Patent Description:
<CIT> relates to systems for treating tissue with electroporation or pulsed-field ablation.

<CIT> relates to the use of electroporation for treatment of diseased tissue by using waveforms capable of inducing electroporation.

<CIT> relates to decreasing the effective threshold for irreversible and reversible electroporation allowing a reduced electric field.

<CIT> relates to a method for treating cardiac arrhythmia for enhancing lesion formation without arrhythmogenic effects within relatively thick target tissue.

<CIT> relates to methods for determining electroporation parameters based on desired lesion characteristics.

Various therapies are used to treat various conditions afflicting the human anatomy. Cardiac arrhythmias, for example are sometimes treated using ablation therapy and, more specifically, electroporation. Ablation therapy is a process by which target tissue of a patient is partially or completely damaged. At least some methods of ablation therapy involve the application of an electric field to target tissue by one or more electrodes connected to a signal generator. The one or more electrodes may be incorporated, for example, onto a catheter, or an ablation catheter, that can be navigated to the target tissue. When tissue is ablated using electroporation, the electrodes deliver current to the target tissue to generate an electric field that creates tissue necrosis in cardiac tissue to correct conditions such as atrial arrhythmia (including, but not limited to, ectopic atrial tachycardia, atrial fibrillation, and atrial flutter).

Arrhythmia (i.e., irregular heart rhythm) can create a variety of dangerous conditions including loss of synchronous atrioventricular contractions and stasis of blood flow that can lead to a variety of ailments and even death. It is believed that the primary cause of atrial arrhythmia is stray electrical signals within the left or right atrium of the heart. The ablation catheter imparts ablative energy (e.g., radio frequency energy, cryoablation, lasers, chemicals, high-intensity focused ultrasound, etc.) to cardiac tissue to create a lesion in the cardiac tissue. This lesion disrupts undesirable electrical pathways and thereby limits or prevents stray electrical signals that lead to arrhythmias.

Electroporation is a non-thermal ablation technique that involves applying strong electric-fields that induce pore formation in the cellular membrane. The electric field may be induced by applying a relatively short-duration pulse of sufficient amplitude. Such a pulse may be repeated to form a pulse train. When such an electric field is applied to tissue in vivo, the cells in the tissue are subjected to a trans-membrane potential that opens the pores on the cell wall, hence the term electroporation. Electroporation may be reversible (i.e., the temporally-opened pores will reseal) or irreversible (i.e., the pores will remain open). For example, in the field of gene therapy, reversible electroporation (i.e., temporarily open pores) is used to transfect high molecular weight therapeutic vectors into the cells. In other therapeutic applications, a suitably configured pulse train alone may be used to cause cell destruction, for instance by causing irreversible electroporation (IRE).

The invention is defined in the appended independent claim. SUMMARY OF THE DISCLOSURE.

The present disclosure is directed to systems and methods that deliver biphasic pulsed waveform IRE energy to target tissue in a patient, for example, suffering from a cardiac arrhythmia.

The present disclosure is further directed to an electroporation system including a catheter shaft, at least one electrode coupled to the catheter shaft at a distal end thereof, and a signal generator. The signal generator is coupled in communication with the at least one electrode. The signal generator is configured to supply a biphasic pulse to the at least one electrode, the biphasic pulse including a first phase having a first polarity, a first initial voltage amplitude, and a first pulse width. The biphasic pulse including a second phase having a second polarity opposite to the first polarity, a second initial voltage amplitude, and a second pulse width, wherein at least one of the first initial voltage amplitude or the first pulse width is different from the second initial voltage amplitude or the second pulse width, respectively. A leading edge of the second phase occurs after an interphase delay following a trailing edge of the first phase.

The present disclosure is further directed to a method of delivering electroporation energy through an ablation catheter. The method includes positioning at least one electrode at a target tissue. The method includes coupling the at least one electrode to a signal generator. The method includes supplying, by the signal generator, a biphasic pulse. Supplying the biphasic pulse includes transmitting a first phase having a first polarity, a first initial voltage amplitude, and a first pulse width. Supplying the biphasic pulse includes supplying zero volt direct current (VDC) for an interphase delay following a trailing edge of the first phase. Supplying the biphasic pulse includes transmitting a second phase having a second polarity opposite the first polarity, a second initial voltage amplitude, and a second pulse width, wherein at least one of the first initial voltage amplitude or the first pulse width is different from the second initial voltage amplitude or the second pulse width, respectively.

Corresponding reference characters indicate corresponding parts throughout the several views of the drawings.

The systems and methods disclosed herein provide electroporation energy, particularly IRE energy, for application to tissue in the human body. The disclosed systems and methods relate to controlling an electroporation system and, more specifically, a signal generator, to deliver IRE energy to target tissue (e.g., about <NUM> V/cm to cardiac tissue) to produce more consistent and improved patient outcomes. For example, disclosed embodiments of the signal generator produce biphasic electroporation waveforms, or signals, having specific parameters that differ between the two phases, including, for example, voltage amplitudes or pulse widths. For example, in one embodiment, pulse widths may be substantially equal, but voltage amplitudes differ. In other embodiments, voltage amplitudes may be substantially equal, but pulse widths differ. In yet other embodiments, voltage amplitudes and pulse widths differ. Generally, voltage amplitudes for each phase are in the range of <NUM> kilovolt (kV) to <NUM> kV, and pulse widths for each phase are in the range of <NUM> nanoseconds (ns) to <NUM> microseconds (us). In certain embodiments, for example, pulse widths are in the range of <NUM> to <NUM>.

Disclosed embodiments of the signal generator produce the biphasic electroporation waveform, or biphasic IRE waveform, as a "burst," or series, of biphasic "pulses" having an interphase delay between each phase, and an interpulse delay between each biphasic pulse. Interphase delay is generally short to reverse current in target tissue to avoid stimulating other cells, for example, in the range of <NUM> ns to <NUM>. In certain embodiments, interphase delay is in the range of <NUM> to <NUM>. Interpulse delay between each pulse is generally in the range of <NUM> to <NUM> milliseconds (ms). In certain embodiments, interpulse delay is in the range of <NUM> to <NUM>. Each burst may include, for example, <NUM>-<NUM> biphasic pulses.

