Spatially Multiplexed Waveforms for Selective Cell Ablation

Abstract

The present invention discloses methods and apparatuses for performing ablation using spatially multiplexed waveforms. By distributing the components of the waveform across multiple electrodes, the increased efficiency of a single-phase waveform is combined with the reduced side effects of a biphasic waveform. Charge balancing occurs after treatment delivery is completed during a period when muscle stimulation is avoided, while allowing an unbalanced waveform to be delivered during stimulation.

Description

[0001] Cross-reference to related patent documents

[0002] This application claims the benefit and priority of U.S. Provisional Patent Application 62 / 819,135, filed on Mar. 15, 2019, and titled "Spatial Multiplexing Waveforms for Selective Cell Ablation", the disclosure of which is incorporated herein by reference. This application is related to U.S. Provisional Patent Application 62 / 819,120, filed on Mar. 15, 2019, and titled "Spatial Multiplexing Waveforms for Selective Cell Ablation", and U.S. Provisional Patent Application 62 / 819,121, filed on Mar. 15, 2019, and titled "Waveform Generators and Controls for Selective Cell Ablation", the disclosures of which are incorporated herein by reference. BACKGROUND OF THE INVENTION

[0003] Removing or destroying diseased tissue is the goal of many cancer treatments. Tumors can be removed surgically; however, less invasive methods are of more interest. Tissue ablation is a minimally invasive method of destroying unwanted tissue in the body. Ablation can be thermal or non-thermal.

[0004] Thermal ablation adds or removes heat to destroy unwanted cells. For example, cryoablation kills cells by freezing the extracellular compartment, which causes cell dehydration starting at -15° C., where membrane rupture occurs at colder temperatures. Cryoablation is known to (beneficially) stimulate the patient's anti-tumor immune response.

[0005] Heat-based thermal ablation adds heat to destroy tissue. Radiofrequency (RF) heat, microwave, and high-intensity focused ultrasound ablation can each be used to raise the local tissue temperature well above the body's normal 37 degrees Celsius. For example, RF thermal ablation uses high-frequency electric fields to cause vibrations in cell membranes, which are converted to heat by friction. Once the cell temperature reaches 50 degrees Celsius, cell death occurs in as little as 30 seconds, and at higher temperatures, cell death is instantaneous. However, heat-based ablation may not elicit the desired immune response associated with cryoablation.

[0006] Using thermal ablation techniques, whether thermal or cold, each has the drawback that they have little or no ability to preserve normal structures in the treatment area. Collateral damage to blood vessels, nerves, and other structures is undesirable. For this reason, various researchers have also explored non-thermal ablation.

[0007] Non-thermal ablation techniques include electrochemotherapy and irreversible electroporation. Electroporation refers to the phenomenon in which the cytoplasmic membrane exposed to a high-voltage pulsed electric field becomes temporarily permeable due to the instability of the lipid bilayer. Then, pores are formed, at least temporarily. Electrochemotherapy combines pore formation with the introduction of chemicals that cause cell death. Since the chemical molecules used are large, only the cells subjected to the electric field will absorb the chemicals and subsequently die, thus facilitating useful selectivity in the treatment area. Irreversible electroporation (IRE) omits the chemicals and instead uses an electric field that typically has an increasing amplitude to expand the pores in the cell membrane beyond the recovery point, resulting in cell death due to the lack of the parental cell membrane. The spatial characteristics of the applied field control which cells and tissues will be affected, allowing for better selectivity in the treatment area compared to thermal techniques.

[0008] One challenge of electrical (whether thermal or not) ablation techniques is local muscle stimulation. In terms of causing certain cell death, a single-phase waveform is considered to provide better results for IRE. However, single-phase waveforms tend to cause muscle stimulation, thus requiring the use of anesthetic agents to facilitate the procedure among other issues. Biphasic waveforms avoid muscle stimulation but may not be as effective as single-phase waveforms at the same energy level and / or amplitude. Simply increasing the power to make the biphasic waveform more effective runs the risk of causing thermal ablation. Enhancements and alternatives to the existing technology are needed to allow the use of waveforms that are as effective as the single-phase stimulation used for IRE while avoiding muscle stimulation and thus obtaining the benefits of both single-phase and biphasic therapies. Summary of the Invention

[0009] The inventors have recognized that, among other things, the problem to be solved is to provide an ablation therapy that combines high performance and tissue selectivity while avoiding muscle stimulation. Many of the examples shown below use spatial multiplexing of the treatment output to achieve these goals.

[0010] The first illustrative, non-limiting example takes the form of a signal generator adapted to deliver tissue ablation energy and includes: a treatment output block including a voltage conversion circuit, an energy storage circuit, and an output control circuit; an input / output circuit adapted to be coupled to a probe for delivering tissue ablation energy, the input / output circuit defining a plurality of output channels such that a probe coupled thereto and having a plurality of electrodes can be used for individual activation of a subset of the plurality of electrodes; a user interface that allows a user to control the signal generator and is adapted to display more than one parameter of the tissue ablation energy to be delivered by the signal generator; a controller coupled to the treatment output block and the user interface; a memory coupled to the controller and having stored instructions for delivering a treatment cycle, the treatment cycle including: a first single-phase pulse between a first pair of electrodes selected from at least three electrodes; a second single-phase pulse between a second pair of electrodes selected from at least three electrodes; and a third single-phase pulse between a third pair of electrodes selected from at least three electrodes; wherein each of the first single-phase pulse, the second single-phase pulse, and the third single-phase pulse uses a unique combination of an anode and a cathode, wherein the stored instructions include a definition of a unique output channel for each of the first single-phase pulse, the second single-phase pulse, and the third single-phase pulse; wherein, at the end of each treatment cycle, the amount of charge delivered via each output channel is balanced to be close to zero; and wherein the stored instructions require that the treatment cycle be completed within a predetermined maximum duration that is less than the time constant of the surrounding tissue, wherein the time constant defines a duration associated with an increased risk of muscle contraction.

[0011] Additionally or alternatively for the first illustrative, non-limiting example, the stored instructions may define an amplitude for each of the first single-phase pulse, the second single-phase pulse, and the third single-phase pulse that exceeds the electroporation threshold for the tissue in or on which the probe is to be placed.

[0012] Additionally or alternatively for the first illustrative, non-limiting example, the stored instructions may define an amplitude for each of the first single-phase pulse, the second single-phase pulse, and the third single-phase pulse that exceeds the irreversible electroporation threshold for the tissue in or on which the probe is to be placed.

[0013] Additionally or alternatively for the first illustrative, non-limiting example, taking into account the probe, the stored instructions may define an amplitude for each of the first single-phase pulse, the second single-phase pulse, and the third single-phase pulse to be more than about 600 volts per centimeter.

