Apparatus, System, and Method for Soft Tissue Ablation

Abstract

The systems, devices, and methods described herein relate to the generation and delivery of pulse waveforms for treatment delivery, for example, in soft tissue ablation procedures. In some embodiments, a pulse generator is configured to generate a voltage pulse train that includes a plurality of biphasic pulses, each biphasic pulse of the plurality of biphasic pulses including a positive pulse, a negative pulse, and a phase delay separating the positive pulse and the negative pulse. In some embodiments, consecutive biphasic pulses of the plurality of biphasic pulses may be separated by an inter-pulse delay such that the plurality of biphasic pulses are separated by a plurality of inter-pulse delays, the plurality of inter-pulse delays may include an increasing sequence or a decreasing sequence of inter-pulse delays.

Description

Technical Field

[0001] Cross - reference to related applications

[0001] This application claims the priority and benefit of U.S. Provisional Patent Application No. 63 / 351,197, entitled "APPARATUS, SYSTEMS AND METHODS FOR SOFT TISSUE ABLATION", filed on June 10, 2022, the disclosure of which is incorporated herein by reference in its entirety.

Background Art

[0002] Background

[0002] Soft tissue ablation is a treatment method related to various clinical applications, ranging from the delivery of cancer treatment for ablation of various tumor types, to ablation of benign tumors such as fibromas, treatment of lesion tissues that may lead to cancer, and ablation of sympathetic or parasympathetic nerves in various situations. Thermal techniques such as radiofrequency (RF) ablation, cryoablation, or ablation by ultrasound have been used in multiple applications. These often involve the risk of associated damage and significant tissue necrosis at the treatment site.

[0003]

[0003] Pulse - field ablation, also known as irreversible electroporation, has emerged as a potentially useful ablation technique, has been studied in the application to some tumors, and has recently been found to be useful in the context of cardiac ablation for the treatment of cardiac arrhythmias. This non - thermal ablation technique can be tissue - selective and can bring about a natural healing process after ablation that retains the integrity of the extracellular matrix and the overall tissue while minimizing associated damage. While devices and waveforms suitable for the context of cardiac ablation have been devised, new devices, tools, and waveforms that may be more suitable for use in the context of soft tissue ablation are needed.

[0004]

[0004] The present disclosure addresses the need for systems and waveforms for the efficient and effective delivery of pulsed field ablation therapy, particularly for soft tissue ablation. Pulsed field ablation procedures are rapid and can minimize the collateral tissue damage often seen with heat-based therapies. At the same time, healing after the procedure is relatively fast and side effects are minimal.

Summary of the Invention

Means for Solving the Problems

[0005] Overview

[0005] The present disclosure discloses a system and method for treatment delivery in soft tissue ablation applications. Specifically, the systems, devices, and methods of the present disclosure provide for the generation of high voltage pulse waveforms delivered to electrodes placed in the vicinity of tissue for rapid and efficient ablation of the tissue. The electrodes can be disposed on minimally invasive intervention devices introduced into a subject's anatomical structure by, for example, endoscopic, laparoscopic, intravascular, or percutaneous access, and in embodiments can include a reference electrode patch placed on the patient. The device can be used in a variety of clinical applications. Generally, the intervention device can have a plurality of electrodes for treatment delivery. In embodiments, the device for pulse delivery can include a pulse generator for generating a pulse waveform. In embodiments, the device for pulse delivery can also include a high voltage signal router for routing the pulse generated by the pulse generator to an appropriate set of electrodes. In embodiments, the pulse generator and the signal router can be separate components of a device intended for modular connection, and in other embodiments, the pulse generator and the signal router can be integrated into a single device in which each circuit board is present. In embodiments, the signal router can incorporate a plurality of output channels, each channel configured as two half-bridges having an upper switch and a lower switch respectively connected to the positive and negative terminals of a voltage source. In the reference state, all switches are open and there is no electrical path for current to flow. Each output channel of the signal router is intended to be connected to an electrode or set of electrodes. When it is desired to pair two channels as electrode terminals for ablation delivery, the upper switch of one channel and the lower switch of the other channel are closed to create an electrical path and enable voltage and current delivery across the pairing and the appropriate device electrodes.

[0006]

[0006] In an embodiment, the pulse waveform has specific characteristics as detailed herein. In an embodiment, the waveform includes at least one pulse train having a plurality of two-phase, substantially rectangular pulses having a positive phase and a negative phase (e.g., having generally substantially equal, opposite amplitudes) separated by an inter-phase delay. Thus, each complete two-phase pulse includes a positive phase, a negative phase, and a delay between the positive phase and the negative phase. In an embodiment, the inter-phase delay is greater than the pulse width of the positive or negative phase. In an embodiment, the inter-phase delay can be at least about three times greater than the pulse width of the positive or negative phase, and in an embodiment, the inter-phase delay can be at least about five times the pulse width of the positive or negative phase. Further, the time delay between one complete two-phase pulse of the pulse train and the next two-phase pulse (referred to as the pulse-to-pulse delay) is not constant across the entire pulse train; rather, such a sequence of delays has a variation in the delays. For example, in an embodiment, the sequence of delays follows an increasing pattern for at least one-third of the number of such delays between pulses. In an embodiment, the pulse-to-pulse delay sequentially follows a decreasing pattern for at least one-third of the number of such delays between pulses.

[0007]

[0007] In an embodiment, the sequence of increasing or decreasing pulse-to-pulse delays follows at least an arithmetical progression. For example, the magnitude of the difference between one pulse-to-pulse delay and the immediately preceding pulse-to-pulse delay is at least a non-zero constant. In an embodiment, the sequence of increasing or decreasing pulse-to-pulse delays follows at least a geometric progression. For example, the ratio of one pulse-to-pulse delay to the immediately preceding pulse-to-pulse delay is, in the case of an increasing sequence of delays, at least a constant greater than 1, or in the case of a decreasing sequence of delays, a constant less than 1. In an embodiment, the ratio of one pulse-to-pulse delay to the immediately preceding pulse-to-pulse delay in an increasing sequence of delays is at least about 1.1. In an embodiment, the ratio of one pulse-to-pulse delay to the immediately preceding pulse-to-pulse delay in a decreasing sequence of delays is less than about 0.9.

[0008]

[0008] In an embodiment, in a given pulse train, the inter-pulse delay follows an increasing pattern sequentially for at least one-third of the number of such delays between pulses and follows a decreasing pattern for at least one-third of the number of such delays between pulses. In an embodiment, the overall waveform includes a plurality of such pulse trains (each of which is also referred to as a packet of pulses), and consecutive pulse packets are separated by a packet delay. In an embodiment, the packet delay is not constant and can vary across the packets.

[0009]

[0009] In an embodiment, in each pulse of a pulse train, each phase (positive or negative) is of a trapezoidal or substantially trapezoidal shape. In this case, the pulse width is defined as the width of one phase of the pulse where the voltage has a value greater than about 70% of the amplitude of the pulse. A complete two-phase pulse includes a positive phase, a negative phase, and an inter-phase delay between the positive and negative phases. In an embodiment, the inter-phase delay is greater than the width of the positive or negative phase. In an embodiment, the inter-phase delay can be at least about three times greater than the width of the positive or negative phase, and in an embodiment, the inter-phase delay can be at least about five times the width of the positive or negative phase. Further, the time delay or inter-pulse delay between one complete two-phase pulse of the pulse train and the next two-phase pulse is not constant across the pulse train; rather, such a sequence of delays follows an increasing pattern for at least one-third of the number of such delays between pulses. In an embodiment, the inter-pulse delay sequentially follows a decreasing pattern for at least one-third of the number of such delays between pulses. In an embodiment, in a given pulse train, the inter-pulse delay follows an increasing pattern sequentially for at least one-third of the number of such delays between pulses and follows a decreasing pattern for at least one-third of the number of such delays between pulses. In an embodiment, the overall waveform includes a plurality of such pulse trains or packets, and consecutive pulse packets are separated by a packet delay. In an embodiment, the packet delay is not constant and can vary across the packets.

[0010]

[0010] In some embodiments, waveform delivery can be performed sequentially across a set of electrode pairs. In an embodiment, when the waveform includes a series of pulse packets, the pulse packets can first all be delivered to one electrode pair, followed by all the pulse packets being delivered to a second electrode pair, and so on. In other embodiments, the pulse packets as defined herein can be interleaved across the electrode pairs. In this case, the first pulse packet can be delivered to the first electrode pair, and during the packet delay time interval, the first pulse packet can be delivered to the second electrode pair, and so on. Thereafter, the second pulse packet can all be delivered to the first electrode pair during the next packet delay, followed by the second pulse packet being delivered to the second electrode pair, and so on. This process can continue until the complete waveform has been delivered to all the electrode pairs.

[0011]

[0011] In yet other embodiments, a single packet or train of pulses can interleave the pulses applied to the electrode pairs. In this case, the first pulse of the pulse train can be applied to the first electrode pair, and during the inter-pulse delay before the next pulse is applied to the first electrode pair, the first pulse can be delivered to the second electrode pair, and so on. Thereafter, the second pulse can all be delivered to the first electrode pair during the next inter-pulse delay, followed by the second pulse being delivered to the second electrode pair, and so on. This process can continue until the complete pulse train has been delivered to all the electrode pairs, and the process can be repeated for each of the remaining pulse packets.

[0012]

[0012] In an embodiment, the signal router can accomplish the tasks of managing the timing of various pulse deliveries to appropriate electrode pairs and / or managing the interleaving process. Logic for this can be implemented in electronic form, for example, in a microcontroller or other types of processing devices. Generally, the generator system can include a pulse generator and a signal router. In an embodiment, when a particular device is connected to the generator system, the system can automatically detect the device and determine a particular waveform and sequence scheme suitable for that device from a list of predetermined options. In an embodiment, the generator system can include only a signal generator, as may be applicable when only a single pair of electrodes or electrode set is required for the intervention device and ablation delivery. In any of the embodiments described in the present disclosure, the term "electrode" can refer to an electrode directly present on the intervention device, or a surface electrode patch or reference electrode placed on the patient.

