Devices, systems, and methods for soft tissue ablation

Abstract

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

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 351,197, filed on June 10, 2022, entitled “APPARATUS, SYSTEMS AND METHODS FOR SOFT TISSUE ABLATION,” the disclosure of which is incorporated herein by reference in its entirety. Background Art

[0003] Soft tissue ablation is a therapeutic method associated with a variety of clinical applications, from cancer therapy delivery for ablation of several tumor types, to ablation of benign tumors such as fibroids, to treatment of diseased tissue that may lead to cancer, and to ablation of sympathetic or parasympathetic nerves in several cases. Thermal modalities such as radiofrequency (RF) ablation, cryoablation, or ablation using ultrasound have been employed in several applications. These generally carry the risk of collateral damage and considerable tissue necrosis in the treatment area.

[0004] Pulsed field ablation (also known as irreversible electroporation) has emerged as a potentially useful ablation modality that has been studied in some oncology applications and has recently been found to be fruitful in the context of cardiac ablation for the treatment of arrhythmias. This non-thermal ablation modality can be tissue selective and minimize collateral damage while also resulting in a natural healing process after ablation that preserves the extracellular matrix and overall tissue integrity. While suitable devices and waveforms have been designed in cardiac ablation, new devices and tools and waveforms that may be more suitable for soft tissue ablation are needed.

[0005] The present disclosure addresses the need for systems and waveforms for efficiently and effectively delivering pulsed field ablation therapy, particularly for soft tissue ablation. The pulsed field ablation process can be rapid while minimizing the collateral tissue damage often seen in heat-based therapies. At the same time, postoperative healing can be relatively rapid with minimal side effects. Summary of the invention

[0006] The present disclosure discloses systems and methods for treatment delivery in soft tissue ablation applications. Specifically, the systems, devices and methods of the present disclosure provide the generation of high-voltage pulse waveforms, which are delivered to electrodes arranged near tissues for rapid and efficient ablation of tissues. The electrodes can be arranged on a minimally invasive interventional device, which is introduced into the subject's anatomical structure, for example, by an endoscope, a laparoscope, an intravascular or a percutaneous access, and in an embodiment can include a reference electrode patch placed on the patient. The device can be used for a variety of clinical applications. Typically, an interventional device can have multiple electrodes for treatment delivery. In an embodiment, a device for pulse delivery may include a pulse generator for generating a pulse waveform. In an embodiment, a device for pulse delivery may also include a high-voltage signal router for routing pulses generated by a pulse generator to an appropriate electrode group. In an embodiment, the pulse generator and the signal router can be separate pieces of an instrument intended for modular connection, while in other embodiments, the pulse generator and the signal router can be integrated into a single piece of instrument in which all of the respective circuit boards reside. In an embodiment, the signal router may incorporate multiple output channels, where each channel is configured as two half-bridges, with the top switch and the bottom switch connected to the positive and negative terminals of the voltage source, respectively. In the baseline state, all switches are open and there is no electrical path for current flow. Each output channel of the signal router is intended to be connected to an electrode or a group of electrodes. When it is necessary to pair two channels as electrode terminals for ablation delivery, the top switch of one channel and the bottom switch of the other channel are closed to create an electrical path and enable pairing and voltage and current delivery across the appropriate device electrodes.

[0007] In an embodiment, the pulse waveform has specific characteristics as described in detail herein. In an embodiment, the waveform may include at least one pulse train having a plurality of biphasic, approximately rectangular pulses having a positive phase and a negative phase separated by an interphase delay (e.g., typically having approximately equal and opposite amplitudes). Thus, each complete biphasic pulse includes a positive phase, a negative phase, and a delay between the positive phase and the negative phase. In an embodiment, the interphase delay is greater than the pulse width of the positive phase or the negative phase. In an embodiment, the interphase delay may be at least about 3 times the pulse width of the positive phase or the negative phase, and in an embodiment, the interphase delay may be at least about 5 times the pulse width of the positive phase or the negative phase. In addition, the time delay between a complete biphasic pulse in a pulse train and the next biphasic pulse (referred to as a pulse-to-pulse delay) is not constant over the entire pulse train, but such a delay sequence has a variation in delay. For example, in an embodiment, for at least one-third of the number of such delays between pulses, the delay sequence follows an increasing pattern. In an embodiment, the pulse-to-pulse delay follows a decreasing pattern sequentially within at least one-third of the number of such delays between pulses.

[0008] In an embodiment, the increasing or decreasing sequence of pulse-to-pulse delays follows at least an arithmetic progression, e.g., the magnitude of the difference between one pulse-to-pulse delay and its immediately preceding pulse-to-pulse delay is at least a non-zero constant. In an embodiment, the increasing or decreasing sequence of pulse-to-pulse delays follows at least a geometric progression, e.g., the ratio of one pulse-to-pulse delay to its immediately preceding pulse-to-pulse delay is at least a constant greater than 1 in the case of an increasing sequence of delays, or is less than or equal to a constant less than 1 in the case of a decreasing sequence of delays. In an embodiment, in an increasing sequence of delays, the ratio of one pulse-to-pulse delay to its immediately preceding pulse-to-pulse delay is at least about 1.1. In an embodiment, in a decreasing sequence of delays, the ratio of one pulse-to-pulse delay to its immediately preceding pulse-to-pulse delay is less than about 0.9.

[0009] In an embodiment, in a given pulse train, the pulse-to-pulse delay sequentially follows an increasing pattern for at least one third of the number of such delays between pulses, and the pulse-to-pulse delay sequentially follows a decreasing pattern for at least one third of the number of such delays between pulses. In an embodiment, the entire waveform comprises a plurality of such pulse trains (each pulse train is also referred to as a pulse packet), wherein consecutive pulse packets are separated by a packet delay. In an embodiment, the packet delay is not constant but may vary over the packet.

[0010] In an embodiment, in each pulse of the pulse train, each phase (positive or negative) is trapezoidal or substantially trapezoidal in 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 pulse amplitude. A complete biphasic pulse includes a positive phase, a negative phase, and an interphase delay between the positive phase and the negative phase. In an embodiment, the interphase delay is greater than the width of the positive phase or the negative phase. In an embodiment, the interphase delay may be at least about 3 times the width of the positive phase or the negative phase, and in an embodiment, it may be at least about 5 times the width of the positive phase or the negative phase. In addition, the time delay between one complete biphasic pulse and the next biphasic pulse in the pulse train, or the pulse-to-pulse delay, is not constant over the entire pulse train, but for at least one-third of the number of such delays between pulses, such delay sequence follows an increasing pattern. In an embodiment, the pulse-to-pulse delay sequentially follows a decreasing pattern within at least one-third of the number of such delays between pulses. In an embodiment, in a given pulse train, the pulse-to-pulse delay sequentially follows an increasing pattern for at least one third of the number of such delays between pulses, and the pulse-to-pulse delay sequentially follows a decreasing pattern for at least one third of the number of such delays between pulses. In an embodiment, the entire waveform comprises a plurality of such pulse trains or packets, wherein consecutive pulse packets are separated by a packet delay. In an embodiment, the packet delay is not constant, but may vary over the packet.

[0011] In some embodiments, waveform delivery can be sequenced on a group of electrode pairs. In embodiments, if the waveform includes a group of pulse packets, the pulse packets can first be all delivered to one electrode pair, and then all pulse packets are delivered to the second electrode pair, etc. In other embodiments, pulse packets as defined herein can be staggered on 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, etc. Then, the second pulse packet can be delivered to the first electrode pair, and then the second pulse packet is delivered to the second electrode pair, and so on, all of which are carried out during the next packet delay. This process can continue until the complete waveform has been delivered to all electrode pairs.

[0012] In other embodiments, a single packet or pulse train may interleave pulses applied to different electrode pairs. In this case, the first pulse of the pulse train is applied to the first electrode pair, and during the pulse-to-pulse delay before the next pulse applied to the first electrode pair, the first pulse may be delivered to the second electrode pair, and so on. Then, the second pulse may be delivered to the first electrode pair, followed by the second pulse being delivered to the second electrode pair, and so on, all during the next pulse-to-pulse delay. This process may continue until the complete pulse train has been delivered to all electrode pairs, and the process may be repeated for each of the remaining pulse packets.

[0013] In an embodiment, a signal router may accomplish the task of managing the timing of various pulse deliveries to appropriate electrode pairs and / or managing the interleaving process. The logic for this may be implemented in electronic form, for example, on a microcontroller or other type of processing device. Typically, a generator system may include a pulse generator and a signal router. In an embodiment, once a particular device is connected to the generator system, the system may automatically detect the device and determine the specific waveform and sequencing scheme suitable for the device from a predetermined list of options. In an embodiment, the generator system may include only a signal generator, such as when an interventional device and ablation delivery only require a single pair of electrodes or electrode groups. In any embodiment described in the present disclosure, the term "electrode" may refer to an electrode directly on an interventional device or to a surface electrode patch or reference electrode placed on a patient.

[0014] A device for ablation delivery using the generator system of the present disclosure can be attached or connected to an electrical conductor that is attached to an electrical cable or connector cable for delivering electrical energy from the generator system to deliver the high voltage pulsed field ablation waveform described herein. Typically, this energy delivery is performed in a monopolar or bipolar mode. In a monopolar mode, a subset of electrodes has one electrical polarity, while a reference patch placed on a subject has an opposite electrical polarity. In a bipolar mode, two different subsets of electrodes are supplied with energy of opposite electrical polarity. In an embodiment, energy can be provided to multiple paired subsets of electrodes in a sequential manner for energy delivery. When a pulsed field ablation waveform is applied, the spatial distribution of the generated electric field determines the cell death area. Depending on the value of the irreversible electroporation threshold for a given target cell type, cells in a spatial region where the electric field strength is greater than the threshold are killed or ablated, while cells in other spatial regions where the electric field strength is lower than the threshold survive. In embodiments, ablation may generate an electric field insufficient to cause irreversible electroporation but sufficient to cause reversible electroporation, wherein cell membranes in the region of reversible electroporation are permeabilized to allow drug molecules or other therapeutic agents to enter the cells, for example to treat cancer.