[0014] Additionally or alternatively for the first illustrative, non-limiting example, the stored instructions may define the first single-phase pulse, the second single-phase pulse, and the third single-phase pulse to each have a pulse width of less than about 10 microseconds.

[0015] Additionally or alternatively, for the first illustrative, non - limiting example, the storage instructions may configure the pulse train to be completed in a time period less than 1 millisecond to prevent muscle contraction.

[0016] Additionally or alternatively, for the first illustrative, non - limiting example, the storage instructions may configure the pulse train such that charge balance cannot be achieved across all output channels until the final single - phase pulse of the delivered pulse train.

[0017] Additionally or alternatively, for the first illustrative, non - limiting example, the device may further include a sensing circuit coupled to the input / output circuit and adapted to monitor at least one of current or voltage at each output channel, wherein the storage instructions further include monitoring impedance during therapy output to facilitate calculation of charge balance.

[0018] Additionally or alternatively, the storage instructions may cause the controller to monitor the charge delivered in each output channel to cause delivery of more than one single - phase pulse before completion of the pulse train to enhance charge balance, which would otherwise be non - zero due to one or more changes in current or impedance during ablation therapy delivery.

[0019] Additionally or alternatively, the storage instructions may cause the controller to monitor the charge delivered in each delivery channel and to adjust the pulse width of more than one therapy pulse before completion of the pulse train to reduce charge imbalance.

[0020] Additionally or alternatively, the storage instructions may cause the controller to monitor the charge delivered in each delivery channel and to adjust the voltage level of more than one therapy pulse before completion of the pulse train to reduce charge imbalance.

[0021] Additionally or alternatively, for the first illustrative, non - limiting example, the storage instructions may require delivery of the pulse train at least twice.

[0022] Another example includes a system comprising a signal generator according to the first illustrative, non - limiting example and a LeVeen needle probe having a plurality of independently addressable electrodes thereon.

[0023] Another example includes a system comprising a signal generator according to the first illustrative, non - limiting example and a return electrode adapted to be placed on a patient's body during probe use.

[0024] The second illustrative, non - limiting example takes the form of a method of ablating tissue using a plurality of electrodes including at least three electrodes, the method comprising: placing at least three electrodes in or on the tissue to be ablated; and delivering a treatment cycle that includes: a first monopolar pulse between a first pair of electrodes selected from the at least three electrodes; a second monopolar pulse between a second pair of electrodes selected from the at least three electrodes; and a third monopolar pulse between a third pair of electrodes selected from the at least three electrodes; wherein each of the first monopolar pulse, the second monopolar pulse, and the third monopolar pulse uses a unique combination of anode and cathode; wherein, at the end of each treatment cycle, the amount of charge delivered through each electrode is balanced to be close to zero; and wherein the treatment cycle is completed within a predetermined maximum duration that is less than the time constant of the surrounding tissue, where the time constant defines a duration associated with an increased risk of muscle contraction.

[0025] Additionally or alternatively for the second illustrative, non - limiting example, the first monopolar pulse, the second monopolar pulse, and the third monopolar pulse can each have an amplitude that exceeds the electroporation threshold for the tissue in or on which the probe is to be placed.

[0026] Additionally or alternatively for the second illustrative, non - limiting example, the first monopolar pulse, the second monopolar pulse, and the third monopolar pulse can each have an amplitude that exceeds the irreversible electroporation threshold for the tissue in or on which the probe is to be placed.

[0027] Additionally or alternatively for the second illustrative, non - limiting example, the first monopolar pulse, the second monopolar pulse, and the third monopolar pulse can each generate a field that exceeds about 600 volts per centimeter.

[0028] Additionally or alternatively for the second illustrative, non - limiting example, the first monopolar pulse, the second monopolar pulse, and the third monopolar pulse can each have a pulse width that is less than about 10 microseconds.

[0029] Additionally or alternatively for the second illustrative, non - limiting example, at least two of the plurality of electrodes can be part of a conformal array adapted to be placed around the target tissue to be ablated such that at least some pairs of electrodes define a treatment vector through the target tissue.

[0030] Additionally or alternatively, at least four of the plurality of electrodes can be placed in or on the tissue to be spatially distributed around a target tissue region, wherein at least one of the first electrode pair, the second electrode pair, and the third electrode pair uses two electrodes with at least one other electrode therebetween.

[0031] Additionally or alternatively, for the second illustrative, non-limiting example, each pulse train can be completed in a time period less than 1 millisecond to prevent muscle contraction.

[0032] Additionally or alternatively, for the second illustrative, non-limiting example, charge balance cannot be achieved across all electrodes until the final monopolar pulse of the delivered pulse train.

[0033] Additionally or alternatively, for the second illustrative, non-limiting example, the method can further include monitoring the impedance between each of the first electrode pair, the second electrode pair, and the third electrode pair to facilitate calculation of charge balance.

[0034] Additionally or alternatively, for the second illustrative, non-limiting example, the method can further include monitoring the current between each of the first electrode pair, the second electrode pair, and the third electrode pair to facilitate calculation of charge balance.

[0035] Additionally or alternatively, for the second illustrative, non-limiting example, the method can further include monitoring the charge delivered by the plurality of electrodes during the pulse train and delivering more than one monopolar pulse before the completion of the pulse train to enhance charge balance, otherwise the charge balance will not be zero due to more than one change in current or impedance in the electrode pairs during ablation therapy delivery.

[0036] Additionally or alternatively, for the second illustrative, non-limiting example, the method can further include adjusting the pulse width of more than one treatment pulse to reduce charge imbalance.

[0037] Additionally or alternatively, for the second illustrative, non-limiting example, the method can further include adjusting the voltage level of more than one treatment pulse to reduce charge imbalance.

[0038] The third illustrative, non-limiting example takes the form of a method of ablating tissue using a plurality of electrodes including at least three electrodes, the method comprising: placing at least three electrodes in or on the tissue to be ablated; and delivering a treatment cycle comprising: a first monopolar pulse between a first pair of electrodes selected from the at least three electrodes; a second monopolar pulse between a second pair of electrodes selected from the at least three electrodes, the second pair being different from the first pair; a third monopolar pulse equal and opposite to the first monopolar pulse using the first pair of electrodes; a fourth monopolar pulse equal and opposite to the second monopolar pulse using the second pair of electrodes; wherein at the end of each treatment cycle, the amount of charge delivered through each electrode is balanced to be close to zero; wherein the second monopolar pulse occurs between the first monopolar pulse and the third monopolar pulse, and the third monopolar pulse occurs between the second monopolar pulse and the fourth monopolar pulse; and wherein the treatment cycle is completed within a predetermined maximum duration less than the time constant of the surrounding tissue, wherein the time constant defines a duration associated with an increased risk of muscle contraction.