Multiple bursts of biphasic pulses are generated with an interburst delay between each burst. Interburst delay generally is in the range of <NUM> to <NUM> seconds (s). The biphasic IRE waveform, or signal, may include, for example, <NUM>-<NUM> bursts of biphasic pulses. In addition to voltage amplitudes and pulse widths, each biphasic pulse can be partially characterized by their tilt, or the charged capacitive load discharged through the patient load. Because the patient load decays as current is conducted through the tissue, the patient load is supplemented by a charged capacitive load that is discharged over time to maintain an effective patient load in an ideal range for the electroporation system, e.g., between about <NUM> ohms and <NUM> ohms. The tilt is exhibited as an initial voltage amplitude of a given phase of the biphasic pulse that decays over the pulse width to an ending voltage amplitude. In certain embodiments, the initial voltage amplitude of a second phase is substantially equal to the ending voltage amplitude of a first phase.

Further, the biphasic waveforms may be generated as inverted or noninverted by functionally reversing the anode and cathode electrodes. In other words, the biphasic pulse may be positive polarity then negative polarity, or may be negative polarity then positive polarity.

Embodiments of the disclosed systems and methods produce biphasic IRE waveforms to reduce or minimize undesirable skeletal muscle excitation and generation of gasses within a patient, and unintended application of IRE energy to surrounding tissue that is not the intended target of IRE therapy. It is contemplated, however, that the described features and methods of the present disclosure as described herein may be incorporated into any number of electric field-based ablation systems as would be appreciated by one of ordinary skill in the art based on the disclosure herein.

The disclosed systems and methods are generally embodied in an electric field-based ablation system, such as an electroporation system. <FIG> illustrates an example embodiment of a system <NUM> for electroporation therapy and other electrophysiology studies, e.g., mapping, or other ablation therapy. Certain embodiments, such as system <NUM>, include an electrode assembly <NUM> disposed at the distal end, for example, of a catheter <NUM>. As used herein, "proximal" refers to a direction toward the end of the catheter <NUM> near the clinician and "distal" refers to a direction away from the clinician and (generally) inside the body of a patient. In alternative embodiments, system <NUM> may include a plurality of needles having one or more electrodes at their respective distal ends (as shown in <FIG>). Electrode assembly <NUM> includes one or more individual, electrically-isolated electrode elements. In some embodiments, each electrode element, also referred to herein as a catheter electrode, is individually wired such that it can be selectively paired or combined with any other electrode element to act as a bipolar or a multi-polar electrode.

System <NUM> may be used for irreversible electroporation (IRE) to destroy tissue. In particular, system <NUM> may be used for electroporation-induced primary necrosis therapy, which refers to the effects of delivering electrical current in such manner as to directly cause an irreversible loss of plasma membrane (cell wall) integrity leading to its breakdown and cell necrosis. This mechanism of cell death may be viewed as an "outside-in" process, meaning that the disruption of the outside wall of the cell causes detrimental effects to the inside of the cell. Typically, for typical plasma membrane electroporation, electric current is delivered as a pulsed electric field in the form of short-duration direct current (DC) pulses between closely spaced electrodes capable of delivering a strong enough electric field to cause irreversible electroporation in the targeted cells. As described in more detail herein, the system <NUM> is configured to deliver a biphasic IRE waveform, or signal, having a relatively high voltage and low pulse duration as compared to at least some prior electroporation systems. Moreover, the biphasic IRE waveform features phases that may differ in voltage amplitude or pulse width, or both. The waveforms generated by system <NUM> and applied to catheter electrodes facilitate reducing and/or preventing skeletal muscle stimulation during IRE therapy.

Irreversible electroporation through a multi-electrode hoop catheter may enable pulmonary vein isolation in as few as one shock per vein, which may produce much shorter procedure times compared to sequentially positioning a radiofrequency (RF) ablation tip around a vein. It should be understood that the mechanism of cell destruction in electroporation is not primarily due to heating effects, but rather to cell membrane disruption through application of a high-voltage electric field. Thus, electroporation may avoid some possible thermal effects that may occur when using RF energy. This "cold" or "non-thermal" therapy thus has desirable characteristics.

Catheter electrode assembly <NUM> includes a plurality of catheter electrodes configured to be used as briefly outlined above and as described in greater detail below. Electrode assembly <NUM> is incorporated as part of catheter <NUM> used for IRE and may also be used for sensing, mapping, and diagnostics to conduct electrophysiology studies to identify and treat, for example, arrhythmias. System <NUM> introduces a modulated electric field into tissue <NUM> in a body of a patient <NUM>. In the illustrative embodiment, tissue <NUM> comprises heart or cardiac tissue. It should be understood, however, that embodiments may be used to map, diagnose, or treat a variety of other body tissues. The blood volume and the moving heart wall surface modify the electric field in a manner that can be detected by catheter <NUM> and, more specifically, electrodes of electrode assembly <NUM>. The electrodes within the heart chamber monitor the modifications to the applied electric field, and the resulting electrical signals enable production of a dynamic representation, e.g., for display to a physician, of the location of the walls of the heart. The electrodes on electrode assembly <NUM> also detect electrical signals generated by the heart itself. The detected electrical signals can then be displayed, e.g., as an electrocardiogram. System <NUM>, in mapping heart or cardiac tissue, may also be used to locate and navigate a therapy catheter in the heart chamber. In such an embodiment, an electrode on the therapy catheter, which may be incorporated with catheter <NUM> and electrode assembly <NUM>, or independent, introduces an electric field that can be detected by electrodes on electrode assembly <NUM>. The detected electrical signals enable locating the therapy catheter within the heart.

System <NUM> enables electroporation therapy to form lesions on target tissue <NUM>. System <NUM> utilizes electric current in the form a biphasic pulsed electric field in the form of short-duration direct current (DC) pulses between closely spaced electrodes on electrode assembly <NUM>. Pulse widths of these biphasic DC pulses are generally on the order of <NUM> ns to several hundred microseconds, and the biphasic DC pulses may be repeated with an interpulse delay on the order of several microseconds to tens of milliseconds to form a pulse train, or burst. Such bursts may also be repeated with an interburst delay on the order of hundreds of microseconds to seconds. When a strong electric field is applied to tissue in vivo, the cells in the tissue are subjected to a trans-membrane potential that opens the pores on the cell wall, hence the term electroporation. While the energization strategies for ablation are described as involving DC waveforms, embodiments may use variations or combinations of AC or DC pulses. For example, exponentially-decaying pulses, exponentially-increasing pulses, and combinations thereof may be used. Moreover, while certain embodiments of system <NUM> are described herein with respect to IRE therapy, it should be understood that system <NUM> may be used, additionally or alternatively, for other forms of electric field-based ablation therapy.