[0015] In embodiments, depending on the application, the voltage amplitude of the waveforms described herein may be in the range of about 300V to about 10,000V, including all values ​​and ranges therebetween. The pulse width of the waveform may range from about 0.5 microseconds to about 150 microseconds, including all values ​​and ranges therebetween. The interphase delay may range from about 5 microseconds to about 3 milliseconds, including all values ​​and ranges therebetween. The pulse-to-pulse delay may range from about 15 microseconds to about 300 milliseconds, including all values ​​and ranges therebetween, and the packet delay may range from 300 milliseconds to about 12 seconds, including all values ​​and ranges therebetween.

[0016] In some embodiments, a device includes: a pulse generator configured to be coupled to an ablation device, the pulse generator configured to generate a voltage pulse train including a plurality of biphasic pulses, each biphasic pulse in the plurality of biphasic pulses including a positive pulse, a negative pulse, and an interphase delay separating the positive pulse and the negative pulse, consecutive biphasic pulses in the plurality of biphasic pulses are separated by pulse-to-pulse delays, such that the plurality of biphasic pulses are separated by a plurality of pulse-to-pulse delays, and the plurality of pulse-to-pulse delays include an increasing sequence of pulse-to-pulse delays, the increasing sequence of pulse-to-pulse delays including a subset of progressively increasing consecutive pulse-to-pulse delays.

[0017] In some embodiments, an apparatus includes: a pulse generator configured to be coupled to an ablation device, the pulse generator configured to generate a voltage pulse train comprising a plurality of biphasic pulses, each of the plurality of biphasic pulses comprising a positive pulse, a negative pulse, and an interphase delay separating the positive pulse and the negative pulse, consecutive biphasic pulses in the plurality of biphasic pulses being separated by pulse-to-pulse delays, such that the plurality of biphasic pulses are separated by a plurality of pulse-to-pulse delays, and the plurality of pulse-to-pulse delays comprising a decreasing sequence of pulse-to-pulse delays, the decreasing sequence of pulse-to-pulse delays comprising a subset of progressively decreasing consecutive pulse-to-pulse delays.

[0018] In some embodiments, a device includes: a pulse generator configured to be coupled to an ablation device, the pulse generator configured to generate a voltage pulse train including a plurality of biphasic pulses, each biphasic pulse in the plurality of biphasic pulses including a positive pulse, a negative pulse, and an interphase delay separating the positive pulse and the negative pulse, consecutive biphasic pulses in the plurality of biphasic pulses are separated by pulse-to-pulse delays, such that the plurality of biphasic pulses are separated by a plurality of pulse-to-pulse delays, and the plurality of pulse-to-pulse delays include: an increasing sequence of pulse-to-pulse delays including a first subset of progressively increasing consecutive pulse-to-pulse delays; and a decreasing sequence of pulse-to-pulse delays including a second subset of progressively decreasing consecutive pulse-to-pulse delays.

[0019] In some embodiments, a system includes: a pulse generator configured to generate biphasic pulses, each biphasic pulse 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 groups, each electrode group including one or more electrodes, the signal router being configured to: (1) set one or more switches to selectively apply the biphasic pulses generated by the pulse generator to one or more electrode groups in the plurality of electrode groups, and (2) generate a series of trigger signals to trigger the pulse generator to generate the biphasic pulses; 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 signal router. The column trigger signal is transmitted to the pulse generator, so that the pulse generator generates a pulse train in response to receiving each trigger signal in the series of trigger signals and delivers the pulse train to the signal router for application to one or more electrode groups in the plurality of electrode groups, the pulse train comprising a plurality of biphasic pulses, consecutive biphasic pulses in the plurality of biphasic pulses being separated by pulse-to-pulse delays in a plurality of pulse-to-pulse delays, the plurality of pulse-to-pulse delays comprising at least one of: an increasing sequence of pulse-to-pulse delays comprising a subset of consecutive pulse-to-pulse delays that are progressively increasing; or a decreasing sequence of pulse-to-pulse delays comprising a subset of consecutive pulse-to-pulse delays that are progressively decreasing.

[0020] In some embodiments, a method includes: using a pulse generator coupled to an ablation device to generate a voltage pulse train comprising a plurality of biphasic pulses, each of the plurality of biphasic pulses comprising a positive pulse, a negative pulse, and an interphase delay separating the positive pulse and the negative pulse, consecutive biphasic pulses in the plurality of biphasic pulses being separated by pulse-to-pulse delays, such that the plurality of biphasic pulses are separated by a plurality of pulse-to-pulse delays, and the plurality of pulse-to-pulse delays comprising an increasing sequence of pulse-to-pulse delays, the increasing sequence of pulse-to-pulse delays comprising a subset of progressively increasing consecutive pulse-to-pulse delays.

[0021] In some embodiments, a method includes: using a pulse generator coupled to an ablation device to generate a voltage pulse train comprising a plurality of biphasic pulses, each of the plurality of biphasic pulses comprising a positive pulse, a negative pulse, and an interphase delay separating the positive pulse and the negative pulse, consecutive biphasic pulses in the plurality of biphasic pulses being separated by pulse-to-pulse delays, such that the plurality of biphasic pulses are separated by a plurality of pulse-to-pulse delays, and the plurality of pulse-to-pulse delays comprising a decreasing sequence of pulse-to-pulse delays, the decreasing sequence of pulse-to-pulse delays comprising a subset of progressively decreasing consecutive pulse-to-pulse delays.

[0022] In some embodiments, a method includes: using a pulse generator coupled to an ablation device to generate a voltage pulse train including a plurality of biphasic pulses, each of the plurality of biphasic pulses including a positive pulse, a negative pulse, and an interphase delay separating the positive pulse and the negative pulse, consecutive biphasic pulses in the plurality of biphasic pulses are separated by pulse-to-pulse delays, so that the plurality of biphasic pulses are separated by a plurality of pulse-to-pulse delays, and the plurality of pulse-to-pulse delays include: an increasing sequence of pulse-to-pulse delays, the increasing sequence of pulse-to-pulse delays including a subset of progressively increasing consecutive pulse-to-pulse delays; and a decreasing sequence of pulse-to-pulse delays, the decreasing sequence of pulse-to-pulse delays including a subset of progressively decreasing consecutive pulse-to-pulse delays. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] Figure 1 is a schematic representation of an endoscope being passed through a subject's stomach and placed in the duodenum.

[0024] Figure 2 is a schematic diagram of a distal portion of an endoscope having multiple lumens, one of which is used for passage of a catheter device having electrodes for ablation delivery, according to an embodiment.

[0025] Figure 3 is an illustration of a catheter device with a needle electrode placed in an organ within a subject, wherein the figure also shows a reference patch, according to an embodiment.

[0026] Figure 4 An embodiment of a pulse train of the invention is shown with an increasing sequence of pulse-to-pulse delays.

[0027] Figure 5 An embodiment of a pulse train of the invention is shown with a decreasing sequence of pulse-to-pulse delays.

[0028] Figure 6 Embodiments of pulse trains of the present invention are shown having both an increasing sequence of pulse-to-pulse delays and a decreasing sequence of pulse-to-pulse delays.

[0029] Figure 7 A trapezoidal biphasic pulse is shown with pulse width and pulse basis elements identified in accordance with an embodiment.

[0030] Figure 8 An embodiment of a trapezoidal pulse train of the present disclosure is shown with an increasing sequence of pulse-to-pulse delays.

[0031] Fig. 9 An embodiment of a trapezoidal pulse train of the present disclosure is shown with a decreasing sequence of pulse-to-pulse delays.

[0032] Fig.10An embodiment of a trapezoidal pulse train of the present disclosure is shown having an increasing sequence of pulse-to-pulse delays and a decreasing sequence of pulse-to-pulse delays.

[0033] Fig.11 A waveform of multiple packets with a burst having a packet delay across the series of packets is shown in accordance with an embodiment.

[0034] Fig.12 Shown is a sequential delivery of a waveform in the form of multiple pulse packets delivered to multiple electrode pairs in accordance with an embodiment.

[0035] Fig.13 A sequential delivery of a pulse train of waveforms in accordance with an embodiment is shown in the form of individual pulses of the pulse train delivered to a plurality of electrode pairs in an interleaved manner, respectively.

[0036] Fig.14 is a schematic diagram of a generator system in the form of a pulse generator and a signal router for delivering a pulsed field ablation waveform to a medical device according to an embodiment.

[0037] Fig.15 is a schematic diagram of a control circuit for operation of a single channel of a generator system according to an embodiment of the present disclosure.

[0038] Fig.16 A half-bridge topology of two channels of a generator system according to an embodiment is shown, which can be combined to deliver a pulsed field ablation waveform to a pair of electrodes connected to the two channels respectively.

[0039] Fig.17 The operation of the system of the present disclosure in one embodiment is shown. DETAILED DESCRIPTION

[0040] Embodiments of the present disclosure generally provide for delivery of customized waveforms disclosed herein for pulsed field ablation of soft tissue structures, for example, for cancer therapy delivery for ablation of several tumor types, for ablation of benign tumors such as fibroids, for treatment of diseased tissue that may lead to cancer, or for ablation of sympathetic or parasympathetic nerves, among others.