[0039] Additionally or alternatively for the third illustrative, non-limiting example, at least one of the first monopolar pulse, the second monopolar pulse, the third monopolar pulse, and the fourth monopolar pulse may have an amplitude exceeding the electroporation threshold for the tissue in or on which the electrodes are to be placed.

[0040] Additionally or alternatively for the third illustrative, non-limiting example, at least one of the first monopolar pulse, the second monopolar pulse, the third monopolar pulse, and the fourth monopolar pulse may have an amplitude exceeding the irreversible electroporation threshold for the tissue in or on which the electrodes are to be placed.

[0041] Additionally or alternatively for the third illustrative, non-limiting example, each of the monopolar pulses may generate a field exceeding about 600 volts per centimeter.

[0042] Additionally or alternatively for the third illustrative, non-limiting example, each of the monopolar pulses may have a pulse width less than about 10 microseconds.

[0043] Additionally or alternatively for the third illustrative, non-limiting example, at least two of the plurality of electrodes may be part of a conformal array adapted to be placed around the target tissue to be ablated such that at least some pairs of electrodes define a treatment vector through the target tissue.

[0044] Additionally or alternatively for the third illustrative, non-limiting example, each pulse train may be completed within a time period less than 1 millisecond to prevent muscle contraction.

[0045] Additionally or alternatively, for a third illustrative, non - limiting example, charge balance cannot be achieved across all electrodes until the final single - phase pulse of a train of delivered pulses.

[0046] Additionally or alternatively, for a third illustrative, non - limiting example, the method may further include monitoring the impedance between each pair of a first electrode pair and a second electrode pair to facilitate calculating charge balance.

[0047] Additionally or alternatively, for a third illustrative, non - limiting example, the method may further include monitoring the current between each pair of a first electrode pair and a second electrode pair to facilitate calculating charge balance.

[0048] Additionally or alternatively, for a third illustrative, non - limiting example, the method may further include monitoring the charge delivered through a plurality of electrodes during a train of pulses, delivering more than one single - phase pulse before the train of pulses is completed to enhance charge balance, otherwise the charge balance would not be zero due to more than one change in current or impedance in the electrode pairs during ablation therapy delivery.

[0049] Additionally or alternatively, for either the second or third illustrative, non - limiting example, the method may further include delivering at least two treatment cycles.

[0050] A fourth illustrative, non - limiting example takes the form of a pulse generator configured to be used with a probe for delivering ablation therapy to a patient. The pulse generator includes an output circuit for delivering voltage - based therapy, a monitoring circuit for monitoring the characteristics of the delivered therapy pulses, and a control circuit including non - volatile memory containing an executable instruction set adapted to deliver therapy as described in either the second or third illustrative, non - limiting example or any of the supplements or alternatives thereto.

[0051] A fifth illustrative, non - limiting example takes the form of a pulse generator as described in the fourth illustrative, non - limiting example and a probe having a plurality of electrodes thereon for delivering ablation signals.

[0052] This summary is intended to provide an introduction to the subject matter of this patent application. It is not intended to provide an exclusive or exhaustive explanation of the invention. The detailed description is included to provide more information about this patent application. BRIEF DESCRIPTION OF THE DRAWINGS

[0053] In the drawings, which are not necessarily to scale, the same numbers may describe the same components in different views. The same numbers with different letter suffixes may represent different instances of the same component. The drawings generally illustrate, by way of example and not limitation, the various embodiments discussed in this document.

[0054] Figure 1 Shows an approximate representation of different treatment modalities associated with combinations of electric field strength and pulse duration;

[0055] Figures 2 to 4 Shows various effects of applying an electric field to cells;

[0056] Figure 5 Shows the prior art "LeVeen" needle.

[0057] Figures 6 to 8 Shows various waveform characteristics;

[0058] Figure 9 Shows a signal generator in the form of a block;

[0059] Figures 10 to 11 Shows target tissue surrounded by electrodes; and

[0060] Figures 12 to 15 Shows various spatially modulated treatment patterns. Detailed Description

[0061] Figure 1 Shows an approximate representation of different biophysical responses depending on the amplitude - time relationship of the delivered electrical pulses. The thresholds between cell responses (10, 20, 30) typically operate based on the applied field strength and pulse duration. Below the first threshold 10, no effect occurs; between the first threshold 10 and the second threshold 20, reversible electroporation occurs. Above the second threshold 20 and below the third threshold 30, mainly irreversible electroporation (IRE) occurs. Above the third threshold 30, mainly thermal effects driven by tissue heating start to appear. Thus, for example, at a given field strength and duration, there may be no effect (position 12), and extending the duration of the field application may result in reversible electroporation (position 22), irreversible electroporation (position 32), and thermal ablation (40).

[0062] As described in U.S. Pat. No. 6,010,613, a transmembrane potential in the range of about 1 volt is required to cause reversible electroporation, however, the relationship between pulse parameters, such as timing and duration, and the transmembrane potential required for reversible electroporation remains a subject of active research. The required field may vary depending on the characteristics of the cells to be treated. At the macroscopic level, reversible electroporation requires voltages at the level of hundreds of volts per centimeter, where irreversible electroporation requires higher voltages. As an example, when considering in vivo electroporation of liver tissue, the threshold field strength for reversible electroporation can be about 360V / cm, and the irreversible electroporation threshold field strength can be about 680V / cm, as described in U.S. Pat. No. 8,048,067. In general, multiple individual pulses are delivered to achieve this effect across a large portion of the treated tissue; for example, 2, 4, 8, 16 or more pulses may be delivered. Some embodiments may deliver hundreds of pulses.

[0063] The electric field used for electroporation is usually applied by delivering a series of individual pulses, each of which has a duration in the range of one to hundreds of microseconds. For example, U.S. Pat. No. 8,048,067 describes a method for electroporation. Figure 1 Analysis and experiments were performed to demonstrate that the region between centerline 20 and line 30 actually exists and that non-thermal IRE treatment can be achieved, using a series of eight 100 microsecond pulses delivered at 1 second intervals in several experiments.

[0064] The tissue membrane does not immediately return from the perforated state to rest. As a result, pulses applied close together in time can have a cumulative effect, as described, for example, in U.S. Pat. No. 8,926,606. In addition, a series of pulses can be used to first perforate the cell membrane and then move macromolecules through the resulting reversible pores, as described in U.S. PG Patent Application Publication No. 2007 / 0025919.