System <NUM> further includes a ground pad <NUM> that provides a ground path, for example, for IRE signals transmitted by a signal generator <NUM> through electrode assembly <NUM> and into the body <NUM> of the patient. <FIG> further shows return electrodes <NUM> and <NUM> representing body connection for the various sub-systems included in the system <NUM>, such as an electrophysiology (EP) monitor such as an electrocardiogram (ECG) monitor <NUM>, or a visualization, navigation, and/or mapping system <NUM> for visualization, mapping and navigation of internal body structures.

In the illustrated embodiment, ground pad <NUM> is a cutaneous patch electrode. Likewise, return electrodes <NUM> and <NUM> may also be cutaneous patch electrodes. Ground pad <NUM> and return electrodes <NUM> and <NUM> may include one or more contact configured to attach to the skin. For example, in certain embodiments, the systems and methods described herein may operate with dual contact ground pads, or ground pads having two or more ground contacts. In certain embodiments, ground pad <NUM> and return electrodes <NUM> and <NUM> may be any other type of electrode suitable for use as a return electrode, or ground path, including, for example, one or more catheter electrodes. Return electrodes that are catheter electrodes may be part of electrode assembly <NUM> or part of a separate catheter (not shown). In some embodiments, for example, system <NUM> includes a bipolar catheter electrode assembly that includes a plurality of electrode pairs, where each electrode pair includes two electrodes with one electrode functioning as the return electrode.

System <NUM> may further include a computer system <NUM> (including an electronic control unit <NUM> and data storage-memory <NUM>) that, in certain embodiments, may be integrated with visualization, navigation, and/or mapping system <NUM>. Computer system <NUM> may further include conventional interface components, such as various user input/output mechanisms 34a and a display 34b, among other components.

System <NUM> may include a suitable detector and tissue sensing circuit integrated with signal generator <NUM> or computer system <NUM> that identify which electrodes of electrode assembly <NUM> have characteristics (e.g., electrical characteristics such as impedance, phase angle, reactance, etc.) indicative of contact with tissue <NUM>. Signal generator <NUM>, or computer system <NUM> may then select which electrodes or electrode pairs of catheter assembly <NUM> to energize based on the electrodes identified as being in contact with tissue <NUM>. Suitable components and methods for identifying electrodes in contact with tissue are described, for example, in <CIT>.

In the embodiment shown in <FIG>, catheter <NUM> includes a cable connector <NUM>, or interface, a handle <NUM>, and a shaft <NUM> having a proximal end <NUM> and a distal end <NUM>. Catheter <NUM> may also include other conventional components not illustrated herein such as a temperature sensor, additional electrodes, and corresponding conductors or leads. The connector <NUM> provides mechanical and electrical connection(s) for cable <NUM> extending from signal generator <NUM>. The connector <NUM> may include conventional components known in the art and, as shown, is disposed at the proximal end of catheter <NUM>.

Handle <NUM> provides a location for the clinician to hold catheter <NUM> and may further provide means for steering or guiding shaft <NUM> within body <NUM>. For example, handle <NUM> may include means to change the length of a guidewire extending through catheter <NUM> to distal end <NUM> of shaft <NUM> or means to steer shaft <NUM>. Moreover, in some embodiments, handle <NUM> may be configured to vary the shape, size, or orientation of a portion of the catheter. Handle <NUM> is also conventional in the art and it will be understood that the construction of handle <NUM> may vary. In an alternate exemplary embodiment, catheter <NUM> may be robotically driven or controlled. Accordingly, rather than a clinician manipulating a handle to advance/retract and/or steer or guide catheter <NUM> (and shaft <NUM> thereof in particular), a robot is used to manipulate catheter <NUM>. Shaft <NUM> is an elongated, tubular, flexible member configured for movement within body <NUM>. Shaft <NUM> is configured to support electrode assembly <NUM> as well as contain associated conductors, and possibly additional electronics used for signal processing or conditioning. Shaft <NUM> may also permit transport, delivery and/or removal of fluids (including irrigation fluids and bodily fluids), medicines, and/or surgical tools or instruments. Shaft <NUM> may be made from conventional materials such as polyurethane and defines one or more lumens configured to house and/or transport electrical conductors, fluids or surgical tools. Shaft <NUM> may be introduced into a blood vessel or other structure within body <NUM> through a conventional introducer. Shaft <NUM> may then be advanced, retracted and/or steered or guided through body <NUM> to a desired location such as the site of tissue <NUM>, including through the use of guidewires or other means known in the art.

In some embodiments, catheter <NUM> is a hoop catheter (shown, for example, in <FIG>), sometimes referred to as a spiral or loop catheter, having catheter electrodes distributed about one or more hoops at the distal end of shaft <NUM>. The diameter of the hoop(s) (sometimes referred to herein as "loops") may be variable. In some embodiments, the hoop catheter diameter is variable by about ten millimeters (mm) between a minimum diameter and a maximum diameter. The minimum diameter in some embodiments may be selected between about thirteen mm and about twenty mm when the catheter <NUM> is manufactured. With a ten mm range of variability, such catheters would have a maximum diameter between twenty-three mm and thirty mm. In other embodiments, the hoop diameter is variable between about fifteen mm and about twenty-eight mm, between about thirteen mm and about twenty-three mm, or between about seventeen mm and about twenty-seven mm. Alternatively, the catheter may be a fixed diameter hoop catheter or may be variable between different diameters. In some embodiments, catheter <NUM> has fourteen catheter electrodes (e.g., grouped as seven pairs of catheter electrodes). In other embodiments, catheter <NUM> includes ten catheter electrodes, twenty catheter electrodes, or any other suitable number of electrodes for performing, for example, sensing, mapping, diagnostics, or ablation. In some embodiments, the catheter electrodes are ring electrodes. Alternatively, the catheter electrodes may be any other suitable type of electrodes, such as single sided electrodes or electrodes printed on a flex material. In various embodiments, the catheter electrodes have lengths of <NUM>, <NUM>, <NUM>, and/or any other suitable length for sensing, mapping, diagnostics, or ablation.

<FIG> illustrate an exemplary electrode assembly <NUM> suitable for use in system <NUM>, illustrated in the form of an electrode hoop or loop assembly <NUM>. <FIG> is a side view of electrode loop assembly <NUM> with a variable diameter loop <NUM> coupled at the distal end <NUM> of a catheter shaft <NUM>. <FIG> is an end view of variable diameter loop <NUM> of electrode loop assembly <NUM>. As shown in <FIG>, electrode loop assembly <NUM> extends from a proximal end <NUM> to a distal end <NUM>, and includes an outer sleeve <NUM> formed in the shape of a loop, and a plurality of catheter electrodes <NUM> mounted on outer sleeve <NUM>. Proximal end <NUM> of electrode loop assembly <NUM> is coupled to catheter shaft <NUM> via a suitable coupler <NUM>. Electrodes <NUM> may be used for a variety of diagnostic and therapeutic purposes including, for example and without limitation, cardiac sensing, mapping, diagnostics, or ablation (e.g., IRE). For example, electrode loop assembly <NUM> may be configured as a monopolar electrode assembly for use in monopolar-based electroporation therapy. In such embodiments, ground pad <NUM> may function as the return electrode.