[0041] For example, for the treatment of pancreatic tumors, endoscopic access can be achieved to the stomach or duodenum, and adjacent organs such as the pancreas can then be accessed through appropriate punctures. Figure 1 Endoscope 101 is shown inserted through the mouth of a subject and down the esophagus 103 to be positioned at the duodenum 107 after passing through the stomach 105. This type of positioning may place the endoscope near the pancreas.

[0042] For the purpose of illustration and examples, Figure 2The distal end portion of an endoscope 204 having multiple lumens 205, 207, and 209 is shown. Lumens 205 and / or 207 may be used for passage of optical imaging fibers or cameras or ultrasound imaging catheters. The lumen or passage 209 shown is used for passage of a catheter device 220, which itself has two lumens carrying needles or needle wires 213 and 215. The endoscope can be manipulated to an appropriate position in the stomach or duodenum, which facilitates the proper deployment and placement of needles 213 and 215. In use, the endoscope 204 reaches the stomach and / or duodenum through the mouth and esophagus, and is placed adjacent to or near a tissue wall, such as near the pancreas. The catheter 220 is extended under image guidance from optical or ultrasound imaging, and is positioned in an appropriate position to enter an appropriate pancreatic site, which is performed using an appropriate imaging device used with the endoscope. Needles 213 and 215 extend from the catheter device 220 for piercing the stomach wall and entering the pancreas to approach the target tumor site. Once needles 213 and 215 are properly positioned in the pancreas, pulsed field ablation is delivered through the needles from a generator system (described below) connected to catheter 220 .

[0043] Figure 3 302 is an illustration of a catheter device 302 according to an embodiment, which is placed near an anatomical organ 310 within a subject's body 320 (shown in cross section in the figure). Needles 304 and 306 extend from the device lumen to penetrate and enter the organ 310. In one embodiment, the needle can be used as a single contact electrode (i.e., polarized with one electrical polarity) and electrically paired with a reference electrode patch 325 (polarized with the opposite electrical polarity) to deliver pulsed field ablation in a monopolar (also known as monopolar) mode. In other embodiments, needles 304 and 306 can be used as a bipolar electrode pair for bipolar pulsed field ablation delivery. Applying a pulsed field ablation waveform to the electrodes results in the generation of an electric field, and depending on the irreversible electroporation threshold of the tissue, a lesion zone, such as a zone with a boundary 313, is generated as a result of ablation. If a larger treatment volume or area is required, needles 304 and 306 can be retracted, catheter 302 is moved and positioned at a different location, needles 304 and 306 are inserted at the new location, and treatment is delivered at the new location.

[0044] Figure 4An embodiment of a pulse train of the present invention having an increasing sequence of pulse-to-pulse delays is shown. The figure shows a biphasic voltage pulse train as a time sequence of four pulses 421, 423, 425 and 427. Each complete biphasic pulse, such as 421, has a positive phase (represented by 401) and a negative phase (represented by 403) separated by an interphase time delay (represented by 405). The pulse train shown has pulses of substantially rectangular form for each phase. The pulse width (represented by 440 in the figure) is the effective duration of each phase. In an embodiment, the interphase delay may be greater than the width of the positive phase or the negative phase. In an embodiment, the interphase delay may be at least about 3 times the width of the positive phase or the negative phase, and in an embodiment, it may be at least about 5 times the width of the positive phase or the negative phase. In an embodiment, the corners of the pulses (such as those indicated by 444 and 446 in the figure) may have a rounded shape (not shown). There is a time delay interval between consecutive biphasic pulses referred to as a pulse-to-pulse delay. As Figure 4 , a pulse-to-pulse delay 408 (measured from the end of pulse 421 to the start of pulse 423) separates first pulse 421 and second pulse 423, a pulse-to-pulse delay 410 separates pulses 423 and 425, and a pulse-to-pulse delay 412 separates pulses 425 and 427. The pulse-to-pulse delays typically vary over a pulse train and follow an increasing or decreasing pattern in at least a portion of a pulse train. Figure 4 The schematic diagram in shows an increasing sequence of pulse-to-pulse delays over time; thus, pulse-to-pulse delay 412 is greater than pulse-to-pulse delay 410 , and pulse-to-pulse delay 410 is greater than pulse-to-pulse delay 408 .

[0045] In embodiments, the increasing sequence of pulse-to-pulse delays follows at least an arithmetic progression, e.g., the difference between one pulse-to-pulse delay and its immediately preceding pulse-to-pulse delay is at least a non-zero constant. In embodiments, the increasing sequence of delays follows at least a geometric progression, e.g., the ratio of one pulse-to-pulse delay to its immediately preceding pulse-to-pulse delay is at least a constant greater than 1. In embodiments, the difference between one pulse-to-pulse delay and its immediately preceding pulse-to-pulse delay in the increasing sequence of pulse-to-pulse delays is at least about 10 microseconds, and in other embodiments, it is at least about 100 microseconds. In embodiments, the ratio of one pulse-to-pulse delay to its immediately preceding pulse-to-pulse delay in the increasing sequence of pulse-to-pulse delays is at least about 1.1. In embodiments, the pulse-to-pulse delays sequentially follow an increasing pattern for at least one-third of the total number of such delays between adjacent pulses in a pulse train.

[0046] Figure 5An embodiment of a pulse train of the present invention with a decreasing sequence of pulse-to-pulse delays is shown. The figure shows a biphasic voltage pulse train as a time sequence with four pulses 521, 523, 525 and 527. Each complete biphasic pulse, such as 521, has a positive phase (indicated by 501) and a negative phase (indicated by 503) separated by an interphase time delay (indicated by 505). The pulse train shown has pulses of substantially rectangular form for each phase. As previously described, in embodiments, the interphase delay may be greater than the width of the positive phase or the negative phase. In embodiments, the interphase delay may be at least about 3 times the width of the positive phase or the negative phase, and in embodiments, it may be at least about 5 times the width of the positive phase or the negative phase. A pulse-to-pulse time delay 508 separates a first pulse 521 from a second pulse 523, a pulse-to-pulse delay 510 separates pulse 523 from pulse 525, and a pulse-to-pulse delay 512 separates pulse 525 from pulse 527. Figure 5 The schematic diagram in shows a decreasing sequence of pulse-to-pulse delays over time; thus, pulse-to-pulse delay 512 is less than pulse-to-pulse delay 510 , and pulse-to-pulse delay 510 is less than pulse-to-pulse delay 508 .

[0047] In embodiments, the decreasing sequence of delays follows at least an arithmetic progression, e.g., the magnitude of the difference between one pulse-to-pulse delay and its immediately preceding pulse-to-pulse delay is at least a non-zero constant. In embodiments, the decreasing sequence of delays follows at least a geometric progression, e.g., the ratio of one pulse-to-pulse delay to its immediately preceding pulse-to-pulse delay is less than or equal to a constant less than 1. In embodiments, the magnitude of the difference between one pulse-to-pulse delay and its immediately preceding pulse-to-pulse delay in the decreasing sequence of pulse-to-pulse delays is at least about 10 microseconds, while in other embodiments, it is at least about 100 microseconds. In embodiments, the ratio of one pulse-to-pulse delay to its immediately preceding pulse-to-pulse delay in the decreasing sequence of delays is less than about 0.9. In embodiments, the pulse-to-pulse delays sequentially follow a decreasing pattern for at least one-third of the total number of such delays between adjacent pulses in a pulse train.

[0048] Figure 6An embodiment of a pulse train of the present invention having both an increasing sequence of pulse-to-pulse delays and a decreasing sequence of pulse-to-pulse delays is illustrated. The figure shows seven biphasic pulses 600, 602, 604, 606, 608, 610, and 612. Each biphasic pulse has a positive phase, a negative phase, and an interphase delay. As previously described, the pulse train shown has pulses of substantially rectangular form for each phase. In an embodiment, the interphase delay may be greater than the width of the positive phase or the negative phase. In an embodiment, the interphase delay may be at least about 3 times the width of the positive phase or the negative phase, and in an embodiment, it may be at least about 5 times the width of the positive phase or the negative phase. Pulses 600 and 602 are separated by a pulse-to-pulse delay 613, pulses 602 and 604 are separated by a pulse-to-pulse delay 615, pulses 604 and 606 are separated by a pulse-to-pulse delay 617, pulses 606 and 608 are separated by a pulse-to-pulse delay 621, pulses 608 and 610 are separated by a pulse-to-pulse delay 623, and pulses 610 and 612 are separated by a pulse-to-pulse delay 625. Pulse-to-pulse delays 613, 615, 617 represent an increasing sequence of pulse-to-pulse delays, and pulse-to-pulse delays 621, 623, and 625 represent a decreasing sequence of pulse-to-pulse delays. In an embodiment, the increasing or decreasing sequence of pulse-to-pulse delays at least follows an arithmetic progression, e.g., the magnitude of the difference between one pulse-to-pulse delay and its immediately preceding pulse-to-pulse delay is at least a non-zero constant. In embodiments, the increasing or decreasing sequence of pulse-to-pulse delays follows at least a geometric progression, e.g., the ratio of one pulse-to-pulse delay to its immediately preceding pulse-to-pulse delay is at least a constant greater than 1 in the case of an increasing sequence of pulse-to-pulse delays, or is less than or equal to a constant less than 1 in the case of a decreasing sequence of pulse-to-pulse delays. In embodiments, in an increasing sequence of pulse-to-pulse delays, the difference between one pulse-to-pulse delay and its immediately preceding pulse-to-pulse delay is at least about 10 microseconds, while in other embodiments, it is at least about 100 microseconds. In embodiments, in an increasing sequence of delays, the ratio of one pulse-to-pulse delay to its immediately preceding pulse-to-pulse delay is at least about 1.1. In embodiments, in a decreasing sequence of pulse-to-pulse delays, the magnitude of the difference between one pulse-to-pulse delay and its immediately preceding pulse-to-pulse delay is at least about 10 microseconds, while in other embodiments, it is at least about 100 microseconds. In an embodiment, in a decreasing sequence of pulse-to-pulse delays, the ratio of one pulse-to-pulse delay to its immediately preceding pulse-to-pulse delay is less than about 0.9. In an embodiment, in a given pulse train, for at least one third of the total number of such delays between adjacent pulses, the pulse-to-pulse delays sequentially follow an increasing pattern, and for at least one third of the total number of such delays between adjacent pulses, the pulse-to-pulse delays sequentially follow a decreasing pattern.