[0013]

[0013] The devices used for ablation delivery by the generator systems of the present disclosure can be attached or connected to an electrical conductor attached to a cable or connector cable for delivering electrical energy from the generator system for delivery of the high voltage pulsed field ablation waveforms described herein. Generally, such energy delivery is performed in either unipolar mode or bipolar mode. In unipolar mode, a subset of the electrodes has one electrical polarity and a reference patch placed on the subject has the opposite electrical polarity. In bipolar mode, two different subsets of the electrodes are energized with opposite electrical polarities. In embodiments, subsets of pairs of electrodes can be sequentially energized for energy delivery. When a pulsed field ablation waveform is applied, the spatial distribution of the resulting electric field determines the region of cell death. Depending on the value of the irreversible electroporation threshold for a given target cell type, cells within the spatial region where the magnitude of the electric field is greater than the threshold are killed or ablated, and cells within other spatial regions where the magnitude of the electric field is below the threshold survive. In embodiments, the ablation can generate an electric field that is insufficient to cause irreversible electroporation but sufficient to cause reversible electroporation, and the cell membranes within the region of reversible electroporation are permeabilized, for example, to allow drug molecules or other therapeutic agents to pass into the cells for treating cancer.

[0014]

[0014] In embodiments, the voltage amplitude of the waveforms described herein can range from about 300 V to about 10,000 V, including all values and ranges therebetween, depending on the application. The pulse width of the waveform can range from about 0.5 microseconds to about 150 microseconds, including all values and ranges therebetween. The interphase delay can range from about 5 microseconds to about 3 milliseconds, including all values and ranges therebetween. The interpulse delay can range from about 15 microseconds to about 300 milliseconds, including all values and ranges therebetween, and the packet delay can range from 300 milliseconds to about 12 seconds, including all values and ranges therebetween.

[0015]

[0015] In some embodiments, the apparatus includes a pulse generator configured to be coupled to an ablation device, the pulse generator being configured to generate a voltage pulse train including a plurality of biphasic pulses, each biphasic pulse of the plurality of biphasic pulses including a positive pulse, a negative pulse, and a phase delay separating the positive pulse and the negative pulse, consecutive biphasic pulses of the plurality of biphasic pulses being separated by an inter-pulse delay such that the plurality of biphasic pulses are separated by a plurality of inter-pulse delays, the plurality of inter-pulse delays including an increasing sequence of inter-pulse delays including a subset of consecutive inter-pulse delays that increase gradually.

[0016]

[0016] In some embodiments, the apparatus includes a pulse generator configured to be coupled to an ablation device, the pulse generator being configured to generate a voltage pulse train including a plurality of biphasic pulses, each biphasic pulse of the plurality of biphasic pulses including a positive pulse, a negative pulse, and a phase delay separating the positive pulse and the negative pulse, consecutive biphasic pulses of the plurality of biphasic pulses being separated by an inter-pulse delay such that the plurality of biphasic pulses are separated by a plurality of inter-pulse delays, the plurality of inter-pulse delays including a decreasing sequence of inter-pulse delays including a subset of consecutive inter-pulse delays that decrease gradually.

[0017]

[0017] In some embodiments, the apparatus includes a pulse generator configured to be coupled to an ablation device, the pulse generator being configured to generate a voltage pulse train including a plurality of biphasic pulses, each biphasic pulse of the plurality of biphasic pulses including a positive pulse, a negative pulse, and a phase delay separating the positive pulse and the negative pulse, consecutive biphasic pulses of the plurality of biphasic pulses being separated by an inter-pulse delay such that the plurality of biphasic pulses are separated by a plurality of inter-pulse delays, the plurality of inter-pulse delays including an increasing sequence of inter-pulse delays including a first subset of consecutive inter-pulse delays that increase gradually and a decreasing sequence of inter-pulse delays including a second subset of consecutive inter-pulse delays that decrease gradually.

[0018]

[0018] In some embodiments, the system comprises a pulse generator configured to generate a two-phase pulse, each including a positive pulse, a negative pulse, and an inter-pulse delay; a signal router operably coupled to the pulse generator and a plurality of electrode sets, each including one or more electrodes, the signal router being configured to: (1) set one or more switches to selectively apply the two-phase pulse generated by the pulse generator to one or more of the plurality of electrode sets; (2) generate a series of trigger signals for triggering the pulse generator to generate the two-phase pulse; and a communication channel disposed between the signal router and the pulse generator, the communication channel being configured to transmit the series of trigger signals to the pulse generator such that, in response to the pulse generator receiving each trigger signal of the series of trigger signals, the pulse generator generates a pulse train and delivers the pulse train to the signal router for application to one or more of the plurality of electrode sets. The pulse train includes a plurality of two-phase pulses, consecutive two-phase pulses of the plurality of two-phase pulses being separated by an inter-pulse delay of a plurality of inter-pulse delays, the plurality of inter-pulse delays including at least one of an increasing sequence of inter-pulse delays including a subset of consecutive inter-pulse delays that gradually increase or a decreasing sequence of inter-pulse delays including a subset of consecutive inter-pulse delays that gradually decrease.

[0019]

[0019] In some embodiments, the method includes generating, using a pulse generator coupled to an ablation device, a voltage pulse train including a plurality of two-phase pulses, each two-phase pulse of the plurality of two-phase pulses including a positive pulse, a negative pulse, and a phase delay separating the positive pulse and the negative pulse, consecutive two-phase pulses of the plurality of two-phase pulses being separated by an inter-pulse delay such that the plurality of two-phase pulses are separated by a plurality of inter-pulse delays, the plurality of inter-pulse delays including an increasing sequence of inter-pulse delays including a subset of consecutive inter-pulse delays that gradually increase.

[0020]

[0020] In some embodiments, the method includes generating a voltage pulse train including a plurality of biphasic pulses using a pulse generator coupled to an ablation device, each biphasic pulse of the plurality of biphasic pulses including a positive pulse, a negative pulse, and a phase delay separating the positive pulse and the negative pulse, consecutive biphasic pulses of the plurality of biphasic pulses being separated by an interpulse delay such that the plurality of biphasic pulses are separated by a plurality of interpulse delays, the plurality of interpulse delays including a decreasing sequence of interpulse delays including a subset of consecutive interpulse delays that decrease gradually.

[0021]

[0021] In some embodiments, the method includes generating a voltage pulse train including a plurality of biphasic pulses using a pulse generator coupled to an ablation device, each biphasic pulse of the plurality of biphasic pulses including a positive pulse, a negative pulse, and a phase delay separating the positive pulse and the negative pulse, consecutive biphasic pulses of the plurality of biphasic pulses being separated by an interpulse delay such that the plurality of biphasic pulses are separated by a plurality of interpulse delays, the plurality of interpulse delays including an increasing sequence of interpulse delays including a subset of consecutive interpulse delays that increase gradually and a decreasing sequence of interpulse delays including a subset of consecutive interpulse delays that decrease gradually.

Brief Description of the Drawings

[0022]

Figure 1

[0022] A schematic view of an endoscope passing through a subject's stomach and disposed within the duodenum.

Figure 2

[0023] A schematic view of a distal portion of an endoscope having a plurality of lumens, one of the lumens being used for passage of a catheter device having electrodes for ablation delivery, according to an embodiment.

Figure 3

[0024] A diagram of a catheter device having a needle electrode disposed within an organ within a subject, according to an embodiment, the figure also showing a reference patch.

Figure 4

[0025] Shows an embodiment of a pulse train of the present disclosure having an increasing sequence of interpulse delays.

Figure 5

[0026] Shows an embodiment of a pulse train of the present disclosure having a pulse - to - pulse delay reduction sequence.

Figure 6

[0027] Shows an embodiment of a pulse train of the present disclosure having both a pulse - to - pulse delay increase sequence and a pulse - to - pulse delay reduction sequence.

Figure 7

[0028] Shows a trapezoidal biphasic pulse with a specified pulse width and pulse - based element according to an embodiment.

Figure 8

[0029] Shows an embodiment of a trapezoidal pulse train of the present disclosure having a pulse - to - pulse delay increase sequence.

Figure 9

[0030] Shows an embodiment of a trapezoidal pulse train of the present disclosure having a pulse - to - pulse delay reduction sequence.

Figure 10

[0031] Shows an embodiment of a trapezoidal pulse train of the present disclosure having both a pulse - to - pulse delay increase sequence and a pulse - to - pulse delay reduction sequence.

Figure 11

[0032] Shows a waveform having a plurality of packets of a pulse train with packet delay over a series of packets according to an embodiment.

Figure 12

[0033] Shows the sequential delivery of waveforms in the form of a plurality of pulse packets delivered to a plurality of electrode pairs according to an embodiment.

Figure 13

[0034] Shows the sequential delivery of a pulse train of waveforms in the form of individual pulses of a pulse train delivered in an interleaved fashion to a plurality of electrode pairs respectively according to an embodiment.

Figure 14

[0035] Is a schematic diagram of a generator system in the form of a pulse generator and a signal router for delivering a pulse - field ablation waveform to a medical device according to an embodiment.

Figure 15

[0036] Is a schematic diagram of a control circuit for single - channel operation of a generator system according to an embodiment of the present disclosure.

Figure 16

[0037] The half - bridge topology of two channels of a generator system that can be combined to deliver a pulsed - field ablation waveform to a pair of electrodes each connected to two channels, according to an embodiment, is shown.

Figure 17

[0038] The operation of the system of the present disclosure in one embodiment is shown.

Mode for Carrying Out the Invention

[0023] Detailed Description

[0039] Embodiments of the present disclosure generally provide for the delivery of customized waveforms disclosed herein for pulsed - field ablation of soft - tissue structures, for example, inter alia, for cancer treatment delivery for ablation of some tumor types, for ablation of benign tumors such as fibromas, for treatment of diseased tissue that may lead to cancer, or for ablation of the sympathetic or parasympathetic nerves.