[0065] Figures 2 to 4 Various effects of applying an electric field to cells are shown. At electric field strengths below the threshold for reversible electroporation, Figure 2 As shown, the cell membrane 62 of the cell 60 remains intact and no pores appear. Figure 3 As shown, at higher electric field strengths above the threshold for reversible electroporation and below the threshold for irreversible electroporation, a pore 74 is formed in the membrane 72 of a cell 70. Depending on the characteristics of the applied field and pulse shape, larger or smaller pores 74 may appear, and the pores formed may last for longer or shorter durations.

[0066] like Figure 4As shown, at higher electric field strengths above the threshold for irreversible electroporation, cell 80 now has a membrane 82 with multiple pores 84, 86. At this higher amplitude or power level, pores 84, 86 may become so large and / or numerous that the cell cannot recover. It can also be noted that, as Figure 4 shown, the pores are spatially concentrated on the left and right sides of cell 80, where there are few or no pores in region 88 where the cell membrane is parallel to the applied field (here assumed to be the field applied between electrodes set to the right and left sides of the cell as Figure 4 shown). This is because the transmembrane potential in region 88 remains low, where the field is more nearly parallel to the cell membrane than orthogonal to it.

[0067] Figure 5 An exemplary prior art "LeVeen" needle is shown. As described in U.S. Patent No. 5,855,576, the device includes an insertable portion 100 having a shaft 104 that extends to a plurality of tissue piercing electrodes 102 that can be extended or retracted once in the target tissue 112 of a patient 110. The proximal end of the device is coupled to a power source 108 via an electrical connection 106, and the power source 108 can be used to supply RF energy.

[0068] Traditionally, the LeVeen needle has been used to deliver thermal ablation to target tissue. For example, as described in the '576 patent, a return electrode in the form of a plate or multiple plates can be disposed on the skin of the patient, the return electrode can be set as another tissue piercing electrode, or the return electrode can be disposed on the shaft 104 near its distal end proximal to the tissue piercing electrodes 102.

[0069] Improvements to the original design can be found, for example, in U.S. Patent No. 6,638,277, which discusses the independent actuation of the tissue piercing electrodes 102, including both movement of the electrodes and individual electrical activation of the individual electrodes. The '5,855,576 and '6,638,277 patents are incorporated herein by reference to show various treatment delivery probes. U.S. Provisional Patent Application Serial No. 62 / 620,873, which is incorporated herein by reference to show the disclosure of various treatment delivery probes, discloses updates and improvements to the LeVeen needle concept, thereby allowing flexibility in electrode spacing, size, and selection.

[0070] Figures 6 to 8 Various waveform characteristics are shown. Refer to Figure 6, a single-phase waveform is shown at 150. The waveform 150 is shown relative to a baseline or equipotential 152. An idealized square wave is shown as having an amplitude 154, a pulse width 156, and a period length 158. The waveform 150 is shown as an ideal square wave that has a vertical rise from the baseline 152 to the specified amplitude 154. When describing such a waveform, the frequency generally refers to the reciprocal of the period length 158. Thus, for example, if a waveform having a one-microsecond pulse width 156 is delivered at two-microsecond intervals 158, the “frequency” of the waveform can be described as 500 kHz (the reciprocal of two microseconds). The waveform 150 can be a current-controlled or voltage-controlled waveform. Each method can be used in various examples, as further described below.

[0071] In any practical application, the edges of the generated waveform will be rounded and the rise from the baseline 152 will be more, as Figure 7 shown, where the upward divergence from the baseline as shown at 162 is characterized by a rise time 160. At the end of the output, there is a non-ideal fall 164 characterized by a fall time 166. The practical application of the waveform will also include some variation in the peak amplitude, as shown in the figure. If the signal output is underdamped, it may include, for example, an overshoot in amplitude, or for a critically damped or overdamped signal, it includes rounding of the edges.

[0072] In some examples, more than one of the rise or fall times 160, 166 can be manipulated. In an illustrative example, the output circuit of the system can include selectable elements such as resistors, inductors, etc., which may slow down the rise time if switched into the circuit. For example, the current through an inductor cannot change immediately, so switching an inductive element into the output circuit can slow down the rise time when the inductor starts to allow current to flow.

[0073] Rise and fall times can be manipulated in several different ways. For example, process settings can be selected to modify the peak voltage target; a higher target can result in a faster rise time because various components respond exponentially to turning on or switching to the output circuit. By monitoring the output, the system can artificially increase the peak voltage target to reduce the rise time, and once the true peak voltage is reached, the system can switch the voltage source or use output regulation (such as by using a rectifier or redirecting the output current through a separate discharge path) to limit the voltage output. In another example, component selection can be used, such as by having multiple different HV switches available for the system to use and select from, where different HV switch types have different rise and fall times. For example, if three output switches are available, each with different rise / fall characteristics, the system can respond to a user input requesting a longer or shorter rise / fall time by selecting the appropriate output switch to use during a particular treatment output session. High-pass or low-pass filtering can also be switched to the output circuit to control the slew rate, or it can be switched to the control signal circuit; for example, a slow turn-on of the output transistor results in a slower rise time for the transistor itself, and conversely, a fast turn-on of the output transistor speeds up the rise time. In another example, a digital-to-analog converter can be used as the output circuit, allowing for digital control of the rise or fall time. In yet another example, the control signal to the output switch can be generated by a digital-to-analog converter, operating the on / off signal to the output circuit itself. In yet another example, using a capacitor stack output as shown in U.S. Provisional Patent Application No. 62 / 819,101, titled Waveform Generator and Controls for Selective Cell Ablation, the disclosure of which is incorporated herein by reference, a fast rise time can be achieved by using a single switch output from the top (or desired target level) of the capacitor stack, while a slow rise time can be achieved by successively turning on less than all of the capacitor stack and then adding more capacitor stack to the output; appropriate placement of diodes in the output circuit will prevent reverse current or short circuit in the newly added portions of the capacitor stack during such operation.

[0074] Figure 8More details are shown, this time for a bipolar signal. Here, the waveform is shown at 180, with the first positive pulse at 182, followed by a negative pulse at 190. The positive pulse 182 has an amplitude 184, and the negative pulse 190 has an amplitude 192, which is typically equal in voltage to the positive pulse but opposite in polarity. The positive pulse 182 has a pulse width 186, and the negative pulse 190 has a pulse width 194; again, typically the two pulse widths 186, 194 will be equal to each other. For the signal as shown, the period length can be determined as shown at 196 as being from the start of the positive pulse 182 to the start of the subsequent period; again, the frequency is the reciprocal of the period length.

[0075] In a typical application or use of a bipolar signal, the goal is in part to achieve charge balance at the end of each period. To this end, the pulse widths of the two phases are kept equal, and the amplitudes are also equal but opposite in polarity. Whether using a voltage control system or a current control system, charge balance can be reasonably maintained simply by controlling the pulse width and amplitude. For example, in a voltage control system, assuming the period length 196 is in the millisecond range or less, the current will be more or less constant over one period. That is, while it is well known that during an ablation procedure, tissue impedance changes as cells are destroyed, expelling cellular media that would normally reduce impedance, the impedance does not change so quickly that charge balance for a single bipolar waveform, even one without voltage control, will be a problem.