In other embodiments, electrode loop assembly <NUM> may be configured as a bipolar electrode assembly. More specifically, electrodes <NUM> may be configured as electrode pairs (e.g., cathode-anode electrode pairs) and electrically coupled to signal generator <NUM> (e.g., via suitable electrical wire or other suitable electrical conductors extending through catheter shaft <NUM>) such that adjacent electrodes <NUM> are energized with opposite polarities to generate a potential and corresponding electric field between adjacent electrodes <NUM>. In other embodiments, any combination of electrodes <NUM> may be configured as electrode pairs (e.g., cathode-anode electrode pairs), including, for example and without limitation, adjacent electrodes, non-adjacent electrodes, and any other combination of electrodes that enables system <NUM> to function as described herein. As described above, for example, signal generator <NUM> and/or computer system <NUM> may selectively energize certain electrodes <NUM> of electrode loop assembly <NUM> to form electrode pairs based on contact between electrodes <NUM> and tissue <NUM>.

In the illustrated embodiment, variable diameter loop <NUM> includes fourteen catheter electrodes <NUM> evenly spaced around the circumference of variable diameter loop <NUM>. In other embodiments, variable diameter loop <NUM> may include any suitable number of catheter electrodes <NUM> made of any suitable material. Each catheter electrode <NUM> is separated from each other catheter electrode by an insulated gap <NUM>. In the example embodiment, each catheter electrode <NUM> has a same length <NUM> (shown in <FIG>) and each insulated gap <NUM> has a same length <NUM> as each other gap <NUM>. Length <NUM> and length <NUM> are both about <NUM> in the example embodiment. In other embodiments, length <NUM> and length <NUM> may be different from each other. Moreover, in some embodiments, catheter electrodes <NUM> may not all have the same length <NUM> and/or insulated gaps <NUM> may not all have the same length <NUM>. In some embodiments, catheter electrodes <NUM> are not spaced evenly around the circumference of variable diameter loop <NUM>.

It should be understood that electrode assembly <NUM> is not limited to the specific constructions shown and described herein, and may include any other suitable electrode assembly and have any other suitable construction that enables system <NUM> to function as described herein. By way of example, electrode assembly <NUM> may have the same or similar construction as electrode assemblies described in <CIT>, <CIT>, <CIT>, <CIT>, <CIT>, and International Patent Application Publication Nos. <CIT>, <CIT>, and <CIT>.

Referring again to <FIG>, visualization, navigation, and/or mapping system <NUM> may include commercially available systems, including electric field-based or magnetic-based systems such as the EnSite™ Velocity™ or EnSite Precision™ cardiac mapping and visualization systems of Abbott Laboratories. Visualization, navigation, and/or mapping system <NUM> may additionally include an impedance-based localization feature such as, for example, the NAVX™ system also commercially available with the EnSite™ Velocity™ or EnSite Precision™ systems from Abbott Laboratories, and as generally shown with reference to <CIT> titled "Method and Apparatus for Catheter Navigation and Location and Mapping in the Heart". Visualization, navigation, and/or mapping system <NUM> may include hybrid mapping and navigation systems such as, for example, the EnSite™ X cardiac mapping system from Abbott Laboratories, which includes integrated impedance and magnetic tracking. In other exemplary embodiments, the visualization, navigation, and/or mapping system <NUM> can comprise other types of systems, such as, for example and without limitation: a magnetic field-based system such as the CARTO System (now in a hybrid form with impedance- and magnetically-driven electrodes) available from Biosense Webster, or the gMPS system from MediGuide Ltd. In accordance with a combination electric field-based and magnetic field-based system, the catheter can include both electrodes as impedance-based electrodes and one or more magnetic field sensing coils. Commonly available fluoroscopic, computed tomography (CT), and magnetic resonance imaging (MRI)-based systems can also be used.

System <NUM> may include a variable impedance <NUM>. The variable impedance may be used to change one or more characteristics, such as amplitude, duration, pulse shape, and the like, of an output of signal generator <NUM> or visualization, navigation, and/or mapping system <NUM>. Although described as a separate component, variable impedance <NUM> may be integrated with catheter <NUM> or signal generator <NUM> and visualization, navigation, and/or mapping system <NUM>. Variable impedance <NUM> includes one or more impedance elements, such as resistors, capacitors, or inductors (not shown) connected in series, parallel, or combinations of series and/or parallel. In the illustrated embodiment, the variable impedance is connected in series with catheter <NUM>. Alternatively, the impedance elements of variable impedance <NUM> may be connected in parallel with catheter <NUM> or in a combination of series and parallel with catheter <NUM>. Moreover, in other embodiments, the impedance elements of the variable impedance are connected in series and/or parallel with ground pad <NUM>. Some embodiments include more than one variable impedance, each of which may include one or more impedance elements. In such embodiments, each variable impedance may be connected to a different catheter electrode or group of catheter electrodes to allow the impedance through each catheter electrode or group of catheter electrodes to be independently varied. In other embodiments, the impedance of system <NUM> may not need to be varied and the variable impedance may be omitted.

The relatively high voltages and short pulse durations of the biphasic waveforms generated by signal generator <NUM> may result in significant electromagnetic interference (EMI), or noise, being introduced into signal generator <NUM>, its components, catheter <NUM>, or tissue <NUM> of the patient, and potentially adversely affecting operation of system <NUM>. Accordingly, embodiments of the present disclosure include certain features to reduce sources of noise and to mitigate the effects of the high frequency high voltage switching within signal generator <NUM> for the purpose of producing the high-amplitude short duration pulses.

For example, <FIG> is a schematic diagram of exemplary signal generator <NUM>. Signal generator <NUM> includes a microcontroller <NUM> or other programmable processing device that controls generation of one or more biphasic pulse in response to a trigger signal <NUM>. Trigger signal <NUM> may be generated internal to signal generator <NUM> or externally by another system. In certain embodiments, trigger signal is a discrete logic-level DC signal supplied to microcontroller <NUM> as a result of, for example, an at least momentary closure of a switching circuit by a switch or button actuated by a user. In response to trigger signal <NUM>, microcontroller <NUM> initiates a single pulse, a burst of pulses, or a plurality of bursts, for example.