[0049] In embodiments, the pulse widths of the waveforms described herein may range from about 0.5 microseconds to about 150 microseconds, including all values ​​and ranges therebetween. In embodiments, the interphase delay may range from about 5 microseconds to about 3 milliseconds, including all values ​​and ranges therebetween. In embodiments, the pulse-to-pulse delay may range from about 15 microseconds to about 300 milliseconds, including all values ​​and ranges therebetween.

[0050] Figure 7 A trapezoidal biphasic voltage pulse is shown with highlighted pulse width and pulse base according to an embodiment. Figure 7 The trapezoidal voltage pulse shown has a positive phase 703 and a negative phase 705 separated by an interphase delay 707. Thus, the complete trapezoidal biphasic pulse includes a positive trapezoidal phase, a negative trapezoidal phase, and a delay between the positive and negative phases. The pulse width of a trapezoidal pulse may be the width of one phase of the pulse where the voltage has a value greater than approximately 70% of the maximum amplitude of that phase. In the accompanying drawings, this is marked by a time interval 712 at which the positive phase 703 has a value greater than or equal to the value indicated by line 703, which marks 70% of the value of the maximum value 710 (i.e., 70% of the amplitude value). In the embodiment shown, the pulse width is equal or approximately equal in the positive and negative phases. In an embodiment, the interphase delay may be greater than the pulse width of the positive or negative phase. In an embodiment, the interphase delay may be at least about 3 times the pulse width of the positive or negative phase, and in an embodiment, it may be at least about 5 times the pulse width of the positive or negative phase.

[0051] In an embodiment, the corners of the pulses (such as those indicated by 723 and 725 in the figure) can have a rounded shape (not shown). In addition, the base width of the pulses is Figure 7 denoted by 715. This represents a time interval 715 for which one phase of the pulse has a value greater than 5% of the magnitude of maximum value 710, as shown by line 712. In an embodiment, the base width of the trapezoidal pulse may be wider than the pulse width by up to about 6 microseconds.

[0052] In an embodiment, the pulse train may include a sequence of trapezoidal pulses. Figure 8 An embodiment of a trapezoidal pulse train of the present disclosure is shown with an increasing sequence of pulse-to-pulse delays. The figure shows four trapezoidal pulses 800, 802, 804, and 806. Each complete biphasic pulse, such as 800, has a positive phase (represented by 808) and a negative phase (represented by 810) separated by an interphase time delay (represented by 814). The pulse train shown has pulses in each phase in the form of a trapezoid, with pulse widths and base widths that are the same as the reference Figure 7In an embodiment, the interphase delay may be greater than the pulse width of the positive phase or the negative phase. In an embodiment, the interphase delay may be at least about 3 times the pulse width of the positive phase or the negative phase, and in an embodiment, it may be at least about 5 times the pulse width of the positive phase or the negative phase. There is a time delay interval between consecutive biphasic pulses called the pulse-to-pulse delay. Figure 8 , a pulse-to-pulse time delay 816 (measured from the end of pulse 800 to the start of pulse 802) separates first pulse 800 from second pulse 802, a pulse-to-pulse delay 818 separates pulses 802 from 804, and a pulse-to-pulse delay 820 separates pulses 804 from 806. The pulse-to-pulse delay may vary over a pulse train and follow an increasing or decreasing pattern in at least a portion of a pulse train. Figure 8 The schematic diagram in shows an increasing sequence of pulse-to-pulse delays over time; thus, pulse-to-pulse delay 818 is greater than pulse-to-pulse delay 816, and pulse-to-pulse delay 820 is greater than pulse-to-pulse delay 818.

[0053] In embodiments, the increasing sequence of pulse-to-pulse delays follows at least an arithmetic progression, e.g., the difference between one pulse-to-pulse delay and its immediately preceding pulse-to-pulse delay is at least a non-zero constant. In embodiments, the increasing sequence of delays follows at least a geometric progression, e.g., the ratio of one pulse-to-pulse delay to its immediately preceding pulse-to-pulse delay is at least a constant greater than 1. In embodiments, in the increasing sequence of pulse-to-pulse delays, the difference between one pulse-to-pulse delay and its immediately preceding pulse-to-pulse delay is at least about 10 microseconds, and in other embodiments, it is at least about 100 microseconds. In embodiments, in the increasing sequence of delays, the ratio of one pulse-to-pulse delay to its immediately preceding pulse-to-pulse delay is at least about 1.1. In embodiments, the pulse-to-pulse delays sequentially follow an increasing pattern for at least one-third of the total number of such delays between adjacent pulses in a pulse train.

[0054] Fig. 9 An embodiment of a trapezoidal pulse train of the present disclosure is shown with a decreasing sequence of pulse-to-pulse delays. The figure shows a biphasic voltage pulse train as a time sequence of four pulses 900, 902, 904, and 906. Each complete biphasic pulse, such as 900, has a positive phase (represented by 908) and a negative phase (represented by 910) separated by an inter-phase time delay (represented by 913). The pulse train shown has pulses in each phase in a trapezoidal form with pulse widths and base widths that are the same as the reference Figure 7Similar to the above. In an embodiment, the interphase delay can be greater than the pulse width of the positive phase or the negative phase. In an embodiment, the interphase delay can be at least about 3 times the pulse width of the positive phase or the negative phase, and in an embodiment, it can be at least about 5 times the pulse width of the positive phase or the negative phase. Pulse-to-pulse time delay 915 separates the first pulse 900 from the second pulse 902, pulse-to-pulse delay 917 separates pulses 902 from 904, and pulse-to-pulse delay 919 separates pulses 904 from 906. Fig. 9 The schematic diagram in shows a decreasing sequence of pulse-to-pulse delays over time; thus, pulse-to-pulse delay 917 is less than pulse-to-pulse delay 915, and pulse-to-pulse delay 919 is less than pulse-to-pulse delay 917.

[0055] In embodiments, the decreasing sequence of pulse-to-pulse delays follows at least an arithmetic progression, e.g., the magnitude of the difference between one pulse-to-pulse delay and its immediately preceding pulse-to-pulse delay is at least a non-zero constant. In embodiments, the decreasing sequence of pulse-to-pulse delays follows at least a geometric progression, e.g., the ratio of one pulse-to-pulse delay to its immediately preceding pulse-to-pulse delay is less than or equal to a constant less than 1. In embodiments, in the decreasing sequence of pulse-to-pulse delays, the magnitude of the difference between one pulse-to-pulse delay and its immediately preceding pulse-to-pulse delay is at least about 10 microseconds, and in other embodiments, it is at least about 100 microseconds. In embodiments, in the decreasing sequence of pulse-to-pulse delays, the ratio of one pulse-to-pulse delay to its immediately preceding pulse-to-pulse delay is less than about 0.9. In embodiments, the pulse-to-pulse delays sequentially follow a decreasing pattern for at least one-third of the total number of such delays between adjacent pulses in a pulse train.

[0056] Fig.10An embodiment of a trapezoidal pulse train of the present disclosure is shown, having an increasing sequence of pulse-to-pulse delays and a decreasing sequence of pulse-to-pulse delays. The figure shows 7 biphasic pulses 1001, 1002, 1003, 1004, 1005, 1006, and 1007. Each complete biphasic pulse has a positive phase, a negative phase, and an interphase delay. As previously described, the pulse train shown has pulses in a trapezoidal form for each phase. In some embodiments, the interphase delay may be greater than the pulse width of the positive phase or the negative phase. In an embodiment, the interphase delay may be at least about 3 times the pulse width of the positive phase or the negative phase, and in an embodiment, it may be at least about 5 times the pulse width of the positive phase or the negative phase. Pulses 1001 and 1002 are separated by a pulse-to-pulse delay 1010, pulses 1002 and 1003 are separated by a pulse-to-pulse delay 1012, pulses 1003 and 1004 are separated by a pulse-to-pulse delay 1014, pulses 1004 and 1005 are separated by a pulse-to-pulse delay 1017, pulses 1005 and 1006 are separated by a pulse-to-pulse delay 1019, and pulses 1006 and 1007 are separated by a pulse-to-pulse delay 1021. Pulse-to-pulse delays 1010, 1012, and 1014 represent an increasing sequence of pulse-to-pulse delays, and pulse-to-pulse delays 1017, 1019, and 1021 represent a decreasing sequence of pulse-to-pulse delays. In an embodiment, the increasing or decreasing sequence of pulse-to-pulse delays at least follows an arithmetic progression, e.g., the magnitude of the difference between one pulse-to-pulse delay and its immediately preceding pulse-to-pulse delay is at least a non-zero constant. In embodiments, the increasing or decreasing sequence of pulse-to-pulse delays follows at least a geometric progression, e.g., the ratio of one pulse-to-pulse delay to its immediately preceding pulse-to-pulse delay is at least a constant greater than 1 in the case of an increasing sequence of pulse-to-pulse delays, or is less than or equal to a constant less than 1 in the case of a decreasing sequence of pulse-to-pulse delays. In embodiments, the ratio of one pulse-to-pulse delay to its immediately preceding pulse-to-pulse delay in the increasing sequence of pulse-to-pulse delays is at least about 1.1. In embodiments, the ratio of one pulse-to-pulse delay to its immediately preceding pulse-to-pulse delay in the decreasing sequence of pulse-to-pulse delays is less than about 0.9. In embodiments, the magnitude of the difference between one pulse-to-pulse delay and its immediately preceding pulse-to-pulse delay in the increasing or decreasing sequence of pulse-to-pulse delays is at least about 10 microseconds, and in other embodiments, is at least about 100 microseconds. In an embodiment, in a given pulse train, for at least one third of the total number of such delays between adjacent pulses, the pulse-to-pulse delay sequentially follows an increasing pattern, and for at least one third of the total number of such delays between adjacent pulses, the pulse-to-pulse delay sequentially follows a decreasing pattern.