[0076] The interphase period 188 represents the time period spent at the baseline between the positive and negative pulses and is typically minimized according to the physical constraints of the underlying circuit. Thus, for example, if a first switch must be turned off to end the positive pulse 182 and a second switch is used to initiate the negative pulse 190, assuming digital control, the system can allow several digital clock cycles to elapse after turning off the first switch before turning on the second switch to avoid any possible internal short circuits. Faster switches can reduce the interphase period, and a great deal of engineering effort has been put into reducing this time period 188.

[0077] For example, a very short interphase period 188 can be achieved using a design such as that shown in U.S. Patent 10,154,869. In the '869 patent, an inductor is placed in parallel with the output load. In the initial stage of treatment delivery, power is applied to the load and the inductor. Turning on the switch between the power supply and the load / inductor causes the current through the load to reverse almost immediately because, after the power supply is disconnected, the inductor draws current from the load.

[0078] From Figures 6 to 8The background for collection is the background of typical usage. In several embodiments further described below, single-phase pulses are used to achieve a biphasic result regarding charge balance to prevent muscle stimulation. It should be noted that within all examples herein, the term "not causing muscle stimulation" allows for some muscle stimulation, but only an amount that is tolerable within the relevant intervention and / or surgical field. For example, the stimulation that occurs is not so much that the patient feels discomfort. In another example, the stimulation that occurs is small enough that a surgical procedure to ablate tissue is not disrupted by movement of the stimulated patient. In another example, the muscle stimulation that occurs is inconsequential to the procedure and allows the procedure to be performed without the need to administer an anesthetic. In some examples, the stimulation that occurs does not affect the placement and fixation of the probe, or is small enough that migration of the probe does not occur.

[0079] Figure 9 A signal generator is shown in block form. The signal generator 200 can be a self - contained unit, or it can include several discrete components coupled together by wire and / or wireless connections. The control block is shown at 202 and can include, as needed, multiple logic circuits in the form of a state machine, a microcontroller and associated digital logic, or a microprocessor, or even an off - the - shelf computing unit such as a laptop or desktop computer. A memory 204 is included, which may or may not be separate from the control block 202, to store an executable instruction set for operation and to save an activity log of the system and any sensor output received during treatment. The memory 204 can be volatile or non - volatile memory and can include optical or digital media, flash drives, hard disk drives, ROM, RAM, etc. A UI or user interface 206 can also be integrated with the control block (such as when using a laptop for the control 202, which will include each of the memory 204 and the UI 206). The UI 206 can include, as needed, a mouse, keyboard, screen touch - screen, microphone, speaker, etc.

[0080] The power input 208 can include one or more batteries and will typically include an electrical coupling for plugging into a wall outlet to receive line power. The treatment block is shown at 210 and includes several stages. The isolation and voltage conversion circuitry is shown at 212 and can include, for example, more than one transformer or other boost converters (such as a capacitive boost conversion circuit) to take the battery or line voltage and increase it to a high voltage output stored in the HV storage device 214. The HV storage device 214 can include batteries, inductors, or other circuit elements but will typically be a capacitive storage block such as a stack of capacitors. The HV storage device 214 may help to acquire the HV signal from block 212 and smooth it over time to provide a more stable high voltage output that is subsequently delivered by the HV output circuit 216. Additionally, the HV storage device 214 can allow a lower power voltage input to generate a very high power output by storing energy over a longer period of time for delivery in short bursts.

[0081] The HV output circuit 216 can be an output control circuit that includes a plurality of switches and other elements including, for example, high voltage switches such as silicon controlled rectifiers, high power Mosfets, and other elements, thereby allowing the high voltage signal to be selectively output to the IO block shown at 218. The IO block 218 can provide a plurality of sockets to receive plugs from more than one delivery probe 220, as well as more than one output to place more than one indifferent electrode on the patient's body, thereby serving as a return electrode or simply grounding the patient and the system.

[0082] In some alternative approaches to the treatment block 210, a resonant circuit can be powered by the HV signal rather than the HV output 216 using a set of switches to directly output the signal from the HV storage device, where the output of the resonant circuit is used for treatment delivery by selectively switching the output of the resonant circuit. For example, a topology using a set of four switches in an “H-bridge” to drive an RF circuit is shown in U.S. Patent 10,105,172. In some embodiments, in the present invention, control of a single pulse is achieved by omitting the driven RF circuit and simply relying on a form of an extended H-bridge circuit as shown in U.S. Provisional Patent Application 62 / 819,101 entitled Waveform Generator and Controls for Selective Cell Ablation, the disclosure of which is incorporated herein by reference.

[0083] One or more sensing circuits 224 may be included to provide feedback to the control block 202. For example, the sensing circuit may measure the voltage at the output node of the probe 220, or may measure the current flowing to the output node coupled to the probe 220, thereby allowing tissue characteristics to be monitored. For example, voltage measurement circuits are well known in the art and include, for example, direct conversion, successive approximation, ramp intersection, Wilkinson, integration, delta encoding, pipelined, Σ-Δ, and / or time-interleaved ADCs, any of which may be used depending on the application. Current measurement circuits may use, for example, trace resistance sensing, current sensors based on Faraday's Law, such as current transformers or Rogowski coils, or magnetic field sensors (Hall effect, fluxgate, and / or magnetoresistive current sensors) that are electrically or magnetically coupled to one or more transmission lines. For safety purposes, current sensors on the output circuit may be used to limit short circuit or overcurrent conditions.

[0084] In another example, the probe 220 may include sensors, such as temperature sensors, force sensors, or chemical or pH sensors, any of which may be used to monitor tissue characteristics during therapy delivery. For example, a temperature sensor may be used to manage non-thermal therapies, such as electroporation, by observing whether the temperature in the area rises above a threshold temperature or shows a rising trend, in which case, one or more elements of the power output may be reduced to ensure that the desired type of therapy predominates. If the probe includes such items, the sensing circuit 224 may include any suitable amplifiers, filters, etc. to allow the sensed signal to be conditioned for use by the control block 202.

[0085] The sensing circuit 224 may include a heart rhythm sensor suitable for use with one or more electrodes, such as surface electrodes placed on a patient's chest, to capture the heart rhythm and identify a physiological window for therapy delivery, as discussed below. The cardiac signal used to identify the therapy physiological window may alternatively be received from an ECG monitor in a clinic, an implantable medical device, such as a cardiac monitor, pacemaker, or defibrillator, or from various wearable products that sense heart rhythm.