[0024]

[0040] As an example, for the treatment of pancreatic tumors, endoscopic access can be obtained to the stomach or duodenum, and then access can be obtained to adjacent organs such as the pancreas by appropriate puncture. FIG. 1 shows an endoscope 101 inserted through the esophagus 103 from the subject's mouth, passing through the stomach 105 and then placed in the duodenum 107. With this type of positioning, the endoscope can be placed in the vicinity of the pancreas.

[0025]

[0041] FIG. 2 shows, for purposes of explanation and illustration, the distal portion of an endoscope 204 having a plurality of lumens 205, 207, and 209. Lumens 205 and / or lumen 207 can be used for the passage of an optical imaging fiber or camera or an ultrasonic imaging catheter. Lumen or channel 209 is shown as being used for the passage of a catheter device 220 having two lumens that themselves carry needles or needle wires 213 and 215. The endoscope can be steered to an appropriate position within the stomach or duodenum to facilitate proper deployment and placement of needles 213 and 215. In use, the endoscope 204 passes through the mouth and esophagus to reach the stomach and / or duodenum and is positioned adjacent to or in proximity to the tissue wall, for example, near the pancreas. The catheter 220 is extended under image guidance by optical or ultrasonic imaging performed by an appropriate imaging device used in conjunction with the endoscope and is positioned in an appropriate location to access an appropriate pancreatic site. Needles 213 and 215 are extended from the catheter device 220, penetrate the stomach wall, enter the pancreas, and are used to access a target tumor site. When needles 213 and 215 are properly positioned within the pancreas, pulsed field ablation is delivered through the needles from a generator system (described below) connected to the catheter 220.

[0026]

[0042] FIG. 3 is a diagram of a catheter device 302 disposed adjacent to an anatomical organ 310 (shown in cross-section in the figure) within a subject's body 320, according to an embodiment. Needles 304 and 306 extend from a device lumen to penetrate and enter the organ 310. In one embodiment, the needles are used as a single bonding electrode (i.e., polarized with one electrical polarity), electrically paired with a reference electrode patch 325 (polarized with the opposite electrical polarity), and can deliver pulsed-field ablation in monopolar (also called monopolar) mode. In other embodiments, needles 304 and 306 can be used as a bipolar electrode plate pair for bipolar pulsed-field ablation delivery. Application of a pulsed-field ablation waveform to the electrodes results in the generation of an electric field, and ablation regions, such as regions having a boundary 313, are generated as a result of ablation, depending on the irreversible electroporation threshold of the tissue. If a larger treatment volume or area is desired, needles 304 and 306 can be retracted, the catheter 302 moved, positioned at different locations, the needles 304 and 306 inserted at the new locations, and treatment delivered at the new locations.

[0027]

[0043] Figure 4 shows an embodiment of a pulse train of the present disclosure having an increasing sequence of inter-pulse delays. This figure shows a two-phase voltage pulse train as a time sequence having four pulses 421, 423, 425, and 427. For example, each complete two-phase pulse such as reference numeral 421 has a positive phase (shown by reference numeral 401) and a negative phase (shown by reference numeral 403) separated by an inter-phase time delay (shown by reference numeral 405). The pulse train shown has pulses in which each phase has a substantially rectangular shape. The pulse width (shown by reference numeral 440 in the figure) is the effective duration of each phase. In an embodiment, the inter-phase delay can be greater than the width of the positive or negative phase. In an embodiment, the inter-phase delay can be at least about three times greater than the width of the positive or negative phase, and in an embodiment, the inter-phase delay can be at least about five times the width of the positive or negative phase. In an embodiment, the corners of the pulses (such as those shown by reference numerals 444 and 446 in the figure) can have a rounded shape (not shown). There is a time delay interval called an inter-pulse delay between consecutive two-phase pulses. As shown in Figure 4, the inter-pulse delay 408 (measured from the end of pulse 421 to the start of pulse 423) separates the first pulse 421 and the second pulse 423, the inter-pulse delay 410 separates the pulse 423 and the pulse 425, and the inter-pulse delay 412 separates the pulse 425 and the pulse 427. The inter-pulse delay generally varies across the pulse train and follows an increasing or decreasing pattern in at least a portion of the pulse train. The schematic of Figure 4 shows an increasing sequence of inter-pulse delays over time, and thus, the inter-pulse delay 412 is greater than the inter-pulse delay 410, and the inter-pulse delay 410 is greater than the inter-pulse delay 408.

[0028]

[0044] In an embodiment, the sequence of increasing inter-pulse delays follows at least an arithmetic progression. For example, the difference between one inter-pulse delay and the immediately preceding inter-pulse delay is at least a non-zero constant. In an embodiment, the sequence of increasing delays follows at least a geometric progression. For example, the ratio of one inter-pulse delay to the immediately preceding inter-pulse delay is at least a constant greater than 1. In an embodiment, the difference between one inter-pulse delay and the immediately preceding inter-pulse delay in the increasing sequence of inter-pulse delays is at least about 10 microseconds, and in other embodiments, at least about 100 microseconds. In an embodiment, the ratio of one inter-pulse delay to the immediately preceding inter-pulse delay in the increasing sequence of inter-pulse delays is at least about 1.1. In an embodiment, the inter-pulse delays sequentially follow an increasing pattern with respect to at least one-third of the total number of such delays between adjacent pulses within the pulse train.

[0029]

[0045] FIG. 5 shows an embodiment of a pulse train of the present disclosure having a decreasing sequence of inter-pulse delays. This figure shows a two-phase voltage pulse train as a time sequence having four pulses 521, 523, 525, and 527. Each complete two-phase pulse, such as reference number 521, has a positive phase (shown by reference number 501) and a negative phase (shown by reference number 503) separated by an inter-phase time delay (shown by reference number 505). The pulse train shown has pulses in which each phase has a substantially rectangular shape. As described above, in an embodiment, the inter-phase delay can be made greater than the width of the positive or negative phase. In an embodiment, the inter-phase delay can be made at least about 3 times greater than the width of the positive or negative phase, and in an embodiment, the inter-phase delay can be made at least about 5 times the width of the positive or negative phase. The inter-pulse time delay 508 separates the first pulse 521 and the second pulse 523, the inter-pulse delay 510 separates the pulse 523 and the pulse 525, and the inter-pulse delay 512 separates the pulse 525 and the pulse 527. The schematic diagram of FIG. 5 shows a decreasing sequence of inter-pulse delays over time, and thus the inter-pulse delay 512 is less than the inter-pulse delay 510, and the inter-pulse delay 510 is less than the inter-pulse delay 508.

[0030]

[0046] In an embodiment, the sequence of decreasing delays follows at least an arithmetic sequence. For example, the magnitude of the difference between one inter-pulse delay and the immediately preceding inter-pulse delay is at least a non-zero constant. In an embodiment, the sequence of decreasing delays follows at least a geometric sequence. For example, the ratio of one inter-pulse delay to the immediately preceding inter-pulse delay is less than or equal to a constant less than 1. In an embodiment, the magnitude of the difference between one inter-pulse delay and the immediately preceding inter-pulse delay in the decreasing sequence of inter-pulse delays is at least about 10 microseconds, and in other embodiments, at least about 100 microseconds. In an embodiment, the ratio of one inter-pulse delay to the immediately preceding inter-pulse delay in the decreasing sequence of delays is less than about 0.9. In an embodiment, the inter-pulse delay sequentially follows a decreasing pattern with respect to at least one-third of the total number of such delays between adjacent pulses within the pulse train.

[0031]

[0047] Figure 6 shows an embodiment of a pulse train of the present disclosure having both an increasing sequence of inter-pulse delays and a decreasing sequence of inter-pulse delays. This figure shows seven two-phase pulses 600, 602, 604, 606, 608, 610, and 612. Each two-phase pulse has a positive phase, a negative phase, and an inter-phase delay. As described above, the pulse train shown has pulses in which each phase has a substantially rectangular shape. In an embodiment, the inter-phase delay can be greater than the width of the positive or negative phase. In an embodiment, the inter-phase delay can be at least about three times greater than the width of the positive or negative phase, and in an embodiment, the inter-phase delay can be at least about five times the width of the positive or negative phase. Pulse 600 and pulse 602 are separated by an inter-pulse delay 613, pulse 602 and pulse 604 are separated by an inter-pulse delay 615, pulse 604 and pulse 606 are separated by an inter-pulse delay 617, pulse 606 and pulse 608 are separated by an inter-pulse delay 621, pulse 608 and pulse 610 are separated by an inter-pulse delay 623, and pulse 610 and pulse 612 are separated by an inter-pulse delay 625. The inter-pulse delays 613, 615, 617 represent an increasing sequence of inter-pulse delays, and the inter-pulse delays 621, 623, and 625 represent a decreasing sequence of inter-pulse delays. In an embodiment, the increasing or decreasing sequence of inter-pulse delays follows at least an arithmetic sequence. For example, the magnitude of the difference between one inter-pulse delay and the immediately preceding inter-pulse delay is at least a non-zero constant. In an embodiment, the increasing or decreasing sequence of inter-pulse delays follows at least a geometric sequence. For example, the ratio of one inter-pulse delay to the immediately preceding inter-pulse delay is, in the case of an increasing sequence of inter-pulse delays, at least a constant greater than 1, or in the case of a decreasing sequence of inter-pulse delays, at most a constant less than 1. In an embodiment, the difference between one inter-pulse delay and the immediately preceding inter-pulse delay in the increasing sequence of inter-pulse delays is at least about 10 microseconds, and in other embodiments, at least about 100 microseconds. In an embodiment, the ratio of one inter-pulse delay to the immediately preceding inter-pulse delay in the increasing sequence of delays is at least about 1.1.In an embodiment, the magnitude of the difference between one inter-pulse delay and the immediately preceding inter-pulse delay in a sequence of decreasing inter-pulse delays is at least about 10 microseconds, and in other embodiments, at least about 100 microseconds. In an embodiment, the ratio of one inter-pulse delay to the immediately preceding inter-pulse delay in a sequence of decreasing inter-pulse delays is less than about 0.9. In an embodiment, in a given pulse train, the inter-pulse delays sequentially follow an increasing pattern with respect to at least one-third of the total number of such delays between adjacent pulses, and follow a decreasing pattern with respect to at least one-third of the total number of such delays between adjacent pulses.