[0057] In an embodiment, the pulse width of the trapezoidal waveform described herein may range from about 0.5 microseconds to about 150 microseconds, including all values ​​and ranges therebetween. The inter-phase delay may range from about 5 microseconds to about 3 milliseconds, including all values ​​and ranges therebetween. The pulse-to-pulse delay may range from about 15 microseconds to about 300 milliseconds, including all values ​​and ranges therebetween.

[0058] Fig.11 1 shows a waveform of multiple packets with pulse trains, where the packet delay spans a series of packets, according to an embodiment. The figure shows multiple pulse trains or packets 1102, 1104, and 1106. In various embodiments, each pulse train or pulse packet (e.g., 1102, 1104, or 1106) includes a series of pulses 1100, which can be similar to Figures 4 to 6 and Figures 8 to 10 The packet delay separates one pulse packet from the next pulse packet. For example, packet delay 1111 separates packets 1102 and 1104, while packet delay 1113 separates packets 1104 and 1106. In embodiments, the packet delay may be non-constant or vary across a series of packets. In embodiments, each packet delay may range from about 300 milliseconds to about 12 seconds, including all values ​​and ranges therebetween.

[0059] In an embodiment, the number of complete biphasic pulses in each pulse train of the present disclosure can be in the range of 1 to about 30, including all values ​​and ranges therebetween, and the number of pulse packets can be in the range of 1 to about 20, including all values ​​and ranges therebetween.

[0060] The waveforms disclosed herein can be applied to more than one electrode set in various formats. For example, Fig.12 The waveform is sequentially delivered to multiple electrode pairs in the form of multiple pulse packets. In the figure, pulse packets 1202 and 1208 represent two pulse packets applied to the first electrode group. Each pulse packet (e.g., 1202 or 1208) includes a pulse train 1201. The packet delay between packets 1202 and 1208 is Fig.12 During the packet delay, pulse packets 1204 and 1206 can be sequentially applied to the second electrode group and the third electrode group, respectively. Subsequently, after the second packet 1208 is applied to the first electrode group, packets 1210 and 1212 are applied to the second electrode group and the third electrode group, respectively. Obviously, the delivery process extends to multiple pulse packets and multiple electrode groups, and is not limited to Fig.12 In embodiments, the number of different electrode groups to which such waveforms are applied can be in the range of 1 to about 20, including all values ​​and ranges therebetween.

[0061] Other methods and sequences of waveform delivery may be constructed based on the teachings herein. For example, Fig.13 A sequential delivery of a pulse train of waveforms is shown in the form of individual pulses of the pulse train being delivered to multiple electrode pairs in an interleaved manner. In the accompanying figure, biphasic pulses 1301, 1307 and 1313 represent three complete biphasic pulses of a pulse train applied to a first electrode group. A time interval or pulse-to-pulse delay 1317 separates pulses 1301 from 1307, while a time interval or pulse-to-pulse delay 1319 separates pulses 1307 from 1313. During time interval or delay 1317, biphasic pulses 1303 and 1305 are applied to the second electrode group and the third electrode group, respectively. During time interval or delay 1319, biphasic pulses 1309 and 1311 are applied to the second electrode group and the third electrode group, respectively. Obviously, the process of electrode interleaved delivery of a pulse train extends to multiple pulse numbers and pulse-to-pulse delays and multiple electrode groups, and is not limited to. Fig.13 In embodiments, the number of different electrode groups to which such waveforms are applied can be in the range of 1 to about 20, including all values ​​and ranges therebetween.

[0062] Fig.141 is a schematic diagram of a generator system according to an embodiment, the generator system including a pulse generator and a signal router for delivering a pulsed field ablation waveform to a medical device. The figure shows a pulse generator 1400 in communication with a signal router 1402. The signal router 1402 includes a control and timing unit, such as a microcontroller. In an embodiment, the pulse generator 1400 may include a microcontroller or a field programmable gate array (FPGA) for timing control of pulses and / or pulse trains, and in an embodiment, the pulse generator 1400 may include 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; in an embodiment, there may be one or more such channels for communication. In an embodiment, there may also be a separate connection (not shown) between the pulse generator 1400 and the signal router 1402 for sending a trigger signal from the signal router 1402 to the pulse generator 1400. In an embodiment, the communication channel 1406 may also be used to deliver a trigger signal from the signal router 1402 to the pulse generator 1400. The communication channel 1406 may define one or more requests for a specific pulse or pulse train from the signal generator 1400 based on a predetermined set of communication signals or words. When a trigger signal (corresponding to a request for a defined pulse or pulse train) is sent from the signal router 1402 to the pulse generator 1400, the pulse generator 1400 generates an appropriate pulse or pulse train and sends it to the signal router 1402 via the high voltage link 1410. The signal router 1402 controls the timing of opening and closing the appropriate switches to route the input pulse or pulse train from the pulse generator 1400 to the appropriate set or subset of channels 1415 so as to deliver the pulse waveform to the desired medical device 1419, such as for tissue ablation. In an embodiment, the number of channels 1415 may be in the range from 2 to about 20, including all values ​​and ranges therebetween. In an embodiment, the output of the channels 1415 may be connected to an appropriate medical device electrode, and in an embodiment, at least one of the channels 1415 may be connected to a reference electrode patch, such as for placement on the body surface of a subject. In embodiments where only two output channels are desired, the signal router 1402 may not be needed, and in such cases, only the pulse generator 1400 comprises the generator system. In embodiments, the signal router 1402 or the pulse generator 1400 or both may include a transformer on the output path for proper electrical isolation. In embodiments, the signal router 1402 may include a relay that closes only during ablation delivery, for example, as additional protection to ensure that output occurs only when desired. In embodiments, the generator system may be modular such that the pulse generator 1400 or the signal router 1402 may be swapped out for a different similar component, for example, as may need to be repaired or replaced.In embodiments, the pulse generator 1400 and the signal router 1402 may be separate units or boxes with appropriate cabling between the two, while in other embodiments, the pulse generator 1400 and the signal router 1402 may be housed as separate electronic board sets within a single unit or box. In embodiments, the signal router 1402 and / or the pulse generator 1400 may have a user interface for user input of parameters such as voltage amplitude, medical device type, number of electrode sets, and other operating parameters. This user input may be used by the generator system to deliver the appropriate waveform.

[0063] Fig.15 1 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 terminals 1500 and 1502 represent the positive terminal and negative terminal of a high voltage source (e.g., a capacitor or transformer depending on the embodiment), respectively. In an embodiment, the high voltage source may be a pulse generator. High power switches 1520 and 1522 are connected between the terminals as shown; for example, these may include high power solid-state switches, such as insulated gate bipolar transistors (IGBTs) or metal oxide field effect transistors (MOSFETs). Switches 1520 and 1522 are controlled by respective drive circuits 1508 and 1510, which are used to turn the switches on or off, and drive circuits 1508 and 1510 are driven by FPGAs or microcontrollers 1506, which control the opening and closing timing of the switches based on the desired waveform output. In an embodiment, specific pulses and / or pulse train details are sent from microcontroller 1513 to FPGA or microcontroller 1506. In an embodiment, the path from terminal 1500 to terminal 1522 may include a current limiting resistor to mitigate any short circuits. At a given time, only one of the switches 1520 or 1522 is closed, while the other remains open. In this way, the channel output 1518 is connected to the positive terminal or the negative terminal. For an approximately constant voltage source at the terminals, the shape of the pulse can be rectangular, trapezoidal, or substantially rectangular or trapezoidal, depending on the rise time or switching time of the switches 1520 and 1522. In an embodiment, the output path 1518 may incorporate a filtering circuit (not shown) to limit voltage or current spikes that can round the corners of the pulse, as previously discussed.