[0086] Optionally, an "other therapy" block 222 may be included. "Other" therapies may include, for example, delivering chemical or biological agents to provide additional treatment, enhance the delivered treatment, or trigger an immune response to facilitate the body's own healing after ablation. Such other therapies 222 may include a reservoir (which may be refillable) for delivering material to the patient via, for example, a syringe or catheter or through a probe. "Other therapies" 222 may include introducing a substance that enhances, augments, synergizes with, or independently increases the ablation effect of an electrically delivered treatment. For example, a substance may be injected to modify or enhance the electric field effect, as disclosed in U.S. Patent Application Serial No. 16 / 188,343, entitled Irreversible Electroporation by the Combination of Substance Injection and Electric Field Application, the disclosure of which is incorporated herein by reference.

[0087] In some examples, cryotherapy may be integrated into the system to allow tissue cooling before, during, or after electroablation, triggering an immune response if desired. Cryotherapy may be delivered, for example, using a balloon on the treatment probe 220 or, alternatively, a nozzle disposed within the balloon and coupled to a pressurized fluid source, such as nitrous oxide; when discharged through the nozzle, the pressurized fluid will expand or undergo a phase change from liquid to gas, which causes local cooling, as disclosed, for example, in U.S. Patent 6,428,534. In another example, a fluid (gas or liquid) may be cooled externally and introduced via a catheter for cryogenic purposes, or, in the alternative, heated externally and introduced via a catheter for thermal ablation purposes.

[0088] In other examples, other therapies 222 may include the transmission of energy, such as mechanical energy (e.g., ultrasound) or light energy, using, for example, a laser source (such as a vertical cavity surface emitting laser) coupled to an optical fiber that extends through the probe to allow delivery of the laser energy to the target tissue. In some examples, as noted, a secondary or "other" therapy may be used to trigger an immune response, even if it is not used as the primary method of destroying the target tissue.

[0089] Figures 10 to 11 Target tissue surrounded by electrodes is shown. As Figure 10 shown, the target tissue 300 may be surrounded by a plurality of electrodes 1 to 6. Above Figure 5The probe shown in [Fig. 0] can be readily used to place several electrodes around the target tissue 300, where individual electrodes 1 through 6 pierce and are advanced through the tissue surrounding the target. In traditional biphasic applications, electrodes can be used in pairs or groups, or as a complete set relative to a remote return electrode, where a negative phase signal follows immediately after a positive phase signal, which have substantially equal but opposite voltages or currents. In contrast to such uses, the present invention instead uses spatial multiplexing of the treatment output to deliver a treatment having the effectiveness of a single-phase output while taking advantage of the reduced side effects (especially muscle stimulation) of biphasic treatment. To this end, in one example, electrodes can be used to deliver a single-phase treatment in a polling-type manner as follows:

[0090] Step Cathode Anode A 1 4 B 2 5 C 3 6 D 4 1 E 5 2 F 6 3

[0091] For this example, each output can be a single-phase waveform. If desired, the pulse width and amplitude during the sequence can be held constant or can vary. In one example, the pulse width of each pulse is in the range of 0.1 to 10 microseconds. The amplitude can be determined based on voltage or current, or can be determined using, for example, visualization or distance estimation to provide an output in volts / cm. For example, the output amplitude can be selected to account for such distance while exceeding the IRE threshold for the target tissue 300. In one example, electrodes 1 and 4 can be estimated to be separated by 2 cm, which can be calculated using radiography or other visualization, or can be determined by measuring the impedance between electrodes 1 and 4 and subsequently calculating the distance by assuming an impedance per unit distance of the tissue in the probe deployment area.

[0092] The treatments can be delivered successively in any order with reference to the above table - i.e., A - B - C - D - E - F can be that order. In some examples, the sequence A - D can be avoided because, even if not nominally, it is essentially a biphasic output in form and may thus not be as effective as those of single-phase outputs. In some examples, to avoid back-to-back or immediate reversal of electrode pairing, rules can be set that require for any given pulse delivery, at least one electrode to be different from the immediately preceding pulse delivery.

[0093] In some examples, the complete sequence is delivered as a train of pulses completed within a time period that satisfies each of the following two rules:

[0094] - Charge balance rule: The pulse sequence is completed so as to provide a charge balance or an approximation of charge balance within the following range:

[0095] A time period less than the time constant of the surrounding tissue, which depends on factors such as tissue type and water content. The time constant of the surrounding tissue reflects the complex impedance of the tissue and cells in an electric field. For example, the time constant of the tissue between two electrodes will be determined by its complex impedance; in a simplified model, the time constant will be the capacitance multiplied by the tissue within the electric field generated between the two electrodes, including the cells. A polarized cell or tissue may have a larger or smaller effective time constant.

[0096] A time period less than about one millisecond

[0097] The maximum time period tolerable by the patient is determined by testing the patient. For example, to test the patient, the treatment output can include a first part and a second part spaced apart by a period of time, and the period of time separating the first part and the second part can be extended until muscle contraction is observed, until the patient reports feeling the contraction or tension, or until the patient indicates discomfort, where the first part of the treatment is a first single-phase pulse that applies a charge imbalance, and the second part of the treatment is configured to eliminate the charge imbalance. For example, by controlling and extending the interphase period ( Figure 8 , 188) to multiples of the individual pulse widths—such as using 5-microsecond pulses spaced tens or hundreds of microseconds, or even more, even a few milliseconds, which is tolerable by the patient and still remains within the complete regularity of the treatment mentioned below.

[0098] - Treatment completion rule: The pulse train is to be delivered within a physiological window determined by observing non-treatment factors such as the patient's heart rhythm.

[0099] Regarding treatment completion rules, using the heart as a driver, the heart rhythm contains various well-known components such as the R wave, QRS complex, P wave, and T wave. Stimulation of non-cardiac tissue for ablation purposes should not interfere with the heart rhythm, and the heart may be less susceptible to electrical signal interference within the interval between the peak of the R wave (or the end of the QRS complex) and the T wave. Sometimes, this interval can be referred to as the S-T interval (end of S wave QRS complex); the S-T interval for a given patient may last for tens of milliseconds and can range from 5 to 100 milliseconds. For a healthy individual, about 60 milliseconds is typical, but it should be noted that the therapies discussed herein are not necessarily applicable to healthy or typical individuals, and thus the S-T interval may not be "typical". In one example, a treatment pulse train is sensed and delivered after a delay of approximately 50 milliseconds from the detection of the R wave or the peak of the R wave. In any case, in some examples, the treatment starts and is completed within the S-T interval window. The heart signals used to identify the S-T interval or other physiologically useful windows can be obtained from a separate device (external or implantable), or can be sensed by a treatment generator having an input for receiving heart signals from electrodes placed on or within the patient. Other sources can be the driver; for example, detecting diaphragm movement may also be useful in order to deliver treatment on time when the patient inhales or exhales.