[0032]

[0048] In an embodiment, the pulse width of the waveforms described herein can range from about 0.5 microseconds to about 150 microseconds, including all values and ranges therebetween. In an embodiment, the phase delay can range from about 5 microseconds to about 3 milliseconds, including all values and ranges therebetween. In an embodiment, the inter-pulse delay can range from about 15 microseconds to about 300 milliseconds, including all values and ranges therebetween.

[0033]

[0049] FIG. 7 shows a trapezoidal two-phase voltage pulse highlighting the pulse width and pulse base according to an embodiment. The trapezoidal voltage pulse shown in FIG. 7 has a positive phase 703 and a negative phase 705 separated by a phase delay 707. Thus, a complete trapezoidal two-phase pulse includes a positive trapezoidal phase, a negative trapezoidal phase, and a delay between the positive and negative phases. The pulse width of the trapezoidal pulse can be the width of one phase of the pulse having a value where the voltage is greater than about 70% of the maximum amplitude of that phase. In this figure, this is shown by a time interval 712 having a value above the value shown by line 703 where the positive phase 703 shows 70% of the value of the maximum value 710 (i.e., 70% of the amplitude value). In the illustrated embodiment, the pulse width is equal or approximately equal in the positive and negative phases. In an embodiment, the phase delay can be made greater than the pulse width of the positive or negative phase. In an embodiment, the phase delay can be made at least about 3 times greater than the pulse width of the positive or negative phase, and in an embodiment, the phase delay can be made at least about 5 times the pulse width of the positive or negative phase.

[0034]

[0050] In an embodiment, the corners of the pulse (such as those indicated by reference numerals 723 and 725 in the figure) can have a rounded shape (not shown). Further, the base width of the pulse is indicated by reference numeral 715 in FIG. 7. This represents a time interval 715 in which one phase of the pulse has a value greater than 5% of the magnitude of the maximum value 710, as indicated by line 712. In an embodiment, the base width of the trapezoidal pulse can be made up to approximately 6 microseconds greater than the pulse width.

[0035]

[0051] In an embodiment, the pulse train can include a sequence of trapezoidal pulses. FIG. 8 shows an embodiment of a trapezoidal pulse train of the present disclosure having an increasing sequence of inter-pulse delays. This figure shows four trapezoidal pulses 800, 802, 804, and 806. Each complete two-phase pulse, such as reference numeral 800, has a positive phase (indicated by reference numeral 808) and a negative phase (indicated by reference numeral 810) separated by an inter-phase time delay (indicated by reference numeral 814). The pulse train shown has pulses in which each phase is in the form of a trapezoid having a pulse width and a base width similar to those described with reference to FIG. 7. In an embodiment, the inter-phase delay can be made greater than the pulse width of the positive or negative phase. In an embodiment, the inter-phase delay can be made at least about three times greater than the pulse width of the positive or negative phase, and in an embodiment, the inter-phase delay can be made at least about five times the pulse width of the positive or negative phase. There is a time delay interval called the inter-pulse delay between consecutive two-phase pulses. As shown in FIG. 8, the inter-pulse time delay 816 (measured from the end of pulse 800 to the start of pulse 802) separates the first pulse 800 from the second pulse 802, the inter-pulse delay 818 separates the pulse 802 from the pulse 804, and the inter-pulse delay 820 separates the pulse 804 from the pulse 806. The inter-pulse delay varies across the pulse train and can follow an increasing or decreasing pattern in at least a portion of the pulse train. The schematic diagram of FIG. 8 shows an increasing sequence of inter-pulse delays over time, and thus, the inter-pulse delay 818 is greater than the inter-pulse delay 816, and the inter-pulse delay 820 is greater than the inter-pulse delay 818.

[0036]

[0052] In an embodiment, the sequence of increasing inter-pulse delays follows at least an arithmetic sequence. For example, the difference between one inter-pulse delay and the immediately preceding inter-pulse delay is at least a non-zero constant. In an embodiment, the sequence of increasing delays follows at least a geometric sequence. For example, the ratio of one inter-pulse delay to the immediately preceding inter-pulse delay is at least a constant greater than 1. In an embodiment, the difference between one inter-pulse delay and the immediately preceding inter-pulse delay in the increasing sequence of inter-pulse delays is at least about 10 microseconds, and in other embodiments, at least about 100 microseconds. In an embodiment, the ratio of one inter-pulse delay to the immediately preceding inter-pulse delay in the increasing sequence of delays is at least about 1.1. In an embodiment, the inter-pulse delay sequentially follows an increasing pattern with respect to at least one-third of the total number of such delays between adjacent pulses within the pulse train.

[0037]

[0053] FIG. 9 shows an embodiment of a trapezoidal pulse train of the present disclosure having a pulse - to - pulse delay reduction sequence. This figure shows a two - phase voltage pulse train as a time sequence having four pulses 900, 902, 904, and 906. For example, each complete two - phase pulse such as reference number 900 has a positive phase (shown by reference number 908) and a negative phase (shown by reference number 910) separated by an inter - phase time delay (shown by reference number 913). The pulse train shown has pulses in the form of trapezoids where each phase has a pulse width and a base width similar to those described with reference to FIG. 7. In an embodiment, the inter - phase delay can be made larger than the pulse width of the positive or negative phase. In an embodiment, the inter - phase delay can be made at least about three times larger than the pulse width of the positive or negative phase, and in an embodiment, the inter - phase delay can be made at least about five times the pulse width of the positive or negative phase. The pulse - to - pulse time delay 915 separates the first pulse 900 and the second pulse 902, the pulse - to - pulse delay 917 separates the pulse 902 and the pulse 904, and the pulse - to - pulse delay 919 separates the pulse 904 and the pulse 906. The schematic of FIG. 9 shows a decreasing sequence of pulse - to - pulse delays over time, and thus, the pulse - to - pulse delay 917 is smaller than the pulse - to - pulse delay 915, and the pulse - to - pulse delay 919 is smaller than the pulse - to - pulse delay 917.

[0038]

[0054] In an embodiment, the sequence of decreasing inter-pulse delays follows at least an arithmetic progression. For example, the magnitude of the difference between one inter-pulse delay and the immediately preceding inter-pulse delay is at least a non-zero constant. In an embodiment, the sequence of decreasing inter-pulse delays follows at least a geometric progression. For example, the ratio of one inter-pulse delay to the immediately preceding inter-pulse delay is less than or equal to a constant less than 1. In an embodiment, the magnitude of the difference between one inter-pulse delay and the immediately preceding inter-pulse delay in the decreasing sequence of inter-pulse delays is at least about 10 microseconds, and in other embodiments, at least about 100 microseconds. In an embodiment, the ratio of one inter-pulse delay to the immediately preceding inter-pulse delay in the decreasing sequence of inter-pulse delays is less than about 0.9. In an embodiment, the inter-pulse delay sequentially follows a decreasing pattern with respect to at least one-third of the total number of such delays between adjacent pulses in the pulse train.

[0039]

[0055] Figure 10 shows an embodiment of a trapezoidal pulse train of the present disclosure having both an increasing sequence of inter-pulse delays and a decreasing sequence of inter-pulse delays. This figure shows seven two-phase pulses 1001, 1002, 1003, 1004, 1005, 1006, and 1007. Each complete two-phase pulse has a positive phase, a negative phase, and an inter-phase delay. As described above, the shown pulse train has pulses in which each phase has a trapezoidal shape. In some embodiments, the inter-phase delay can be greater than the pulse width of the positive or negative phase. In an embodiment, the inter-phase delay can be at least about three times greater than the pulse width of the positive or negative phase, and in an embodiment, the inter-phase delay can be at least about five times the pulse width of the positive or negative phase. Pulse 1001 and pulse 1002 are separated by an inter-pulse delay 1010, pulse 1002 and pulse 1003 are separated by an inter-pulse delay 1012, pulse 1003 and pulse 1004 are separated by an inter-pulse delay 1014, pulse 1004 and pulse 1005 are separated by an inter-pulse delay 1017, pulse 1005 and pulse 1006 are separated by an inter-pulse delay 1019, and pulse 1006 and pulse 1007 are separated by an inter-pulse delay 1021. The inter-pulse delays 1010, 1012, and 1014 represent an increasing sequence of inter-pulse delays, and the inter-pulse delays 1017, 1019, and 1021 represent a decreasing sequence of inter-pulse delays. In an embodiment, the increasing or decreasing sequence of inter-pulse delays follows at least an arithmetic sequence. For example, the magnitude of the difference between one inter-pulse delay and the immediately preceding inter-pulse delay is at least a non-zero constant. In an embodiment, the increasing or decreasing sequence of inter-pulse delays follows at least a geometric sequence. For example, the ratio of one inter-pulse delay to the immediately preceding inter-pulse delay is, in the case of an increasing sequence of inter-pulse delays, at least a constant greater than 1, or in the case of a decreasing sequence of inter-pulse delays, a constant less than 1. In an embodiment, the ratio of one inter-pulse delay to the immediately preceding inter-pulse delay in the increasing sequence of inter-pulse delays is at least about 1.1. In an embodiment, the ratio of one inter-pulse delay to the immediately preceding inter-pulse delay in the decreasing sequence of inter-pulse delays is less than about 0.9.In an embodiment, the magnitude of the difference between one inter-pulse delay and the immediately preceding inter-pulse delay in an increasing or decreasing sequence of inter-pulse delays is at least about 10 microseconds, and in other embodiments, at least about 100 microseconds. In an embodiment, in a given pulse train, the inter-pulse delays sequentially follow an increasing pattern with respect to at least one-third of the total number of such delays between adjacent pulses, and follow a decreasing pattern with respect to at least one-third of the total number of such delays between adjacent pulses.