[0064] By Fig.15 A single channel topology is paired with a second similar channel to establish current paths and channel pairing for waveform output between any pair of channels connected to separate device electrodes or electrode groups. Fig.16 A half-bridge topology of two channels of a generator system according to an embodiment is shown, which can be combined to deliver a pulsed field ablation waveform to a pair of electrodes or electrode groups connected to the two channels, respectively. Fig.16The output channel 1620 in is connected to a half-bridge topology, which includes switches 1603 and 1605, which are respectively connected to the positive terminal 1615 and the negative terminal 1617 of the high voltage source. Similarly, Fig.16 Output channel 1622 in is connected to a half-bridge topology including switches 1609 and 1611, which are connected to positive terminal 1615 and negative terminal 1617 of the same high voltage source, respectively. When switches 1603 and 1611 are closed and 1605 and 1609 are open, a positive voltage pulse is delivered to output channels 1620 and 1622, at which time a current path is established through tissue impedance between the device electrodes connected to channels 1620 and 1622. Similarly, when switches 1605 and 1609 are closed and 1603 and 1611 are open, a negative voltage pulse is delivered to output channels 1620 and 1622. By appropriate timing of the opening and closing of the switches, the desired complete biphasic pulse can be generated.

[0065] Fig.17 The operation of the system for waveform delivery of the present disclosure is shown in one embodiment. When a user passes a generator system (similar to other generator systems described herein, such as Fig.14When the user interface of the generator system (shown in FIG. 1 ) enables waveform delivery, at 1703, the 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 disabled, a system error is called, otherwise at 1705, the signal router sends a first message to the pulse generator, which includes the expected output form from the pulse generator, that is, whether it is a single pulse or a whole pulse train. In an embodiment, the receipt of the message is confirmed to the signal router by the pulse generator. Subsequently, at 1707, the signal router sends a second message to the pulse generator, which includes details of a single pulse or a whole pulse train to the pulse generator. In an embodiment, the receipt of the second message is confirmed to the signal router by the pulse generator. Next, at 1709, the signal router sets the appropriate switches to route the pulse or pulse train delivery to the appropriate output channel, and then sends a trigger signal to the pulse generator. At 1711, upon receiving the trigger signal, the pulse generator generates the desired pulse or pulse train and outputs it to the signal router, from which the output is routed to the appropriate device electrode. In an embodiment, the signal router may include a current measurement circuit to check for appropriate pulse delivery. In such an embodiment, if an incorrect or unexpected measurement result is seen at 1713, the signal router reports an error and opens all switches at 1715 to stop further output delivery. Otherwise, at 1717, the signal router opens all switches and checks whether more pulses or pulse trains are needed, for example to other channels or electrode pairs. If further pulse delivery is needed or desired, the process returns to 1709, where the signal router updates its signal routing switches appropriately and sends another trigger signal to the pulse generator. The process continues in this manner until the check at 1717 indicates that waveform delivery is complete. Upon completion, at 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.

[0066] In embodiments where only a pulse generator is needed, e.g., for fixed or limited signal routing, the pulse generator may appropriately direct the opening and closing of switches for pulse train delivery. It should be noted that a suitable user interface may include any of a variety of such interfaces known in the art, including but not limited to a computer monitor, touch screen, mouse, wand, joystick, voice activation, foot switch, gesture recognition, etc.

[0067] Pulsed waveform delivery as disclosed herein can be applied to pulsed field ablation delivery in a unipolar (also referred to as monopolar) mode between one or more device electrodes and a reference electrode patch on the surface of a subject, or in embodiments, a subset of the device electrodes can be used as a bipolar electrode 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 depending on the irreversible electroporation threshold of the tissue, a lesion zone having boundaries determined by the threshold of the electric field is generated as a result of the ablation. In embodiments, if a larger treatment volume or area is required, the medical device can be moved to and positioned at a different location, and treatment can be delivered at the new location. In embodiments, more than one ablation or waveform delivery can be performed at a given anatomical location for ease of application.

[0068] The systems, devices, and methods described herein may be embodied in one or more embodiments, as set forth below.

[0069] Embodiment 1: A system for ablation therapy delivery, comprising a pulse generator coupled to an ablation device, the pulse generator configured to generate a voltage pulse train of biphasic pulses, each biphasic pulse comprising a positive pulse and a negative pulse, an interphase delay separating the positive pulse and the negative pulse, and continuous biphasic pulses separated by pulse-to-pulse delays, wherein a subset of the continuous pulse-to-pulse delays in the pulse train comprises an increasing sequence of delays.

[0070] Embodiment 2: A system for ablation therapy delivery, comprising a pulse generator coupled to an ablation device, the pulse generator configured to generate a voltage pulse train of biphasic pulses, each biphasic pulse comprising a positive pulse and a negative pulse, an interphase delay separating the positive pulse and the negative pulse, and continuous biphasic pulses separated by pulse-to-pulse delays, wherein a subset of the continuous pulse-to-pulse delays in the pulse train comprises a decreasing sequence of delays.

[0071] Embodiment 3: A system for ablation therapy delivery, comprising a pulse generator coupled to an ablation device, the pulse generator configured to generate a voltage pulse train of biphasic pulses, each biphasic pulse comprising a positive pulse and a negative pulse, an interphase delay separating the positive pulse and the negative pulse, and continuous biphasic pulses separated by pulse-to-pulse delays, wherein a first subset of continuous pulse-to-pulse delays in the pulse train comprises an increasing sequence of delays, and a second subset of continuous pulse-to-pulse delays in the pulse train comprises a decreasing sequence of delays.

[0072] Embodiment 4: The system of Embodiment 1, wherein the increasing sequence of successive pulse-to-pulse delays follows at least an arithmetic progression.

[0073] Embodiment 5: The system of Embodiment 2, wherein the decreasing sequence of successive pulse-to-pulse delays follows at least an arithmetic progression.

[0074] Embodiment 6: A system according to embodiment 3, wherein an increasing sequence of delays in a first subset of consecutive pulse-to-pulse delays in a pulse train follows at least an arithmetic series, and a decreasing sequence of delays in a second subset of consecutive pulse-to-pulse delays in a pulse train follows at least an arithmetic series.

[0075] Embodiment 7: The system of Embodiment 1, wherein the increasing sequence of successive pulse-to-pulse delays follows at least a geometric progression.

[0076] Embodiment 8: The system of Embodiment 2, wherein the decreasing sequence of successive pulse-to-pulse delays follows at least a geometric progression.

[0077] Embodiment 9: A system according to embodiment 3, wherein an increasing sequence of delays in a first subset of consecutive pulse-to-pulse delays in a pulse train follows at least a geometric series, and a decreasing sequence of delays in a second subset of consecutive pulse-to-pulse delays in a pulse train follows at least a geometric series.

[0078] Embodiment 10: The system of Embodiment 1, wherein the increasing sequence of pulse-to-pulse delays in the pulse train comprises at least one third of the total number of pulse-to-pulse delays in the pulse train.

[0079] Embodiment 11: The system of Embodiment 2, wherein the decreasing sequence of pulse-to-pulse delays in the pulse train comprises at least one third of the total number of pulse-to-pulse delays in the pulse train.

[0080] Embodiment 12: A system according to embodiment 3, wherein the pulse train includes up to 30 complete biphasic pulses.

[0081] Embodiment 13: The system of Embodiment 1, wherein the positive pulse and the negative pulse of each biphasic pulse comprise substantially rectangular pulses.

[0082] Embodiment 14: The system of Embodiment 2, wherein the positive pulse and the negative pulse of each biphasic pulse comprise substantially rectangular pulses.

[0083] Embodiment 15: A system according to embodiment 1, wherein the positive pulse and the negative pulse of each biphasic pulse include a trapezoidal pulse, wherein the pulse width of the positive phase or the negative phase is a width or duration at which the voltage value is at least 70% of the maximum amplitude value.

[0084] Embodiment 16: A system according to Embodiment 2, wherein the positive pulse and the negative pulse of each biphasic pulse comprise a trapezoidal pulse, wherein the pulse width of the positive phase or the negative phase is a width or duration at which the voltage value is at least 70% of the maximum amplitude value.

[0085] Embodiment 17: The system of Embodiment 13, wherein the interphase delay is at least three times the pulse width.

[0086] Embodiment 18: The system of Embodiment 14, wherein the inter-phase delay is at least three times the pulse width.

[0087] Embodiment 19: The system of Embodiment 15, wherein the inter-phase delay is at least three times the pulse width.

[0088] Embodiment 20: The system of Embodiment 16, wherein the inter-phase delay is at least three times the pulse width.

[0089] Embodiment 21: A system according to embodiment 3, wherein the phase delay is at least 5 microseconds.

[0090] Embodiment 22: The system of Embodiment 3, wherein the pulse width is in a range between about 0.5 microseconds and about 150 microseconds.

[0091] Embodiment 23: A system for delivering ablation therapy, comprising a pulse generator coupled to an ablation device, the pulse generator configured to generate a plurality of voltage pulse packets, the plurality of voltage pulse packets having consecutive packets separated by a series of packet delays, each pulse packet comprising a voltage pulse train of biphasic pulses, each biphasic pulse comprising a positive pulse and a negative pulse, an interphase delay separating the positive pulse and the negative pulse, consecutive biphasic pulses separated by pulse-to-pulse delays, wherein a subset of consecutive pulse-to-pulse delays in the pulse train comprises an increasing sequence of delays.

[0092] Embodiment 24: A system for delivering ablation therapy, comprising a pulse generator coupled to an ablation device, the pulse generator configured to generate a plurality of voltage pulse packets, the plurality of voltage pulse packets having consecutive packets separated by a series of packet delays, each pulse packet comprising a voltage pulse train of biphasic pulses, each biphasic pulse comprising a positive pulse and a negative pulse, an interphase delay separating the positive pulse and the negative pulse, consecutive biphasic pulses separated by pulse-to-pulse delays, wherein a subset of consecutive pulse-to-pulse delays in the pulse train comprises a decreasing sequence of delays.