[0100] In other examples, one, the other, or both of these timing rules can be omitted. In some examples, a window can be approximated by setting rules such as the charge state of the pulse train must return to balance within less than one millisecond, or 800 microseconds, or 500 microseconds.

[0101] In another example, multiple electrodes can be combined together as a cathode:

[0102] Step Cathode Anode A 1,2,3 5 B 2,3,4 6 C 3,4,5 1 D 4,5,6 2 E 5,6,1 3 F 6,1,2 4

[0103] In yet another example, multiple electrodes can be combined together as an anode:

[0104] Step Cathode Anode A 1 3,4,5 B 2 4,5,6 C 3 5,6,1 D 4 6,1,2 E 5 1,2,3 F 6 2,3,4

[0105] Both the anode and the cathode can be combined:

[0106] Step Cathode Anode A 1,2 4,5 B 2,3 5,6 C 3,4 6,1 D 4,5 1,2 E 5,6 2,3 F 6,1 3,4

[0107] Various such pairings can be used. As described above, treatment can be delivered according to a set of rules. As needed, the device for delivering treatment can incorporate such rules into a stored instruction set or hardwire them.

[0108] In view of the foregoing, the illustrative examples take the form of a therapy delivery method that includes delivering a plurality of single-phase outputs between selected electrode pairs or groups of electrodes in a pulse train. Additionally, therapy delivery and the delivery of the pulse train can be performed using a first rule that requires each successive pulse in the pulse train to use at least one different electrode (either by omitting a previously used electrode, adding an electrode, or replacing more than one electrode with more than one other electrode) rather than the immediately preceding pulse. A second rule requires the pulse train to be delivered within a preset time period, such as less than the time constant of the surrounding tissue or less than one millisecond. A third rule requires the pulse train to be delivered within a specified physiological window, where the physiological window corresponds to the time during the cardiac cycle when the heart is resistant or at least relatively less sensitive to electrical interference. Another illustrative example can take the form of a signal generator as shown above Figure 9 configured to incorporate the first rule, the second rule, and the third rule in executable form or in some other form. For each of these illustrative examples, the output therapy pulses can be, for example, in the range of about 0.1 to 10 microseconds per pulse, where the pulse train has any suitable length, such as about 4 to about 100 pulses, and the pulse train may be repeated.

[0109] In some examples, when delivering therapy using various electrodes, the output current into and out of each electrode can be tracked. At the end of a pulse train or a series of pulse trains, the sum of the currents through each electrode can be determined, and one or more corrective outputs can be generated by delivering a predetermined amount of current or voltage that may cancel the accumulated charge at any one of the electrode interfaces. The various illustrative examples can include a combination of monitoring the delivered charge and subsequently providing "corrective" pulses to cancel the accumulated charge at more than one of the electrode surfaces. Corrective pulses can be particularly useful when using voltage-controlled outputs rather than current-controlled outputs.

[0110] Figure 11 Another example is shown. Here, an electrode array surrounding an irregularly shaped target tissue 320 is shown. In this example, the electrodes are not all equidistant from each other or from the target tissue 320. To account for this variation in distance / spacing, an additional set of calculations can be performed prior to delivering the therapy output. Using a visualization tool or relying on tissue impedance, the distances between the various electrode pairs used in the therapy can be calculated. Subsequently, the therapy sequence can be as follows:

[0111] Step Voltage Cathode Anode A V1 1 4 B V2 2 5 C V3 3 6 D V1* 4 1 E V2* 5 2 F V3* 6 3

[0112] Wherein V1 is a voltage that exceeds the IRE threshold in the target tissue 320 selected according to the electrode pair (1, 4) used to deliver it. Thus, for example, if electrodes 1 and 4 are separated by 3 cm and electrodes 3 and 6 are separated by 2 cm, then V1 may be selected to be approximately 1.5 times the voltage V3. Using a rough requirement of 700 v / cm for IRE, then V1 may be 2100 volts and V3 may be 1400 volts. As needed, the electrodes can also be grouped together as described above.

[0113] If desired, within the pulse train shown, V1 and V1* can be the same. Alternatively, for example, monitoring impedance or other factors during step A can inform a modification during step D so that if the impedance is too high, the voltage is increased, or if the impedance is too low, the voltage is decreased. However, generally, within a pulse train, the starred voltage is more likely to be the same as an earlier delivery.

[0114] For the pulse sequence of A - B - C - D - E - F, a set of measured impedances can be generated during treatment delivery. When multiple pulse trains are delivered, the measured impedance may change, assuming the treatment is effective, because cells rupture and fluid is expelled through the openings formed in the cell membranes, which generally reduces the impedance. When the impedance drops, one may be more concerned that the current will rise, leading to a greater thermal effect. Thus, in some examples, when each pulse train is completed and before the subsequent pulse train is delivered, the impedance can be checked and the output voltage can be reduced to avoid or limit the thermal effect.

[0115] Although Figures 10 to 11 the examples shown basically use electrode pairs to provide a matching output to produce charge balance, other methods can alternatively be used. Figure 12 An example with steps A, B, C, and D as described below is shown:

[0116] Step Voltage 1 2 3 4 A V1 Cathode Anode Open Open B V2 Open Cathode Anode Open C V3 Open Open Cathode Anode D V4 Anode Open Open Cathode

[0117] In this pulse train, each electrode used for treatment delivery is used as an anode at least once and as a cathode at least once. Each pulse can be single - phase, such that none of the treatment pulses in steps A to D individually provide charge balance, but the entire pulse train does. In some examples, each of V1 to V4 can be substantially the same.

[0118] For this method and if V1 through V4 are all the same, then again, it may be helpful to monitor the current during each step and use more than one corrective output at the end. For example, the electrodes may not be evenly spaced such that more current flows during one step than during another, which may leave a charge imbalance across more than one electrode interface. In some examples, as long as each electrode is generally used in a balanced manner, this may be sufficient. In other examples, monitoring may be performed relative to a charge balance threshold, such that, for example, determining that the charge imbalance for an electrode exceeds the threshold, more than one corrective pulse may be generated.