Microcontroller <NUM>, in generating a single biphasic pulse, generates a first pulse control signal <NUM> and a second pulse control signal <NUM> for the purpose of controlling a plurality of semiconductor switches. First pulse control signal <NUM> and second pulse control signal <NUM> are logic level DC signals generated by microcontroller <NUM>. The semiconductor switches may be any suitable power semiconductor capable of a high-voltage standoff, high current conduction, and operable at a high frequency, such as an insulated-gate bipolar transistor (IGBT). In the embodiment of <FIG>, the semiconductor switches are implemented as IGBTs <NUM>, <NUM>, <NUM>, <NUM> connected in a bridge configuration to regulate application of positive high voltage DC (+HVDC) supply <NUM> and negative high voltage DC (-HVDC) supply <NUM> to one or more conductors such as first or second conductors <NUM> or <NUM> that deliver the biphasic pulses using, for example, electrode assembly <NUM> and a return electrode, such as ground pad <NUM>. Microcontroller <NUM>, in generating a burst of biphasic pulses, controls IGBTs <NUM>, <NUM>, <NUM>, <NUM> to commutate at a frequency (e.g., in the range of about <NUM> hertz to about <NUM>) to produce a series of biphasic pulses. The biphasic pulses, in certain embodiments, may be delivered over one conductor to one or more monopolar electrodes. For example, the biphasic pulses are delivered over first conductor <NUM> while second conductor <NUM> is connected to a return electrode such as, or in addition to, ground pad <NUM> and serves as a return path for the current delivered by first conductor <NUM>. Alternatively, biphasic pulses may be delivered over first and second conductors <NUM> and <NUM> to one or more pairs of bipolar electrodes.

Microcontroller <NUM> is communicatively coupled and electrically isolated from IGBTs <NUM>, <NUM>, <NUM>, <NUM> by an opto-isolator <NUM>. Opto-isolator <NUM>, also referred to as an opto-coupler, prevents, for example, noise generated by high frequency switching of IGBTs <NUM>, <NUM>, <NUM>, <NUM> from reaching microcontroller <NUM>. Opto-isolator <NUM> relays first pulse control signal <NUM> and second pulse control signal <NUM> from microcontroller <NUM> to a logic circuit <NUM> that translates the two logic level DC signals into four gate driving signals <NUM>, <NUM>, <NUM>, <NUM>. Logic circuit <NUM> derives each of gate driving signals <NUM>, <NUM>, <NUM>, <NUM> from first pulse control signal <NUM> and second pulse control signal <NUM>, and ensures that gate driving signals <NUM>, <NUM>, <NUM>, <NUM> do not connect, or short, the opposite-polarity HVDC supplies (+HVDC supply <NUM> and -HVDC supply <NUM>), for example, momentarily during a transition from a +HVDC phase to a -HVDC phase of the biphasic pulse. For example, in certain embodiments, logic circuit <NUM> derives gate driving signals <NUM> and <NUM> as inversions of gate driving signals <NUM> and <NUM>.

Generally, in at least some embodiments, microcontroller <NUM> does not source sufficient current to drive the gates of IGBTs <NUM>, <NUM>, <NUM>, <NUM>. Gate current for power semiconductor switches typically rises with high voltage and high current capacity. Accordingly, signal generator <NUM> includes gate drivers <NUM>, <NUM>, <NUM>, <NUM> for operating IGBTs <NUM>, <NUM>, <NUM>, <NUM>, respectively. Gate drivers <NUM>, <NUM>, <NUM>, <NUM> further isolate microcontroller <NUM> and other aspects of the digital circuit from the high-voltage high-current portions of signal generator <NUM>. Gate drivers <NUM>, <NUM>, <NUM>, <NUM> control commutation of IGBTs <NUM>, <NUM>, <NUM>, <NUM> according to gate driving signals <NUM>, <NUM>, <NUM>, <NUM>. Gate drivers <NUM>, <NUM>, <NUM>, <NUM> drive gates of IGBTs <NUM>, <NUM>, <NUM>, <NUM> through gate driving impedances <NUM>, <NUM>, <NUM>, <NUM>. Gate driving impedances <NUM>, <NUM>, <NUM>, <NUM> are selected both to produce a sufficient current rise through IGBTs <NUM>, <NUM>, <NUM>, <NUM> and to avoid oscillatory responses by IGBTs <NUM>, <NUM>, <NUM>, <NUM>. In certain embodiments, gate driving impedances <NUM>, <NUM>, <NUM>, <NUM> are resistors in the range of <NUM>-<NUM> ohms. In at least some embodiments, gate driving impedances <NUM>, <NUM>, <NUM>, <NUM> are <NUM> ohm resistors.

Signal generator <NUM> may be implemented, in certain embodiments, on one or more printed circuit boards (PCBs) on which microcontroller <NUM>, opto-isolator <NUM>, logic circuit <NUM>, gate drivers <NUM>, <NUM>, <NUM>, <NUM>, and IGBTs <NUM>, <NUM>, <NUM>, <NUM> may be disposed. At least some traces on the PCB conduct high-voltage DC that is switched at a high frequency. For example, traces connecting +HVDC supply <NUM> to IGBTs <NUM>, <NUM>, <NUM>, <NUM>, and traces supplying current from IGBTs <NUM>, <NUM>, <NUM>, <NUM> to terminals <NUM> and <NUM> for first and second conductors <NUM> and <NUM> each carry the pulses generated by highfrequency switching of IGBTs <NUM>, <NUM>, <NUM>, <NUM>, and thus are susceptible to introducing noise to signal generator <NUM>. In certain embodiments, such traces should be sufficiently wide and as short as possible to reduce the introduction of noise resulting from the periodic high di/dt conditions on those traces. In certain embodiments, these traces should be at least <NUM> (<NUM> inches) wide. Likewise, at least some traces conduct significant amounts of highfrequency switched current for the purpose of driving gates of IGBTs <NUM>, <NUM>, <NUM>, <NUM>. For example, traces extending between gate drivers <NUM>, <NUM>, <NUM>, <NUM> and their respective IGBTs <NUM>, <NUM>, <NUM>, <NUM> are each also susceptible to introducing noise resulting from high di/dt conditions on those traces. Accordingly, those traces should also be sufficiently wide and as short as possible to reduce the introduction of noise. In certain embodiments, for example, the traces between gate drivers <NUM>, <NUM>, <NUM>, <NUM> and their respective IGBTs <NUM>, <NUM>, <NUM>, <NUM> should be at least <NUM> (<NUM> inches) wide.