[0040]

[0056] In an embodiment, the pulse width of the trapezoidal waveform described herein can range from about 0.5 microseconds to about 150 microseconds, including all values and ranges therebetween. The inter-phase delay can range from about 5 microseconds to about 3 milliseconds, including all values and ranges therebetween. The inter-pulse delay can range from about 15 microseconds to about 300 milliseconds, including all values and ranges therebetween.

[0041]

[0057] FIG. 11 shows a waveform having a plurality of packets of a pulse train having packet delays over a series of packets according to an embodiment. This figure shows a plurality of pulse trains or packets 1102, 1104, and 1106. In various embodiments, each pulse train or packet, such as reference number 1102, reference number 1104, or reference number 1106, can include a series of pulses 1100 similar to those described in FIGS. 4-6 and FIGS. 8-10. The packet delay separates one pulse packet from the next. For example, packet delay 1111 separates packet 1102 from packet 1104, and packet delay 1113 separates packet 1104 from packet 1106. In an embodiment, the packet delay can be non-constant or can vary over a series of packets. In an embodiment, each packet delay can range from about 300 milliseconds to about 12 seconds, including all values and ranges therebetween.

[0042]

[0058] In an embodiment, the number of complete biphasic pulses within each pulse train of the present disclosure can range from 1 to approximately 30, including all values and ranges therebetween, and the number of pulse packets can range from 1 to approximately 20, including all values and ranges therebetween.

[0043]

[0059] The waveforms of the present disclosure can be applied to more than one set of electrodes in various formats. For example, FIG. 12 shows the sequential delivery of waveforms in the form of a plurality of pulse packets delivered to a plurality of electrode pairs. In the figure, pulse packet 1202 and pulse packet 1208 represent two pulse packets applied to a first set of electrodes. Each pulse packet, such as reference number 1202 or reference number 1208, includes a pulse train 1201. In FIG. 12, the packet delay between packet 1202 and packet 1208 is the sum of time interval 1213 and time interval 1215. During this packet delay, pulse packet 1204 and pulse packet 1206 can be sequentially applied to a second set of electrodes and a third set of electrodes, respectively. Thereafter, after the second packet 1208 is applied to the first set of electrodes, packet 1210 and packet 1212 are applied to the second set of electrodes and the third set of electrodes, respectively. The delivery process is not limited to the specific number shown in FIG. 12 and should be apparent to extend to a plurality of numbers of pulse packets and a plurality of numbers of electrode sets. In an embodiment, the number of separate electrode sets to which such waveforms are applied can range from 1 to approximately 20, including all values and ranges therebetween.

[0044]

[0060] Other methods and sequences of waveform delivery can be constructed in accordance with the teachings of this specification. For example, FIG. 13 shows the sequential delivery of a pulse train of waveforms in the form of individual pulses of a pulse train delivered in an interleaved format to a plurality of electrode pairs. In this figure, biphasic pulses 1301, 1307, and 1313 represent three complete biphasic pulses of a pulse train applied to a first set of electrodes. Time interval or inter-pulse delay 1317 separates pulse 1301 and pulse 1307, and time interval or inter-pulse delay 1319 separates pulse 1307 and pulse 1313. During time interval or delay 1317, biphasic pulse 1303 and biphasic pulse 1305 are applied to a second set of electrodes and a third set of electrodes, respectively. During time interval or delay 1319, biphasic pulse 1309 and biphasic pulse 1311 are applied to a second set of electrodes and a third set of electrodes, respectively. This process of electrode interleaved delivery of a pulse train is clearly not limited to the specific number shown in FIG. 13 and can extend to a plurality of numbers of pulses and inter-pulse delays and a plurality of numbers of electrode sets. In embodiments, the number of separate electrode sets to which such waveforms are applied can range from 1 to about 20, including all values and ranges therebetween.

[0045]

[0061] FIG. 14 is a schematic diagram of a generator system including a pulse generator and a signal router for delivering a pulsed field ablation waveform to a medical device according to an embodiment. This figure shows a pulse generator 1400 in communication with a signal router 1402. The signal router 1402 incorporates a control and timing unit, such as a microcontroller. In an embodiment, the pulse generator 1400 can incorporate a microcontroller or a field programmable gate array (FPGA) for timing control of pulses and / or pulse trains. In an embodiment, the pulse generator 1400 can incorporate at least one FPGA and at least one microcontroller. Communication signals in either direction between the signal router 1402 and the pulse generator 1400 pass through at least one communication channel 1406, and in an embodiment, one or more such channels for communication can exist. In an embodiment, there can also be a separate connection (not shown) between the pulse generator 1400 and the signal router 1402 for transmitting a trigger signal from the signal router 1402 to the pulse generator 1400. In an embodiment, the communication channel 1406 can also function to transmit a trigger signal from the signal router 1402 to the pulse generator 1400. The communication channel 1406 can define one or more requests for a particular pulse or pulse train from the signal generator 1400 based on a predetermined series of communication signals or communication terms. When a trigger signal (corresponding to a request for a defined pulse or pulse train) is transmitted from the signal router 1402 to the pulse generator 1400, the pulse generator 1400 generates an appropriate pulse or pulse train and transmits it to the signal router 1402 via a high voltage link 1410. The signal router 1402 controls the timing of opening and closing of appropriate switches to route an input pulse or pulse train to an appropriate set or subset of channels 1415 from the pulse generator 1400 for delivering the pulse waveform to a desired medical device 1419, such as for tissue ablation. In an embodiment, the number of channels 1415 can range from 2 to about 20, including all values and ranges therebetween.In an embodiment, the output of channel 1415 can be connected to a suitable medical device electrode. In an embodiment, at least one of channel 1415 can be connected to a reference electrode patch for placement on the subject's body surface, for example. In embodiments where only two output channels are required, signal router 1402 may not be necessary, in which case only pulse generator 1400 is included in the generator system. In an embodiment, either signal router 1402 or pulse generator 1400, or both, can include a transformer on the output path for proper electrical insulation. In an embodiment, signal router 1402 can include a relay that is closed only during ablation delivery as additional protection to ensure that an output occurs only when desired, for example. In an embodiment, the generator system can be modular so that either pulse generator 1400 or signal router 1402 can be replaced with a different similar component when needed, for example for repair or replacement. In an embodiment, pulse generator 1400 and signal router 1402 can be separate units or boxes having a suitable cable connection therebetween. In other embodiments, pulse generator 1400 and signal router 1402 can be housed as separate sets of electronic substrates within a single unit or box. In an embodiment, signal router 1402 and / or pulse generator 1400 can have a user interface for user input of parameters such as, for example, voltage amplitude, medical device type, number of electrode sets, and other operating parameters. This user input can be used by the generator system to deliver an appropriate waveform.

[0046]

[0062] Figure 15 is a schematic diagram of a control circuit for the operation of a single channel of a generator system according to the present disclosure. Voltage terminal 1500 and voltage terminal 1502 represent the positive and negative terminals of a high voltage source (e.g., a capacitor or a transformer depending on the embodiment), respectively. In an embodiment, the high voltage source can be a pulse generator. High power switches 1520 and 1522 are connected as shown between the terminals and can include, for example, high power solid state switches such as insulated gate bipolar transistors (IGBTs) or metal oxide semiconductor field effect transistors (MOSFETs). Switches 1520 and 1522 are controlled by respective drive circuits 1508 and 1510 that function to turn the switches on or off, and drive circuits 1508 and 1510 are driven by an FPGA or microcontroller 1506 that controls the opening and closing timing of the switches based on a desired waveform output. In an embodiment, details of a particular pulse and / or pulse train are transmitted from microcontroller 1513 to the FPGA or microcontroller 1506. In an embodiment, the path from terminal 1500 to terminal 1522 can include a current limiting resistor to reduce any short circuits. Only one of switches 1520 or 1522 is closed at a given time, and the other remains open. In this way, channel output 1518 is connected to either the positive or negative terminal. For a substantially constant voltage source at the terminals, depending on the rise time or switching time of switches 1520 and 1522, the shape of the pulse can be rectangular, trapezoidal, or substantially rectangular or trapezoidal. In an embodiment, output path 1518 can incorporate a filtering circuit (not shown) to limit voltage or current spikes that may round the corners of the pulse as described above.

[0047]

[0063] By pairing the single-channel topology of FIG. 15 with a second similar channel, a current path and channel pairing for waveform output between any pair of channels connected to separate device electrodes or electrode sets can be established. FIG. 16 shows a half-bridge topology of two channels of a generator system that can be combined to deliver a pulsed-field ablation waveform to a pair of electrodes or electrode sets each connected to two channels, according to an embodiment. The output channel 1620 of FIG. 16 is connected to a half-bridge topology including switches 1603 and 1605, and switches 1603 and 1605 are connected to the positive terminal 1615 and the negative terminal 1617 of a high-voltage source, respectively. Similarly, the output channel 1622 of FIG. 16 is connected to a half-bridge topology including switches 1609 and 1611, and switches 1609 and 1611 are connected to the positive terminal 1615 and the negative terminal 1617 of the same high-voltage source, respectively. When switches 1603 and 1611 are closed while switches 1605 and 1609 are open, a current path is established between the electrodes and the tissue impedance seen between the device electrodes connected to channel 1620 and channel 1622, so that a positive voltage pulse is delivered to output channel 1620 and output channel 1622. Similarly, when switches 1605 and 1609 are closed while switches 1603 and 1611 are open, a negative voltage pulse is delivered to output channel 1620 and output channel 1622. By the appropriate timing of opening and closing the switches, a desired complete biphasic pulse can be generated.