[0093] Embodiment 25: A system for delivering ablation therapy, comprising a pulse generator coupled to an ablation device, the pulse generator configured to generate a plurality of voltage pulse packets, the plurality of voltage pulse packets having consecutive packets separated by a series of packet delays, each pulse packet comprising a voltage pulse train of biphasic pulses, each biphasic pulse comprising a positive pulse and a negative pulse, an interphase delay separating the positive pulse and the negative pulse, consecutive biphasic pulses separated by pulse-to-pulse delays, wherein a first subset of consecutive pulse-to-pulse delays in the pulse train comprises an increasing sequence of delays, and a second subset of consecutive pulse-to-pulse delays in the pulse train comprises a decreasing sequence of delays.

[0094] Embodiment 26: The system of Embodiment 23, wherein the plurality of pulse packets comprises up to 20 packets.

[0095] Embodiment 27: The system of Embodiment 25, wherein each packet delay is in a range between approximately 300 milliseconds and approximately 12 seconds.

[0096] Embodiment 28: The system of Embodiment 25, wherein the voltage amplitude of the pulses is in a range between approximately 300 volts and 10,000 volts.

[0097] Embodiment 29: A system for ablation therapy delivery, comprising a pulse generator coupled to a router, the router having an activated switch for channel routing to an electrode group, an ablation device having a plurality of electrodes coupled to the router, a communication channel between the pulse generator and the router for delivering a trigger signal from the router to the pulse generator, and different subsets of router switches for channel routing to different electrode groups activated during at least two consecutive trigger signals, wherein the pulse generator generates a biphasic voltage pulse train of bidirectional pulses upon receiving the trigger signal, each biphasic pulse comprising a positive pulse and a negative pulse, an interphase delay separating the positive pulse and the negative pulse, and the generated pulses are delivered to the electrodes on the ablation device via the router.

[0098] Embodiment 30: A system for ablation therapy delivery, comprising a pulse generator coupled to a router, the router having an activated switch for channel routing to an electrode group, an ablation device having a plurality of electrodes coupled to the router, a communication channel between the pulse generator and the router for delivering a trigger signal from the router to the pulse generator, and having different subsets of router switches for channel routing to different electrode groups activated during at least two consecutive trigger signals, wherein the pulse generator generates a biphasic voltage pulse train of biphasic pulses upon receiving the trigger signal, each biphasic pulse comprising a positive pulse and a negative pulse, an interphase delay separating the positive pulse and the negative pulse, consecutive biphasic pulses being separated by a pulse-to-pulse delay, and a subset of consecutive pulse-to-pulse delays in the pulse train comprising an increasing sequence of delays.

[0099] Embodiment 31: A system for ablation therapy delivery, comprising a pulse generator coupled to a router, the router having an activated switch for channel routing to an electrode group, an ablation device having a plurality of electrodes coupled to the router, a communication channel between the pulse generator and the router for delivering a trigger signal from the router to the pulse generator, and having different subsets of router switches for channel routing to different electrode groups activated during at least two consecutive trigger signals, wherein the pulse generator generates a biphasic voltage pulse train of biphasic pulses upon receiving the trigger signal, each biphasic pulse comprising a positive pulse and a negative pulse, an interphase delay separating the positive pulse and the negative pulse, consecutive biphasic pulses being separated by a pulse-to-pulse delay, and a subset of consecutive pulse-to-pulse delays in the pulse train comprising a decreasing sequence of delays.

[0100] Although specific examples are provided in the various figures for purposes of illustration and description, it should be clear that variations such as different numbers of pulses, pulse packets, electrode groups, etc. are included in the present disclosure. Although specific medical devices are shown as examples in the present disclosure, it should be clear 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, loops, balloons, solid tips, curved geometries, etc. can be used to deliver therapy with the devices, methods, and waveforms described herein to treat several types of benign or cancerous tumors, deliver ablations for renal or other denervation, or ablate various types of soft tissues. The electrodes of the catheter devices or other medical devices described herein can typically be attached or connected to an electrical conductor that is attached to a cable or connector cable for delivering electrical energy from a generator system, such as for delivering a high voltage pulsed field ablation waveform.

[0101] In an embodiment, ablation can generate an electric field that is insufficient to cause irreversible electroporation but sufficient to cause reversible electroporation, wherein the cell membrane in the reversible electroporation region is permeabilized to allow drug molecules or other therapeutic agents to enter the cell, for example to treat cancer. It should be understood that the term "ablation" herein includes reversible or temporary permeabilization of the cell membrane as well as irreversible or permanent permeabilization of the cell membrane. Depending on the clinical application, such as tumor treatment, it may be necessary to destroy the target cells for treatment, or temporarily permeabilize the cell membrane to allow the passage of a therapeutic agent, such as a drug molecule or viral vector carrying gene therapy or other such agents known in the art for tumor treatment.

[0102] The voltage amplitude of the waveform described herein may be in the range of about 300V to about 10,000V, including all values ​​and ranges therebetween, depending on the application. The pulse width of the waveform may be in the range of from about 0.5 microseconds to about 150 microseconds, including all values ​​and ranges therebetween. The interphase delay may range from about 5 microseconds to about 3 milliseconds, including all values ​​and ranges therebetween. The pulse-to-pulse delay may range from about 15 microseconds to about 300 milliseconds, including all values ​​and ranges therebetween, and the packet delay may range from 300 milliseconds to about 12 seconds, including all values ​​and ranges therebetween.

[0103] As used herein, the terms "about" and / or "approximately" when used in conjunction with numerical values ​​and / or ranges, generally refer to those numerical values ​​and / or ranges that are close to the cited numerical values ​​and / or ranges. In some cases, the terms "about" and "approximately" can refer to within ±10% of the quoted value. For example, in some cases, "about 100 [units]" can mean within ±10% of 100 (e.g., from 90 to 110). The terms "about" and "approximately" can be used interchangeably.

Claims

1. A device comprising: a pulse generator configured to be coupled to the ablation device, the pulse generator configured to generate a voltage pulse train comprising a plurality of biphasic pulses, Each of the plurality of biphasic pulses comprises a positive pulse, a negative pulse, and an interphase delay separating the positive pulse from the negative pulse, consecutive biphasic pulses of the plurality of biphasic pulses are separated by pulse-to-pulse delays, such that the plurality of biphasic pulses are separated by a plurality of pulse-to-pulse delays, and The plurality of pulse-to-pulse delays comprises an increasing sequence of pulse-to-pulse delays comprising a subset of progressively increasing consecutive pulse-to-pulse delays.

2. The device according to claim 1, wherein: The increasing sequence of pulse-to-pulse delays increases at least according to an arithmetic progression.

3. The device according to claim 1, wherein: The increasing sequence of pulse-to-pulse delays increases at least according to a geometric progression.

4. The device according to any one of claims 1 to 3, wherein: The increasing sequence of pulse-to-pulse delays includes at least one third of the total number of the plurality of pulse-to-pulse delays.

5. The device according to any one of claims 1 to 4, wherein: The plurality of biphasic pulses includes up to about thirty biphasic pulses.

6. The device according to any one of claims 1 to 5, wherein: The positive pulse and the negative pulse of each of the plurality of biphasic pulses comprise substantially rectangular pulses.

7. The device according to claim 6, wherein: An interphase delay of each of the plurality of biphasic pulses is at least three times a pulse width of a positive pulse and a negative pulse of each of the plurality of biphasic pulses.

8. The device according to any one of claims 1 to 5, wherein: The positive pulse and negative pulse of each biphasic pulse in the multiple biphasic pulses include substantially trapezoidal pulses, and each positive pulse or each negative pulse has a pulse width corresponding to a voltage value of the positive pulse or the negative pulse that is at least about 70% of the maximum amplitude value of the positive pulse or the negative pulse.

9. The device according to claim 8, wherein: An interphase delay of each of the plurality of biphasic pulses is at least three times a pulse width of a positive pulse and a negative pulse of each of the plurality of biphasic pulses.

10. The device according to any one of claims 1 to 9, wherein: The interphase delay of each biphasic pulse of the plurality of biphasic pulses is at least about five microseconds.

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

12. The device according to any one of claims 1 to 11, wherein: The maximum amplitude of each positive pulse or each negative pulse in the plurality of biphasic pulses is between about 300 volts and about 10,000 volts.

13. The device according to any one of claims 1 to 12, wherein: The pulse generator is configured to generate a plurality of packets, each packet of the plurality of packets comprising a pulse train identical to the pulse train, and consecutive packets of the plurality of packets are separated by an inter-packet delay of a plurality of inter-packet delays.

14. The device according to claim 13, wherein: The plurality of packages includes up to approximately twenty packages.

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 device comprising: a pulse generator configured to be coupled to the ablation device, the pulse generator configured to generate a voltage pulse train comprising a plurality of biphasic pulses, Each of the plurality of biphasic pulses comprises a positive pulse, a negative pulse, and an interphase delay separating the positive pulse from the negative pulse, consecutive biphasic pulses of the plurality of biphasic pulses are separated by pulse-to-pulse delays, such that the plurality of biphasic pulses are separated by a plurality of pulse-to-pulse delays, and The plurality of pulse-to-pulse delays comprises a decreasing sequence of pulse-to-pulse delays comprising progressively decreasing subsets of consecutive pulse-to-pulse delays.

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

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

20. The apparatus according to any one of claims 16 to 19, wherein: The plurality of biphasic pulses includes up to about thirty biphasic 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 biphasic pulses comprise substantially rectangular pulses.

22. The apparatus according to claim 21, wherein An interphase delay of each of the plurality of biphasic pulses is at least three times a pulse width of a positive pulse and a negative pulse of each of the plurality of biphasic pulses.