In certain embodiments, signal generator <NUM> includes additional components between each of gate drivers <NUM>, <NUM>, <NUM>, <NUM> and IGBTs <NUM>, <NUM>, <NUM>, <NUM>. For example, in certain embodiments, one or more capacitors are coupled in parallel with the gate of the semiconductor switch to function as a current supply for driving that gate. In certain embodiments, one or more diodes are coupled in parallel with the gate of the semiconductor switch to function, for example, as transient voltage suppression or as current blocking devices. In certain embodiments, one or more EMI suppression devices are coupled to the gate driving branch to mitigate noise originating from, for example, high frequency switching of IGBTs <NUM>, <NUM>, <NUM>, <NUM>.

In certain embodiments, signal generator <NUM> includes one or more impedance matching circuits (not shown) connected in series with the high-voltage DC output, i.e., in series with first and second conductors <NUM> and <NUM>. The impedance matching circuits mitigate impedance discontinuities that may occur or that may be inherent at various portions of the high-voltage DC transmission line formed by the traces or other conductors between +HVDC supply <NUM>, -HVDC supply <NUM>, and electrode assembly <NUM> of catheter <NUM>. For example, an impedance discontinuity may exist where catheter <NUM> connects to signal generator <NUM>, which may result in signal reflections within signal generator <NUM> that ultimately manifest as noise and losses in system <NUM>.

Signal generator <NUM> is configured to energize the electrode element(s) in accordance with an electroporation energization strategy, which may be predetermined or may be user-selectable. For electroporation-induced primary necrosis therapy, signal generator <NUM> may be configured to produce an electric current that is delivered via electrode assembly <NUM> as a pulsed electric field in the form of a biphasic IRE waveform transmitted from one or more monopolar electrodes and utilizing, for example, ground pad <NUM> or another patch electrode as a return path. In alternative embodiments, the biphasic IRE waveform is transmitted between closely spaced electrodes (e.g., electrode pairs of electrode assembly <NUM>). The biphasic IRE waveform is capable of delivering an electric field strength of about <NUM> to <NUM> kV/cm (e.g., at the tissue site). Biphasic pulses generated by signal generator <NUM> are specifically shaped (e.g., by controlling the phases, amplitude, and pulse duration) to prevent activation of skeletal muscles and nerves (e.g., Phrenic nerve), as well as the myocardium. By avoiding activation of the myocardium, the biphasic pulses generated by signal generator <NUM> do not have to be timed or gated based on the cardiac cycle or rhythm (e.g., along the R-wave). More specifically, biphasic pulses generated by signal generator <NUM> are shaped to have a pulse width and voltage amplitude below the strength-duration curve associated with nerve or muscle activation. The biphasic pulses generated by signal generator <NUM> are relatively high strength (i.e., voltage) and frequency (i.e., short pulse duration). Cardiac tissue, for example, needs electric field strength of <NUM> V/cm to damage the cellular membrane. In generating a biphasic IRE pulse, in some embodiments, signal generator <NUM> provides +HVDC supply <NUM> at a potential of about zero VDC to <NUM> VDC and -HVDC supply <NUM> may be at a potential of about zero VDC to -<NUM> VDC. Alternatively, signal generator <NUM> may provide +HVDC supply <NUM> and -HVDC supply <NUM> at potentials having magnitudes greater than <NUM> VDC, for example, up to <NUM> VDC, <NUM> VDC, or greater. Signal generator <NUM>, in at least some embodiments, includes at least one high-voltage capacitor <NUM> to function as the high voltage current source for electrode assembly <NUM>.

<FIG> is a plot of an example biphasic IRE pulse <NUM> produced by signal generator <NUM>. Biphasic IRE pulse <NUM> is illustrated as a voltage (shown on a vertical axis) versus time (shown on a horizontal axis). Biphasic IRE pulse <NUM> includes a first phase <NUM> and a second phase <NUM>, with an interphase delay <NUM> between a trailing edge <NUM> of the first phase <NUM> and a leading edge <NUM> of the second phase <NUM>. The interphase delay <NUM> should be brief enough to effectively reverse current conduction in the tissue of the patient to avoid stimulating or damaging non-target tissue. For example, the interphase delay <NUM> is in the range of <NUM> ns to <NUM>. In certain embodiments, the interphase delay <NUM> is in the narrower range of <NUM> to <NUM>.

First phase <NUM> and second phase <NUM> have different voltage amplitudes or different pulse widths, or both. For example, first phase <NUM> has an initial voltage amplitude <NUM> that decays over the duration of first phase <NUM> as capacitor <NUM> discharges through the patient load. First phase <NUM> has an ending voltage amplitude <NUM> before falling to zero at the beginning of interphase delay <NUM>. The peak voltage amplitude, e.g., the initial voltage amplitude <NUM>, should be large enough to create a lesion-depth large enough to be durable in the target tissue, e.g., in an atrium or ventricle. Initial voltage amplitude <NUM> is in the range of <NUM> VDC to <NUM> VDC. Likewise, an initial voltage amplitude <NUM> of second phase <NUM> is in the range of -<NUM> VDC to -<NUM> VDC, and decays over the duration of second phase <NUM> to an ending voltage amplitude <NUM>. In certain embodiments, initial voltage amplitude <NUM> and initial voltage amplitude <NUM> are different, and a pulse width <NUM> of first phase is about equal to a pulse width <NUM> of second phase <NUM>. Alternatively, pulse width <NUM> and pulse width <NUM> may be different, while initial voltage amplitude <NUM> and initial voltage amplitude <NUM> are about equal, or different.

Catheter <NUM> supplies the biphasic IRE pulse <NUM>, for example, over first conductor <NUM> coupled to one or more monopolar electrodes of electrode assembly <NUM>. In such an embodiment, second conductor <NUM> may be coupled to a patch electrode that functions as a return path for the current delivered in biphasic IRE pulse <NUM>. Alternatively, first conductor <NUM> may be referenced to ground using ground pad <NUM>. The polarity of the high voltage pulse can be alternated by alternating application of +HVDC supply <NUM> and - HVDC supply <NUM> to first conductor <NUM>. A zero VDC is achieved, e.g., during interphase delay <NUM>, by disconnecting both +HVDC supply <NUM> and -HVDC supply <NUM> from first conductor <NUM>, and allowing its potential to float relative to second conductor <NUM> (or ground pad <NUM>). Given the conductive properties of a blood/saline solution in the body <NUM> of the patient, there should be no potential between electrodes of electrode assembly <NUM> and second conductor <NUM> (or ground pad <NUM>), and thus no potential between first conductor <NUM> and second conductor <NUM> (or ground pad <NUM>).