[0048]

[0064] Figure 17 shows the operation of the system of the present disclosure for waveform delivery in one embodiment. When a user enables waveform delivery via the user interface of a generator system (such as the generator system shown in FIG. 14, similar to other generator systems described herein), at reference numeral 1703, communication between the signal router of the generator system and the pulse generator of the generator system is checked and confirmed. If the communication is invalid, a system error is called; otherwise, at reference numeral 1705, the signal router sends a first message to the pulse generator that includes the form of the desired output from the pulse generator, i.e., whether it is a single pulse or the entire pulse train. In an embodiment, receipt of this message is confirmed by the pulse generator to the signal router. Thereafter, at reference numeral 1707, the signal router sends a second message to the pulse generator that includes details of a single pulse or the entire pulse train. In an embodiment, receipt of this second message is confirmed by the pulse generator to the signal router. Next, at reference numeral 1709, the signal router sets the appropriate switch to route the delivery of the pulse or pulse train to the appropriate output channel and then sends a trigger signal to the pulse generator. Upon receiving the trigger signal, the pulse generator generates the desired pulse or pulse train and outputs it to the signal router, from which, at reference numeral 1711, the output is routed to the appropriate device electrode. In an embodiment, the signal router can include a current measurement circuit for checking proper pulse delivery. In such an embodiment, at reference numeral 1713, if inaccurate or unexpected measurements are seen, the signal router reports an error at reference numeral 1715, opens all switches, and stops further output delivery. Otherwise, at reference numeral 1717, the signal router opens all switches and checks, for example, for other channels or electrode pairings, to see if more pulses or pulse trains are needed. If further pulse delivery is needed or desired, the process returns to reference numeral 1709, the signal router appropriately updates its signal routing switch, and sends another trigger signal to the pulse generator.The process continues in this way until the check at reference number 1717 indicates that the waveform delivery is complete. When complete, at reference number 1721, the process ends and, in an embodiment, the system can indicate to the user via the user interface that the waveform delivery has been successfully completed.

[0049]

[0065] In one embodiment where only a pulse generator is required, for example, for fixed or limited signal routing, the pulse generator can appropriately direct the opening and closing of a switch for pulse train delivery. It should be noted that a suitable user interface can include any of the various such interfaces well known in the art, including but not limited to a computer monitor, touch screen, mouse, wand, joystick, voice activation, foot switch, gesture recognition, etc.

[0050]

[0066] The pulsed waveform delivery disclosed herein can be applied to monopolar (also called monopolar) mode pulsed field ablation delivery between one or more device electrodes and a reference electrode patch on the surface of a subject, or in an embodiment, a subset of the device electrodes can be used as bipolar electrode plate pairs for bipolar pulsed field ablation delivery. Applying a pulsed field ablation waveform to the electrodes results in the generation of an electric field, and as a result of ablation, a ablation region having a boundary determined by the threshold of the electric field is generated, depending on the irreversible electroporation threshold of the tissue. In an embodiment, if a larger treatment volume or area is desired, the medical device can be moved and positioned at different locations and treatment can be delivered at the new location. In an embodiment, more than one ablation or waveform delivery can be performed at a given anatomical location that is convenient for application.

[0051]

[0067] The systems, devices, and methods described herein can be embodied in one or more of the embodiments described below.

[0052]

[0068] Embodiment 1: A system for ablation therapy delivery, comprising a pulse generator coupled to an ablation device, the pulse generator being configured to generate a voltage pulse train of biphasic pulses, each biphasic pulse including a positive pulse, a negative pulse, and a phase delay separating the positive pulse and the negative pulse, consecutive biphasic pulses being separated by an inter-pulse delay, and a subset of consecutive inter-pulse delays within the pulse train including an increasing sequence of delays.

[0053]

[0069] Embodiment 2: A system for ablation therapy delivery, comprising a pulse generator coupled to an ablation device, the pulse generator being configured to generate a voltage pulse train of biphasic pulses, each biphasic pulse including a positive pulse, a negative pulse, and a phase delay separating the positive pulse and the negative pulse, consecutive biphasic pulses being separated by an inter-pulse delay, and a subset of consecutive inter-pulse delays within the pulse train including a decreasing sequence of delays.

[0054]

[0070] Embodiment 3: A system for ablation therapy delivery, comprising a pulse generator coupled to an ablation device, the pulse generator being configured to generate a voltage pulse train of biphasic pulses, each biphasic pulse including a positive pulse, a negative pulse, and a phase delay separating the positive pulse and the negative pulse, consecutive biphasic pulses being separated by an inter-pulse delay, a first subset of consecutive inter-pulse delays within the pulse train including an increasing sequence of delays, and a second subset of consecutive inter-pulse delays within the pulse train including a decreasing sequence of delays.

[0055]

[0071] Embodiment 4: The system of Embodiment 1, wherein the increasing sequence of consecutive inter-pulse delays follows at least an arithmetic progression.

[0056]

[0072] Embodiment 5: The system of Embodiment 2, wherein the decreasing sequence of consecutive inter-pulse delays follows at least an arithmetic progression.

[0057]

[0073] Embodiment 6: The system of Embodiment 3, wherein the increasing sequence of delays within the first subset of consecutive pulse - to - pulse delays in the pulse train follows at least an arithmetic progression, and the decreasing sequence of delays within the second subset of consecutive pulse - to - pulse delays in the pulse train follows at least an arithmetic progression.

[0058]

[0074] Embodiment 7: The system of Embodiment 1, wherein the increasing sequence of consecutive pulse - to - pulse delays follows at least a geometric progression.

[0059]

[0075] Embodiment 8: The system of Embodiment 2, wherein the decreasing sequence of consecutive pulse - to - pulse delays follows at least a geometric progression.

[0060]

[0076] Embodiment 9: The system of Embodiment 3, wherein the increasing sequence of delays within the first subset of consecutive pulse - to - pulse delays in the pulse train follows at least a geometric progression, and the decreasing sequence of delays within the second subset of consecutive pulse - to - pulse delays in the pulse train follows at least a geometric progression.

[0061]

[0077] Embodiment 10: The system of Embodiment 1, wherein the increasing sequence of pulse - to - pulse delays in the pulse train includes at least one - third of the total number of pulse - to - pulse delays in the pulse train.

[0062]

[0078] Embodiment 11: The system of Embodiment 2, wherein the decreasing sequence of pulse - to - pulse delays in the pulse train includes at least one - third of the total number of pulse - to - pulse delays in the pulse train.

[0063]

[0079] Embodiment 12: The system of Embodiment 3, wherein the pulse train includes a maximum of 30 complete biphasic pulses.

[0064]

[0080] Embodiment 13: The system of Embodiment 1, wherein the positive and negative pulses of each biphasic pulse include substantially rectangular pulses.

[0065]

[0081] Embodiment 14: The system of Embodiment 2, wherein the positive and negative pulses of each two-phase pulse include substantially rectangular pulses.

[0066]

[0082] Embodiment 15: The system of Embodiment 1, wherein the positive and negative pulses of each two-phase pulse include trapezoidal pulses, and the pulse width of the positive or negative phase is a width or duration in which the voltage value is at least 70% of the maximum amplitude value.

[0067]

[0083] Embodiment 16: The system of Embodiment 2, wherein the positive and negative pulses of each two-phase pulse include trapezoidal pulses, and the pulse width of the positive or negative phase is a width or duration in which the voltage value is at least 70% of the maximum amplitude value.

[0068]

[0084] Embodiment 17: The system of Embodiment 13, wherein the phase delay is at least three times the pulse width.

[0069]

[0085] Embodiment 18: The system of Embodiment 14, wherein the phase delay is at least three times the pulse width.

[0070]

[0086] Embodiment 19: The system of Embodiment 15, wherein the phase delay is at least three times the pulse width.

[0071]

[0087] Embodiment 20: The system of Embodiment 16, wherein the phase delay is at least three times the pulse width.

[0072]

[0088] Embodiment 21: The system of Embodiment 3, wherein the phase delay is at least 5 microseconds.

[0073]

[0089] Embodiment 22: The system of Embodiment 3, wherein the pulse width ranges from about 0.5 microseconds to about 150 microseconds.

[0074]

[0090] Embodiment 23: A system for ablation treatment delivery, including a pulse generator coupled to an ablation device, the pulse generator being configured to generate a plurality of voltage pulse packets, consecutive packets being separated by a series of packet delays, each pulse packet including a voltage pulse train of biphasic pulses, each biphasic pulse including a positive pulse, a negative pulse, and a phase delay separating the positive pulse and the negative pulse, consecutive biphasic pulses being separated by an inter-pulse delay, and a subset of consecutive inter-pulse delays within the pulse train including a sequence of increasing delays.

[0075]

[0091] Embodiment 24: A system for ablation treatment delivery, including a pulse generator coupled to an ablation device, the pulse generator being configured to generate a plurality of voltage pulse packets, consecutive packets being separated by a series of packet delays, each pulse packet including a voltage pulse train of biphasic pulses, each biphasic pulse including a positive pulse, a negative pulse, and a phase delay separating the positive pulse and the negative pulse, consecutive biphasic pulses being separated by an inter-pulse delay, and a subset of consecutive inter-pulse delays within the pulse train including a sequence of decreasing delays.

[0076]

[0092] Embodiment 25: A system for ablation treatment delivery, including a pulse generator coupled to an ablation device, the pulse generator being configured to generate a plurality of voltage pulse packets, consecutive packets being separated by a series of packet delays, each pulse packet including a voltage pulse train of biphasic pulses, each biphasic pulse including a positive pulse, a negative pulse, and a phase delay separating the positive pulse and the negative pulse, consecutive biphasic pulses being separated by an inter-pulse delay, a first subset of consecutive inter-pulse delays within the pulse train including a sequence of increasing delays, and a second subset of consecutive inter-pulse delays within the pulse train including a sequence of decreasing delays.

[0077]

[0093] Embodiment 26: The system of Embodiment 23, wherein the plurality of pulse packets includes a maximum of 20 packets.

[0078]

[0094] Embodiment 27: The system of Embodiment 25, wherein each packet delay is in the range of about 300 milliseconds to about 12 seconds.

[0079]

[0095] Embodiment 28: The system of Embodiment 25, wherein the voltage amplitude of the pulse is in the range of about 300 volts to 10,000 volts.

[0080]

[0096] Embodiment 29: An ablation treatment delivery system comprising a pulse generator coupled to a router, an activation switch for channel routing to an electrode set, an ablation device having a plurality of electrodes coupled to the router, a communication channel between the pulse generator and the router for transmitting a trigger signal from the router to the pulse generator, and different subsets of router switches for channel routing to different electrode sets activated during at least two consecutive trigger signals, wherein the pulse generator generates a two-phase voltage pulse including a positive pulse and a negative pulse having a phase delay separating the positive pulse and the negative pulse, and the generated pulse passes through the router and reaches the electrodes of the ablation device.