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

24. The apparatus of claim 23, wherein: An interphase delay of each of the plurality of biphasic pulses is at least three times a pulse width of a positive pulse and a negative pulse of each of the plurality of biphasic pulses.

25. The apparatus according to any one of claims 16 to 24, wherein: The interphase delay of each biphasic pulse of the plurality of biphasic pulses is at least about five microseconds.

26. The apparatus according to any one of claims 16 to 25, wherein: The pulse width of each positive pulse or each negative pulse of the plurality of biphasic 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 each negative pulse in the plurality of biphasic 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 comprising a pulse train identical to 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 of claim 27, wherein: The plurality of packages includes up to approximately twenty packages.

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

31. An apparatus comprising: a pulse generator configured to be coupled to the ablation device, the pulse generator configured to generate a voltage pulse train comprising a plurality of biphasic pulses, Each of the plurality of biphasic pulses comprises a positive pulse, a negative pulse, and an interphase delay separating the positive pulse from the negative pulse, consecutive biphasic pulses of the plurality of biphasic pulses are separated by pulse-to-pulse delays, such that the plurality of biphasic pulses are separated by a plurality of pulse-to-pulse delays, and The plurality of pulse-to-pulse delays include: an increasing sequence of pulse-to-pulse delays comprising a first subset of progressively increasing consecutive pulse-to-pulse delays; and The decreasing sequence of pulse-to-pulse delays comprises a second subset of progressively decreasing consecutive pulse-to-pulse delays.

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

33. Apparatus according to any one of claims 31 to 32, wherein: The decreasing sequence of pulse-to-pulse delays decreases at least according to an arithmetic progression.

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

35. The apparatus according to any one of claims 31-32, wherein: The decreasing sequence of pulse-to-pulse delays decreases at least according to a geometric progression.

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

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

38. The apparatus according to any one of claims 31 to 37, wherein: The plurality of biphasic pulses includes up to about thirty biphasic pulses.

39. The apparatus according to any one of claims 31 to 38, wherein: The positive pulse and the negative pulse of each of the plurality of biphasic pulses comprise substantially rectangular pulses.

40. The apparatus of claim 39, wherein: An interphase delay of each of the plurality of biphasic pulses is at least three times a pulse width of a positive pulse and a negative pulse of each of the plurality of biphasic pulses.

41. The apparatus according to any one of claims 31 to 38, wherein: The positive pulse and negative pulse of each biphasic pulse in the multiple biphasic pulses include substantially trapezoidal pulses, and each positive pulse or each negative pulse has a pulse width corresponding to a voltage value of the positive pulse or the negative pulse that is at least about 70% of the maximum amplitude value of the positive pulse or the negative pulse.

42. The apparatus of claim 41, wherein: An interphase delay of each of the plurality of biphasic pulses is at least three times a pulse width of a positive pulse and a negative pulse of each of the plurality of biphasic pulses.

43. The apparatus according to any one of claims 31 to 42, wherein: The interphase delay of each biphasic pulse of the plurality of biphasic pulses is at least about five microseconds.

44. The apparatus according to any one of claims 31 to 43, wherein: The pulse width of each positive pulse or each negative pulse of the plurality of biphasic pulses is between about 0.5 microseconds and about 150 microseconds.

45. The apparatus according to any one of claims 31 to 44, wherein: The maximum amplitude of each positive pulse or each negative pulse in the plurality of biphasic pulses is between about 300 volts and about 10,000 volts.

46. ​​The apparatus of any one of claims 31 to 45, wherein: The pulse generator is configured to generate a plurality of packets, each packet of the plurality of packets comprising a pulse train identical to the pulse train, and consecutive packets of the plurality of packets are separated by a packet delay of a plurality of packet delays.

47. The apparatus of claim 46, wherein: The plurality of packages includes up to approximately twenty packages.

48. The apparatus of claim 46, wherein: Each packet delay of the plurality of packet delays is between approximately 300 milliseconds and approximately 12 seconds.

49. A system comprising: a pulse generator configured to generate biphasic pulses, each biphasic pulse comprising 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 groups, each electrode group comprising one or more electrodes, the signal router being configured to: (1) set one or more switches to selectively apply the biphasic pulses generated by the pulse generator to one or more electrode groups among the plurality of electrode groups, and (2) generate a series of trigger signals to trigger the pulse generator to generate the biphasic pulses; as well as 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, so that the pulse generator generates a pulse train in response to receiving each trigger signal in the series of trigger signals and delivers the pulse train to the signal router for application to one or more electrode groups of the plurality of electrode groups, The pulse train comprises a plurality of biphasic pulses, consecutive biphasic pulses of the plurality of biphasic pulses being separated by pulse-to-pulse delays of a plurality of pulse-to-pulse delays, the plurality of pulse-to-pulse delays comprising at least one of: an increasing sequence of pulse-to-pulse delays, comprising a subset of progressively increasing consecutive pulse-to-pulse delays; or A decreasing sequence of pulse-to-pulse delays comprises progressively decreasing subsets of consecutive pulse-to-pulse delays.

50. The system of claim 49, wherein: The plurality of electrode groups include at least a first electrode group and a second electrode group, The signal router is configured to set the one or more switches and generate the series of trigger signals such that the signal router: applying a first plurality of packets to a first electrode set, wherein: (a) consecutive packets in the first plurality of packets are separated by a first packet delay, and (b) each packet in the first plurality of packets comprises a pulse train; and A second plurality of packets is applied to a second electrode set, wherein: (a) consecutive packets of the first plurality of packets are separated by a second packet delay, and (b) each packet of the first plurality of packets comprises a pulse train.

51. The system of claim 50, wherein: Each packet of the second plurality of packets is applied during the first packet delay separating consecutive packets of the first plurality of packets.

52. The system of claim 50, wherein: Each biphasic pulse within the second plurality of packets is applied during a pulse-to-pulse delay separating successive biphasic pulses within the first plurality of packets.

53. A system according to any one of claims 49 to 52, wherein: The signal router is configured to set the one or more switches and to generate the series of trigger signals such that the signal router applies the pulse trains generated in response to consecutive trigger signals to different electrode groups among the plurality of electrode groups.

54. A system comprising: a pulse generator configured to generate biphasic pulses, each biphasic pulse comprising 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 groups, each electrode group comprising one or more electrodes, the signal router being configured to: (1) set one or more switches to selectively apply the biphasic pulses generated by the pulse generator to one or more electrode groups among the plurality of electrode groups, and (2) generate a series of trigger signals to trigger the pulse generator to generate the biphasic pulses; as well as A communication channel is arranged between the signal router and the pulse generator, the communication channel is configured to transmit the series of trigger signals to the pulse generator, so that the pulse generator generates a biphasic voltage pulse including a positive pulse and a negative pulse in response to receiving each trigger signal in the series of trigger signals, the phase delay separates the positive pulse and the negative pulse, and wherein for at least two consecutive trigger signals, the signal router is configured to set a switch to selectively apply the biphasic voltage pulse to different electrode groups.

55. The system of claim 54, wherein: An interphase delay of each biphasic pulse of the plurality of biphasic pulses is at least three times a pulse width of a positive pulse or a negative pulse of each biphasic pulse.

56. The system of claim 54, wherein: The interphase delay of each biphasic pulse is at least about five microseconds.

57. A method comprising: generating a voltage pulse train comprising a plurality of biphasic pulses using a pulse generator coupled to the ablation device, Each of the plurality of biphasic pulses comprises a positive pulse, a negative pulse, and an interphase delay separating the positive pulse from the negative pulse, consecutive biphasic pulses of the plurality of biphasic pulses are separated by pulse-to-pulse delays, such that the plurality of biphasic pulses are separated by a plurality of pulse-to-pulse delays, and The plurality of pulse-to-pulse delays comprises an increasing sequence of pulse-to-pulse delays comprising a subset of progressively increasing consecutive pulse-to-pulse delays.

58. The method of claim 57, wherein: The plurality of pulse-to-pulse delays further comprises a decreasing sequence of pulse-to-pulse delays comprising a subset of progressively decreasing consecutive pulse-to-pulse delays.

59. The method according to any one of claims 57-58, wherein: The positive pulse and the negative pulse of each of the plurality of biphasic pulses comprise substantially rectangular pulses.

60. The method of claim 59, wherein: An interphase delay of each of the plurality of biphasic pulses is at least three times a pulse width of a positive pulse and a negative pulse of each of the plurality of biphasic pulses.

61. The method according to any one of claims 57-58, wherein: The positive pulse and negative pulse of each biphasic pulse in the multiple biphasic pulses include substantially trapezoidal pulses, and each positive pulse or each negative pulse has a pulse width corresponding to a voltage value of the positive pulse or the negative pulse that is at least about 70% of the maximum amplitude value of the positive pulse or the negative pulse.

62. The method of claim 61, wherein: An interphase delay of each of the plurality of biphasic pulses is at least three times a pulse width of a positive pulse and a negative pulse of each of the plurality of biphasic pulses.

63. The method according to any one of claims 57 to 62, wherein: The interphase delay of each biphasic pulse of the plurality of biphasic pulses is at least about five microseconds.

64. The method according to any one of claims 57 to 63, wherein: The pulse width of each positive pulse or each negative pulse of the plurality of biphasic pulses is between about 0.5 microseconds and about 150 microseconds.

65. The method according to any one of claims 57 to 64, wherein: The maximum amplitude of each positive pulse or each negative pulse in the plurality of biphasic pulses is between about 300 volts and about 10,000 volts.

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