In an example embodiment, first phase <NUM> of biphasic IRE pulse <NUM> begins with initial voltage amplitude <NUM> between about <NUM> VDC and <NUM> VDC, and second phase <NUM> begins with initial voltage amplitude <NUM> roughly equal in magnitude or less than ending voltage amplitude <NUM>, or about <NUM> VDC to <NUM> VDC. In certain embodiments, +HVDC supply <NUM> provides a potential between <NUM> VDC and <NUM> VDC, and -HVDC supply <NUM> provides a potential between <NUM> VDC and <NUM> VDC, and a monopolar electrode coupled to first conductor <NUM> utilizes ground pad <NUM> as a return path for current delivered by biphasic IRE pulse <NUM>. For example, where +HVDC supply <NUM> is at a potential of about <NUM> VDC and -HVDC supply <NUM> is at a potential of about - <NUM> VDC, first phase <NUM> of biphasic IRE pulse <NUM> is produced by closing IGBT <NUM> and opening IGBT <NUM> to apply +HVDC supply <NUM> to first conductor <NUM> producing a +<NUM> VDC signal for a first duration, e.g., pulse width <NUM>. The voltage amplitude applied to first conductor <NUM> decays over pulse width <NUM> from initial voltage amplitude <NUM> to ending voltage amplitude <NUM>, or about <NUM> VDC. After the first duration, IGBT <NUM> and IGBT <NUM> are opened to allow the potential of first conductor <NUM> to float, thereby producing zero VDC for the duration of interphase delay <NUM>. After interphase delay <NUM>, IGBT <NUM> is closed to apply -HVDC supply <NUM> to first conductor <NUM>. At that time, the initial voltage amplitude <NUM> for second phase <NUM> is generally equal in magnitude or less than ending voltage amplitude <NUM>, e.g., about <NUM> VDC. The initial voltage amplitude <NUM> further decays over the duration of second phase <NUM>, i.e., pulse width <NUM>, to ending voltage amplitude <NUM>. IGBT <NUM> is opened to return the potential of first conductor <NUM> to <NUM> VDC.

In one alternative embodiment, second conductor <NUM> is utilized as a return path for current delivered in biphasic IRE pulse <NUM> via a monopolar electrode coupled to first conductor <NUM>. In such an embodiment, the potential delivered in the biphasic IRE waveform <NUM> is a differential between first conductor <NUM>, regulated by IGBT <NUM> and <NUM>, and second conductor <NUM>, regulated by IGBT <NUM> and <NUM>.

In certain embodiments, high voltage capacitor <NUM> may be initially charged by +HVDC supply <NUM>, e.g., to about <NUM> VDC, and functions as a current supply for both first phase <NUM> and second phase <NUM>. High voltage capacitor <NUM> may be partially discharged over the duration of first phase <NUM>, e.g., pulse width <NUM>, to ending voltage amplitude <NUM>. High voltage capacitor <NUM> may be further discharged during second phase <NUM>, but with a reversed polarity achieved by "re-referencing," or reconfiguring a plurality of switches (not shown) through which high voltage capacitor <NUM> is coupled to first conductor <NUM> and ground. Accordingly, initial voltage amplitude <NUM> for second phase <NUM> is roughly equal in magnitude to ending voltage amplitude <NUM> of first phase <NUM>, which is the remaining charge on high voltage capacitor <NUM> after first phase <NUM>. According to the invention, the magnitude of initial voltage amplitude <NUM> is reduced further by "bleeding off," during interphase delay <NUM>, some energy stored in high voltage capacitor <NUM>, resulting in a reduced charge on high voltage capacitor <NUM> at the beginning of second phase <NUM>. For example, if ending voltage amplitude <NUM> is about <NUM> VDC, high voltage capacitor <NUM> may be discharged to about <NUM> VDC during interphase delay <NUM>, resulting in initial voltage amplitude <NUM> of about <NUM> VDC.

In an alternative embodiment, catheter <NUM> supplies the biphasic IRE pulse <NUM>, for example, over first and second conductors <NUM> and <NUM> to one or more pairs of bipolar electrodes of electrode assembly <NUM>. Accordingly, the polarity of the high voltage signal can be switched by alternatingly applying, in time, +HVDC supply <NUM> to first conductor <NUM> and second conductor <NUM>, and -HVDC supply <NUM> to second conductor <NUM> and first conductor <NUM>. Likewise, <NUM> VDC is achieved by disconnecting both first and second conductors <NUM> and <NUM> and allowing their potential to float. Consequently, due to the conductive properties of a blood/saline solution in the body <NUM> of the patient, there should be no potential between electrodes of electrode assembly <NUM>, and thus no potential between first and second conductors <NUM> and <NUM>.

<FIG> is a plot of an example burst <NUM> of biphasic IRE pulses <NUM> shown in <FIG>. Burst <NUM> includes four instances of biphasic IRE pulse <NUM> separated by an interpulse delay <NUM>. Although <FIG> illustrates burst <NUM> with four biphasic IRE pulses <NUM>, burst <NUM> may include any number of biphasic IRE pulses <NUM>. Interpulse delay <NUM> is in the range of <NUM> to <NUM>. In certain embodiments, interpulse delay <NUM> is in the range of <NUM> to <NUM>. <FIG> is a plot of an example biphasic IRE waveform <NUM> having multiple bursts <NUM> of biphasic IRE pulses <NUM>. Each burst <NUM> is separated by an interburst delay <NUM> in a range of <NUM> to <NUM>. Although <FIG> illustrates biphasic IRE waveform <NUM> having two bursts <NUM>, biphasic IRE waveform <NUM> may have any number of bursts <NUM>, each with any number of biphasic IRE pulses <NUM>.

<FIG> is a plot of an example inverted biphasic IRE pulse <NUM> having a first phase <NUM> that is negative in polarity, and a second phase <NUM> that is positive in polarity. First phase <NUM> has an initial voltage amplitude <NUM> decaying to an ending voltage amplitude <NUM> over a pulse width <NUM>. Likewise, second phase <NUM> has an initial voltage amplitude <NUM> decaying to an ending voltage amplitude <NUM> over a pulse width <NUM>. First phase <NUM> is separated from second phase <NUM> by an interphase delay <NUM>.