[0081]

[0097] Embodiment 30: An ablation treatment delivery system comprising a pulse generator coupled to a router, an activation switch for channel routing to an electrode set, an ablation device having a plurality of electrodes coupled to the router, a communication channel between the pulse generator and the router for transmitting a trigger signal from the router to the pulse generator, and different subsets of router switches for channel routing to different electrode sets activated during at least two consecutive trigger signals, wherein the pulse generator generates a two-phase voltage pulse train of two-phase pulses when receiving a trigger signal, each two-phase pulse includes a positive pulse, a negative pulse, and a phase delay separating the positive pulse and the negative pulse, consecutive two-phase pulses are separated by an inter-pulse delay, and a subset of consecutive inter-pulse delays within the pulse train includes an increasing sequence of delays.

[0082]

[0098] Embodiment 31: It includes a pulse generator coupled to a router, an activation switch for channel routing to an electrode set, an ablation device having a plurality of electrodes coupled to the router, a communication channel between the pulse generator and the router for transmitting a trigger signal from the router to the pulse generator, and different subsets of router switches for channel routing to different electrode sets activated during at least two consecutive trigger signals. The pulse generator, when receiving a trigger signal, generates a two-phase voltage pulse train of two-phase pulses, each two-phase pulse including a positive pulse, a negative pulse, and a phase delay separating the positive pulse and the negative pulse. Consecutive two-phase pulses are separated by an inter-pulse delay, and a subset of consecutive inter-pulse delays within the pulse train includes a decreasing sequence of delays. A system for ablation therapy delivery.

[0083]

[0099] Specific examples have been provided for purposes of illustration and explanation in various figures, but it should be apparent that variations such as different numbers of pulses, pulse packets, electrode sets, etc. are included in the present disclosure. Although specific medical devices are illustrated as examples in the present disclosure, it should be apparent that various other types of medical devices for various clinical applications can be used with the systems, methods, and waveforms described herein. For example, various types of medical devices having electrodes in the form of needles, rings, balloons, solid tips, curved shapes, etc. can be used with the devices, methods, and waveforms described herein to treat various types of benign or malignant tumors, to deliver ablation for kidney or other nerve resection, or to ablate various types of soft tissue. The electrodes of the catheter device or other medical devices described herein can generally be attached or connected to an electrical conductor for delivering electrical energy from a generator system, for example, a cable or connector cable for delivering a high voltage pulsed field ablation waveform.

[0084]

[0100] In an embodiment, ablation can generate an electric field that is insufficient to cause irreversible electroporation but sufficient to cause reversible electroporation. The cell membrane within the region of reversible electroporation is permeabilized, for example, to allow drug molecules or other therapeutic agents to pass into the cell for treating cancer. The term "ablation" as used herein is understood to include both reversible or temporary permeabilization of the cell membrane and irreversible or permanent permeabilization of the cell membrane. Depending on the clinical application, for example, tumor treatment, it may be desirable to destroy target cells for treatment or temporarily permeabilize the cell membrane for the passage of therapeutic agents such as drug molecules or viral vectors carrying gene therapy or other such agents known in the art for tumor treatment.

[0085]

[0101] The voltage amplitude of the waveforms described herein can range from about 300 V to about 10,000 V, including all values and ranges therebetween, depending on the application. The pulse width of the waveform can range from about 0.5 microseconds to about 150 microseconds, including all values and ranges therebetween. The phase delay can range from about 5 microseconds to about 3 milliseconds, including all values and ranges therebetween. The inter-pulse delay can range from about 15 microseconds to about 300 milliseconds, including all values and ranges therebetween, and the packet delay can range from 300 milliseconds to about 12 seconds, including all values and ranges therebetween.

[0086]

[0102] As used herein, the terms "about" and / or "approximately" when used with numerical values and / or ranges generally refer to numerical values and / or ranges close to the recited numerical values and / or ranges. In some cases, the terms "about" and "approximately" may mean within ±10% of the recited value. For example, in some cases, "about 100 [units]" may mean within ±10% of 100 (e.g., 90 to 110). The terms "about" and "approximately" may be used interchangeably with each other.

Claims

**Claim 1** A pulse generator configured to be coupled to an ablation device, the pulse generator being configured to generate a voltage pulse train including a plurality of two-phase pulses comprising each two-phase pulse of the plurality of two-phase pulses includes a positive pulse, a negative pulse, and a phase delay separating the positive pulse and the negative pulse successive two-phase pulses of the plurality of two-phase pulses are separated by an inter-pulse delay such that the plurality of two-phase pulses are separated by a plurality of inter-pulse delays the plurality of inter-pulse delays includes an increasing sequence of inter-pulse delays including a subset of successive inter-pulse delays that increase gradually device **Claim 2** The device according to claim 1, wherein the increasing sequence of inter-pulse delays increases at least according to an arithmetic progression **Claim 3** The device according to claim 1, wherein the increasing sequence of inter-pulse delays increases at least according to a geometric progression **Claim 4** The device according to any one of claims 1 to 3, wherein the increasing sequence of inter-pulse delays includes at least one-third of the total number of the plurality of inter-pulse delays **Claim 5** The device according to any one of claims 1 to 4, wherein the plurality of two-phase pulses includes up to about 30 two-phase pulses **Claim 6** The device according to any one of claims 1 to 5, wherein the positive pulse and the negative pulse of each two-phase pulse of the plurality of two-phase pulses include substantially rectangular pulses **Claim 7** The device according to claim 6, wherein the phase delay of each two-phase pulse of the plurality of two-phase pulses is at least three times the pulse width of the positive pulse and the negative pulse of each two-phase pulse of the plurality of two-phase pulses **Claim 8** The device according to any one of claims 1 to 5, wherein the positive pulse and the negative pulse of each two-phase pulse of the plurality of two-phase pulses include substantially trapezoidal pulses, and each positive pulse or negative pulse has a pulse width corresponding to a width or duration in which the voltage value of the positive pulse or the negative pulse is at least about 70% of the maximum amplitude value of the positive pulse or the negative pulse **Claim 9** The device according to claim 8, wherein the phase delay of each two-phase pulse of the plurality of two-phase pulses is at least three times the pulse width of the positive pulse and the negative pulse of each two-phase pulse of the plurality of two-phase pulses **Claim 10** The apparatus according to any one of claims 1 to 9, wherein the phase delay between the two-phase pulses of each of the plurality of two-phase pulses is at least about 5 microseconds.

11. The apparatus according to any one of claims 1 to 10, wherein the pulse width of each positive pulse or negative pulse of the plurality of two-phase pulses is between about 0.5 microseconds and about 150 microseconds.

12. The apparatus according to any one of claims 1 to 11, wherein the maximum amplitude of each positive pulse or negative pulse of the plurality of two-phase pulses is between about 300 volts and about 10,000 volts.

13. The pulse generator is configured to generate a plurality of packets, each packet of the plurality of packets includes the same pulse train as the pulse train, and consecutive packets of the plurality of packets are separated by an inter-packet delay of the plurality of inter-packet delays. The apparatus according to any one of claims 1 to 12.

14. The apparatus according to claim 13, wherein the plurality of packets includes a maximum of about 20 packets.

15. The apparatus according to claim 13, wherein each packet delay of the plurality of packet delays is between about 300 milliseconds and about 12 seconds.

16. A pulse generator configured to be coupled to an ablation device, the pulse generator being configured to generate a voltage pulse train including a plurality of two-phase pulses. including Each two-phase pulse of the plurality of two-phase pulses includes a positive pulse, a negative pulse, and a phase delay separating the positive pulse and the negative pulse. Consecutive two-phase pulses of the plurality of two-phase pulses are separated by an inter-pulse delay such that the plurality of two-phase pulses are separated by a plurality of inter-pulse delays. The plurality of inter-pulse delays includes a decreasing sequence of inter-pulse delays including a subset of consecutive inter-pulse delays that decrease gradually. device

17. The apparatus according to claim 16, wherein the decreasing sequence of inter-pulse delays decreases at least according to an arithmetic progression.

18. The apparatus according to claim 16, wherein the decreasing sequence of inter-pulse delays decreases at least according to a geometric progression.

19. The apparatus according to any one of claims 16 to 18, wherein the decreasing sequence of inter-pulse delays includes at least one-third of the total number of the plurality of inter-pulse delays.

20. The apparatus according to any one of claims 16 to 19, wherein the plurality of two-phase pulses includes a maximum of about 30 two-phase pulses.

21. The apparatus according to any one of claims 16 to 20, wherein the positive pulse and the negative pulse of each of the plurality of two-phase pulses include substantially rectangular pulses.

22. The apparatus according to claim 21, wherein the phase delay between the positive pulse and the negative pulse of each of the plurality of two-phase pulses is at least three times the pulse width of the positive pulse and the negative pulse of each of the plurality of two-phase pulses.

23. The apparatus according to any one of claims 16 to 20, wherein the positive pulse and the negative pulse of each of the plurality of two-phase pulses include substantially trapezoidal pulses, and each positive pulse or negative pulse has a pulse width corresponding to a width or duration in which the voltage value of the positive pulse or the negative pulse is at least about 70% of the maximum amplitude value of the positive pulse or the negative pulse.

24. The apparatus according to claim 23, wherein the phase delay between the positive pulse and the negative pulse of each of the plurality of two-phase pulses is at least three times the pulse width of the positive pulse and the negative pulse of each of the plurality of two-phase pulses.

25. The apparatus according to any one of claims 16 to 24, wherein the phase delay between the positive pulse and the negative pulse of each of the plurality of two-phase pulses is at least about 5 microseconds.

26. The apparatus according to any one of claims 16 to 25, wherein the pulse width of each positive pulse or negative pulse of the plurality of two-phase pulses is between about 0.5 microseconds and about 150 microseconds.

