or mitigate electrical arcing of the energy delivery device.

65. The system according to claim 1 and / or any one or more other claims herein, wherein the energy delivery device comprises a catheter and wherein the system is configured to perform a catheter conditioning procedure on the catheter.

66. The system according to claim 1 and / or any one or more other claims herein, wherein the system comprises a microbubble power threshold, and wherein the system is configured to limit microbubble formation based on the microbubble power threshold.

67. The system according to claim 1 and / or any one or more other claims herein, wherein the system is configured to determine a number of ablations to efficaciously treat a pulmonary vein target.

68. The system according to claim 1 and / or any one or more other claims herein, wherein the system is configured to prevent or at least reduce hemolysis during the delivery of ablative energy to cardiac tissue.

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