<FIG> is a plot of another example of a biphasic IRE pulse <NUM> having a first phase <NUM> and a second phase <NUM>. Similar to biphasic IRE pulse <NUM>, first phase <NUM> and second phase <NUM> are separated by interphase delay <NUM>. First phase <NUM> has a pulse width <NUM> and a peak voltage amplitude, or initial voltage amplitude <NUM>, and ending voltage amplitude <NUM>. Second phase <NUM> has a pulse width <NUM> and a peak voltage amplitude, or initial voltage amplitude <NUM>, and ending voltage amplitude <NUM>. Notably, an area <NUM> under first phase <NUM> is about equal to an area <NUM> under second phase <NUM>. Areas <NUM> and <NUM> relate to an aggregate applied charge, or energy delivered, to the tissue of the patient over the duration of first phase <NUM> and second phase <NUM>. For example, as illustrated in <FIG>, pulse width <NUM> is shorter in duration than pulse width <NUM>, and that difference is offset by first phase <NUM> having higher voltage amplitudes <NUM> and <NUM> than voltage amplitudes <NUM> and <NUM> of second phase <NUM>. In alternative embodiments, area <NUM> under second phase <NUM> is a percentage of area <NUM> under first phase <NUM>. For example, in one embodiment, area <NUM> is <NUM>% of area <NUM> under first phase <NUM>. In another embodiment, area <NUM> is <NUM>% of area <NUM> under first phase <NUM>.

<FIG> is a flow diagram of an example method <NUM> of delivering electroporation energy through an ablation catheter, such as catheter <NUM> shown in <FIG>. Catheter <NUM> and at least one electrode are positioned <NUM> at target tissue <NUM>. The electrode is coupled <NUM> to signal generator <NUM>. Signal generator <NUM> supplies <NUM> a biphasic pulse, such as biphasic pulse <NUM> shown in <FIG>. Supplying <NUM> the biphasic pulse <NUM> includes transmitting <NUM> first phase <NUM> having a first polarity (e.g., positive), a first initial voltage amplitude <NUM>, and a first pulse width <NUM>. Signal generator <NUM> then supplies <NUM> zero VDC during interphase delay <NUM> following a trailing edge <NUM> of first phase <NUM>. Signal generator <NUM> then transmits <NUM> second phase <NUM> having a second polarity opposite the first polarity (e.g., negative), a second initial voltage amplitude <NUM>, and a second pulse width <NUM>. At least one of the first initial voltage amplitude <NUM> or the first pulse width <NUM> is different from the second initial voltage amplitude <NUM> or the second pulse width <NUM>, respectively. That is, either first initial voltage amplitude <NUM> and second initial voltage amplitude <NUM> are of different magnitude, or first pulse width <NUM> and second pulse width <NUM> are different, or both.

Although certain steps of the example method are numbered, such numbering does not indicate that the steps must be performed in the order listed. Thus, particular steps need not be performed in the exact order they are presented, unless the description thereof specifically require such order. The steps may be performed in the order listed, or in another suitable order.

Although the embodiments and examples disclosed herein have been described with reference to particular embodiments, it is to be understood that these embodiments and examples are merely illustrative of the principles and applications of the present disclosure. It is therefore to be understood that numerous modifications can be made to the illustrative embodiments and examples and that other arrangements can be devised without departing from the scope of the present disclosure as defined by the claims. Thus, it is intended that the present application cover the modifications and variations of these embodiments and their equivalents.

Some embodiments involve the use of one or more electronic processing or computing devices. As used herein, the term "microcontroller" and related terms, e.g., "processor," "computer," "processing device," "computing device," and "controller," are not limited to just those integrated circuits referred to in the art as a computer, but broadly refer to a processor, a processing device, a controller, a general purpose central processing unit (CPU), a graphics processing unit (GPU), a microcontroller, a microcomputer, a programmable logic controller (PLC), a reduced instruction set computer (RISC) processor, a field programmable gate array (FPGA), a digital signal processing (DSP) device, an application specific integrated circuit (ASIC), and other programmable circuits or processing devices capable of executing the functions described herein, and these terms may be used interchangeably herein. These processing devices are generally "configured" to execute functions by programming or being programmed, or by the loading or other provisioning of instructions for execution. The above examples are not intended to limit in any way the definition or meaning of the terms processor, processing device, and related terms.

In the embodiments described herein, memory may include, but is not limited to, a non-transitory computer-readable medium, such as flash memory, a random access memory (RAM), read-only memory (ROM), erasable programmable read-only memory (EPROM), electrically erasable programmable read-only memory (EEPROM), and non-volatile RAM (NVRAM). As used herein, the term "non-transitory computer-readable media" is intended to be representative of any tangible, computer-readable media, including, without limitation, non-transitory computer storage devices, including, without limitation, volatile and non-volatile media, and removable and non-removable media such as a firmware, physical and virtual storage, CD-ROMs, DVDs, and any other digital source such as a network or the Internet, as well as yet to be developed digital means, with the sole exception being a transitory, propagating signal. Alternatively, a floppy disk, a compact disc - read only memory (CD-ROM), a magneto-optical disk (MOD), a digital versatile disc (DVD), or any other computer-based device implemented in any method or technology for short-term and long-term storage of information, such as, computer-readable instructions, data structures, program modules and sub-modules, or other data may also be used. Therefore, the methods described herein may be encoded as executable instructions, e.g., "software" and "firmware," embodied in a non-transitory computer-readable medium. Further, as used herein, the terms "software" and "firmware" are interchangeable, and include any computer program stored in memory for execution by personal computers, workstations, clients and servers. Such instructions, when executed by a processor, cause the processor to perform at least a portion of the methods described herein.

Claim 1:
An electroporation system comprising:
a catheter shaft (<NUM>);
at least one electrode (<NUM>) coupled to the catheter shaft at a distal end (<NUM>) thereof; and
a signal generator (<NUM>) coupled in communication with the at least one electrode (<NUM>), the signal generator (<NUM>) includes at least one high-voltage capacitor (<NUM>) and is configured to supply a biphasic pulse (<NUM>) to the at least one electrode (<NUM>), the biphasic pulse (<NUM>) comprising:
a first phase (<NUM>) having a first polarity, a first initial voltage amplitude (<NUM>), an ending voltage amplitude (<NUM>) less than the first initial voltage amplitude (<NUM>), and a first pulse width (<NUM>); and
a second phase (<NUM>) having a second polarity opposite to the first polarity, a second initial voltage amplitude (<NUM>), and a second pulse width (<NUM>),
wherein a leading edge (<NUM>) of the second phase occurs after an interphase delay (<NUM>) following a trailing edge (<NUM>) of the first phase (<NUM>), characterized in that
the initial voltage amplitude (<NUM>) of the second phase (<NUM>) has a lower magnitude than the ending voltage amplitude (<NUM>) of the first phase (<NUM>)
characterized by the signal generator (<NUM>) bleeding off energy stored in the at least one high voltage capacitor (<NUM>) during the interphase delay (<NUM>).