27. The apparatus according to any one of claims 16 to 26, wherein the maximum amplitude of each positive pulse or negative pulse of the plurality of two-phase pulses is between about 300 volts and about 10,000 volts.

28. The apparatus according to any one of claims 16 to 27, wherein the pulse generator is configured to generate a plurality of packets, each packet of the plurality of packets includes the same pulse train as the pulse train, and consecutive packets of the plurality of packets are separated by a packet delay of a plurality of packet delays.

29. The apparatus according to claim 27, wherein the plurality of packets includes a maximum of about 20 packets.

30. The apparatus according to claim 27, wherein each packet delay of the plurality of packet delays is between about 300 milliseconds and about 12 seconds.

31. A pulse generator configured to be coupled to an ablation device, the pulse generator being configured to generate a voltage pulse train including a plurality of two-phase pulses including each two-phase pulse of the plurality of two-phase pulses includes a positive pulse, a negative pulse, and a phase delay separating the positive pulse and the negative pulse successive two-phase pulses of the plurality of two-phase pulses are separated by an inter-pulse delay such that the plurality of two-phase pulses are separated by a plurality of inter-pulse delays the plurality of inter-pulse delays an increasing sequence of inter-pulse delays including a first subset of successive inter-pulse delays that increase gradually and a decreasing sequence of inter-pulse delays including a second subset of successive inter-pulse delays that decrease gradually including, an apparatus

32. The apparatus according to claim 31, wherein the increasing sequence of inter-pulse delays increases at least according to an arithmetic progression

33. The apparatus according to claim 31 or 32, wherein the decreasing sequence of inter-pulse delays decreases at least according to an arithmetic progression

34. The apparatus according to claim 31, wherein the increasing sequence of inter-pulse delays increases at least according to a geometric progression

35. The apparatus according to claim 31 or 32, wherein the decreasing sequence of inter-pulse delays decreases at least according to a geometric progression

36. The apparatus according to any one of claims 31 to 35, wherein the increasing sequence of inter-pulse delays includes at least one-third of the total number of the plurality of inter-pulse delays

37. The apparatus according to claim 36, wherein the decreasing sequence of inter-pulse delays includes at least one-third of the total number of the plurality of inter-pulse delays

38. The apparatus according to any one of claims 31 to 37, wherein the plurality of two-phase pulses includes at most about 30 two-phase pulses

39. The apparatus according to any one of claims 31 to 38, wherein the positive pulse and the negative pulse of each two-phase pulse of the plurality of two-phase pulses include substantially square pulses

40. The apparatus according to claim 39, wherein the phase delay of each two-phase pulse of the plurality of two-phase pulses is at least three times the pulse width of the positive pulse and the negative pulse of each two-phase pulse of the plurality of two-phase pulses

41. For the apparatus according to any one of claims 31 to 38, the positive pulse and the negative pulse of each two-phase pulse of the plurality of two-phase pulses include substantially trapezoidal pulses, and each positive pulse or negative pulse has a pulse width corresponding to a width or duration in which the voltage value of the positive pulse or the negative pulse is at least about 70% of the maximum amplitude value of the positive pulse or the negative pulse.

42. For the apparatus according to claim 41, the phase delay of each two-phase pulse of the plurality of two-phase pulses is at least three times the pulse width of the positive pulse and the negative pulse of each two-phase pulse of the plurality of two-phase pulses.

43. For the apparatus according to any one of claims 31 to 42, the phase delay of each two-phase pulse of the plurality of two-phase pulses is at least about 5 microseconds.

44. For the apparatus according to any one of claims 31 to 43, the pulse width of each positive pulse or negative pulse of the plurality of two-phase pulses is between about 0.5 microseconds and about 150 microseconds.

45. For the apparatus according to any one of claims 31 to 44, the maximum amplitude of each positive pulse or negative pulse of the plurality of two-phase pulses is between about 300 volts and about 10,000 volts.

46. The pulse generator is configured to generate a plurality of packets, each packet of the plurality of packets includes the same pulse train as the pulse train, and consecutive packets of the plurality of packets are separated by a packet delay of a plurality of packet delays. For the apparatus according to any one of claims 31 to 45.

47. For the apparatus according to claim 46, the plurality of packets includes a maximum of about 20 packets.

48. For the apparatus according to claim 46, each packet delay of the plurality of packet delays is between about 300 milliseconds and about 12 seconds.

49. A pulse generator configured to generate a two-phase pulse each including a positive pulse, a negative pulse, and an inter-pulse delay, A signal router operably coupled to the pulse generator and a plurality of electrode sets each including one or more electrodes, the signal router configured to: (1) set one or more switches to selectively apply the two-phase pulse generated by the pulse generator to one or more of the plurality of electrode sets; and (2) generate a series of trigger signals for triggering the pulse generator to generate the two-phase pulse, a signal router; A communication channel disposed between the signal router and the pulse generator, the communication channel configured to transmit the series of trigger signals to the pulse generator such that in response to the pulse generator receiving each trigger signal of the series of trigger signals, the pulse generator generates a pulse train and delivers the pulse train to the signal router for application to one or more of the plurality of electrode sets; comprising The pulse train includes a plurality of two-phase pulses, consecutive two-phase pulses of the plurality of two-phase pulses being separated by a pulse-to-pulse delay of a plurality of pulse-to-pulse delays, the plurality of pulse-to-pulse delays an increasing sequence of pulse-to-pulse delays including a subset of consecutively increasing pulse-to-pulse delays, or a decreasing sequence of pulse-to-pulse delays including a subset of consecutively decreasing pulse-to-pulse delays including at least one of a system.

50. The plurality of electrode sets includes at least a first electrode set and a second electrode set, the signal router sets the one or more switches, and the signal router applies a first plurality of packets to the first electrode set, (a) consecutive packets of the first plurality of packets being separated by a first packet delay, and (b) each packet of the first plurality of packets including a pulse train, applies a second plurality of packets to the second electrode set, (a) consecutive packets of the first plurality of packets being separated by a second packet delay, and (b) each packet of the first plurality of packets including a pulse train configured to generate the series of trigger signals as The system according to claim 49.

51. The system according to claim 50, wherein each packet of the second plurality of packets is applied during the first packet delay that separates consecutive packets of the first plurality of packets.

52. The system according to claim 50, wherein each two-phase pulse in the second plurality of packets is applied during the inter-pulse delay that separates consecutive two-phase pulses in the first plurality of packets.

53. The system according to any one of claims 49 to 52, wherein the signal router sets the one or more switches so that the signal router applies the pulse train generated in response to consecutive trigger signals to different electrode sets of the plurality of electrode sets, and is configured to generate the series of trigger signals.

54. A pulse generator configured to generate a two-phase pulse each including a positive pulse, a negative pulse, and an inter-pulse delay, A signal router operably coupled to the pulse generator and a plurality of electrode sets each including one or more electrodes, the signal router (1) setting one or more switches to selectively apply the two-phase pulse generated by the pulse generator to one or more electrode sets of the plurality of electrode sets, and (2) configured to generate a series of trigger signals for triggering the pulse generator to generate the two-phase pulse. A communication channel disposed between the signal router and the pulse generator, the communication channel being configured to transmit the series of trigger signals to the pulse generator such that the pulse generator generates a two-phase voltage pulse including a positive pulse and a negative pulse in response to receiving each trigger signal of the series of trigger signals, and having an inter-phase delay that separates the positive pulse and the negative pulse, and for at least two consecutive trigger signals, the signal router is configured to set the switch to selectively apply the two-phase voltage pulse to different electrode sets. A system comprising.

55. The system according to claim 54, wherein the inter-phase delay of each two-phase pulse of the plurality of two-phase pulses is at least three times the pulse width of the positive pulse or the negative pulse of each two-phase pulse.

56. The system according to claim 54, wherein the inter-phase delay of each two-phase pulse is at least about 5 microseconds.

57. Generating a voltage pulse train including a plurality of two-phase pulses using a pulse generator coupled to an ablation device Including, Each of the plurality of two-phase pulses includes a positive pulse, a negative pulse, and a phase delay separating the positive pulse and the negative pulse. Successive two-phase pulses of the plurality of two-phase pulses are separated by an inter-pulse delay such that the plurality of two-phase pulses are separated by a plurality of inter-pulse delays. The plurality of inter-pulse delays includes an increasing sequence of inter-pulse delays including a subset of successive inter-pulse delays that increase gradually. Method. **Claim 58** The method according to claim 57, wherein the plurality of inter-pulse delays further includes a decreasing sequence of inter-pulse delays including a subset of successive inter-pulse delays that decrease gradually. **Claim 59** The method according to claim 57 or 58, wherein the positive pulse and the negative pulse of each of the plurality of two-phase pulses include substantially square pulses. **Claim 60** The method according to claim 59, wherein the phase delay of each of the plurality of two-phase pulses is at least three times the pulse width of the positive pulse and the negative pulse of each of the plurality of two-phase pulses. **Claim 61** The method according to claim 57 or 58, wherein the positive pulse and the negative pulse of each of the plurality of two-phase pulses include substantially trapezoidal pulses, and each positive pulse or negative pulse has a pulse width corresponding to a width or duration in which the voltage value of the positive pulse or the negative pulse is at least about 70% of the maximum amplitude value of the positive pulse or the negative pulse. **Claim 62** The method according to claim 61, wherein the phase delay of each of the plurality of two-phase pulses is at least three times the pulse width of the positive pulse and the negative pulse of each of the plurality of two-phase pulses. **Claim 63** The method according to any one of claims 57 to 62, wherein the phase delay of each of the plurality of two-phase pulses is at least about 5 microseconds. **Claim 64** The method according to any one of claims 57 to 63, wherein the pulse width of each positive pulse or negative pulse of the plurality of two-phase pulses is between about 0.5 microseconds and about 150 microseconds. **Claim 65** The method according to any one of claims 57 to 64, wherein the maximum amplitude of each positive pulse or negative pulse of the plurality of two-phase pulses is between about 300 volts and about 10,000 volts.

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