[0119] In another example, V1 through V4 can be modified to account for impedance, which can be measured prior to delivering a pulse train, or in a previous pulse train, or by performing a pre-test with a lower output voltage for therapeutic purposes. Knowing the impedance for each output pair (i.e., between 1 and 2 for step A, between 2 and 3 for step B, etc.), there will be a set of impedances I(1,2), I(2,3), I(3,4), I(4,1) and one can operate as follows to calculate V1 through V4:

[0120] V1 = Vn × I(1,2) / In

[0121] V2 = Vn × I(2,3) / In

[0122] V3 = Vn × I(3,4) / In

[0123] V4 = Vn × I(4,1) / In

[0124] where Vn is the nominal voltage and In is the nominal impedance. In can even be the average impedance of a set of four impedances I(1,2), I(2,3), I(3,4), I(4,1). At least for a first order approximation, this method will equalize the current in each step. In another example, instead of modifying the applied voltage, variable resistors can be switched into or out of the current flow path to make the impedance seen by the therapeutic output the same in each step.

[0125] In some examples, the corrective modification can be to vary the pulse width on a pulse-to-pulse basis within a pulse train rather than the amplitude as an active method to reduce residual charge by calculating impedance or distance. For example:

[0126] Step Voltage Time 1 2 3 4 A V1 PW1 Cathode Anode Open Open B V2 PW2 Open Cathode Anode Open C V3 PW3 Open Open Cathode Anode D V4 PW4 Anode Open Open Cathode

[0127] Here, if, for example, due to the impedance between electrodes 1 and 2 being less than that between electrodes 3 and 4, step A has a higher current than the other steps, PW1 can be shortened to equalize the current in each step. The charge delivered in each step will be:

[0128] Q1 = V1 × PW1 / I(1,2)

[0129] Q2 = V2 × PW2 / I(2,3)

[0130] Q3 = V3 × PW3 / I(3,4)

[0131] Q4 = V4 × PW4 / I(4,1)

[0132] An equalization calculation can be performed and the resulting pulse widths used in the treatment delivery. For example, using PWn as the nominal pulse width, which can be user input or a system default, and In as the nominal impedance, the following can be used to adjust the pulse width:

[0133] PW1 = PWT × I(1,2) / In

[0134] PW2 = PWT × I(2,3) / In

[0135] PW3 = PWT × I(3,4) / In

[0136] PW4 = PWT × I(4,1) / In

[0137] Thus, in these formulas, a larger impedance will result in a longer pulse width to account for the lower current associated with that treatment delivery vector. Instead of the nominal impedance In, the above formulas can use the average impedance of a set of impedances I(1,2), I(2,3), I(3,4), I(4,1). The calculated pulse widths may be limited by certain boundary conditions, such as by requiring that the calculated adjustment of the pulse width be only a fixed amount or percentage relative to the nominal, such as by allowing adjustment of only a few microseconds or twenty to thirty percent. For example, if using a nominal pulse width of 10 microseconds, the maximum adjusted pulse width could be 12 microseconds and the minimum 8 microseconds (plus / minus 2 microseconds, or plus / minus 20%). In some examples, the variation limit can be up to 25% of the nominal value with a maximum of 2 microseconds.

[0138] In yet another example, a common or default method could be to provide equal voltage at each step, thus simplifying the output. If muscle stimulation of the patient is observed, a correction function can be enabled, such as by calculating impedance and modifying the voltage or changing the pulse width, or by adding or removing resistance in the treatment path. Again, residual charge can be removed by adding more pulses at the end of the pulse train or a series of pulse trains. However, in the context of an ablation treatment that is not maintained in a patient implant, delivering this function at the end of a pulse train may not be very useful; the short-term effects of muscle stimulation are the factors to be tracked, rather than avoiding long-term imbalances that can lead to degradation of the electrode / tissue interface. Instead, the correction output can be determined by monitoring the charge balance during treatment delivery and issuing a correction output when a threshold charge imbalance is calculated or detected.

[0139] Figure 13 Another example is shown where the electrodes are grouped into a four-step treatment output for this time:

[0140] Step Voltage 1 2 3 4 A V1 Cathode Anode Anode Cathode B V2 Cathode Cathode Anode Anode C V3 Anode Cathode Cathode Anode D V4 Anode Anode Cathode Cathode

[0141] Again, voltages V1 to V4 can be equal in each step, or can vary using the methods and principles discussed above with respect to Figure 12 In addition, the applied pulse width can be modified as described above.

[0142] Figure 14 Another example is shown where pairs of alternating electrodes alternate as anode and cathode. Here, electrodes 1 and 3 are in one group, and electrodes 2 and 4 are in another group. Then, the treatment method or mode alternates as anode / cathode between the two groups. What is different about this example from several previous examples is that it completely reverses the polarity of each group; if this switching occurs quickly, the output will essentially be a biphasic treatment. Therefore, the system applies one or more additional constraints. In an illustrative example, instead of a biphasic method where an immediate or nearly immediate polarity switch occurs between steps A and B, the following pattern can be used:

[0143] Step Voltage Time 1 2 3 4 A V1 PW1 Cathode Anode Cathode Anode A’ Not applicable T1 Open Open Open Open B V2 PW2 Anode Cathode Anode Cathode B’ Not applicable T2 Open Open Open Open

[0144] where T1 is greater than or equal to PW1, and T2 is greater than or equal to PW2. In this example, PW1 and / or PW2 can be in the range of 0.1 to 10 microseconds, or longer or shorter. Instead of opening each of the connections to electrodes 1, 2, 3, and 4 as shown in the figure, the system can ground or couple each one to a reference voltage.

[0145] In the examples above, in some embodiments, the electrode identified as the anode can be used to apply a negative voltage with respect to ground, while a positive voltage is applied by the cathode. In other examples, the anode is just the ground or reference of the system.

[0146] Figure 15 Another example is shown. Here, this set of outputs uses a single cathode while the other electrodes operate as anodes:

[0147]

[0148]

[0149] Again, the current can be monitored through any or all of the output electrodes, and the management of voltage levels and / or pulse widths or the application of corrective pulses can be used to maintain a desired degree of charge balance.

[0150] Each of these non - limiting examples can exist independently or can be combined with one or more of the other examples in various permutations or combinations.

[0151] The above detailed description includes reference to the accompanying drawings, which form a part of the detailed description. The drawings illustrate, by way of example, specific embodiments in which the invention can be practiced. These embodiments are also referred to herein as "examples". Such examples can include elements in addition to those shown or described. However, the inventors also contemplate examples that provide only those elements shown or described. Further, the inventors also contemplate examples that use any combination or permutation of those elements (or one or more aspects thereof) in relation to a particular example (or one or more aspects thereof) or in relation to other examples (or one or more aspects thereof) shown or described herein.

[0152] If there is an inconsistency in the usage between this document and any document incorporated by reference, the usage in this document shall prevail.

[0153] In this document, as is common in patent documents, the term "a" is used to include one or more than one, independent of any other instance or usage of "at least one" or "one or more". Further, in the following claims, the terms "first", "second", "third", etc. are used only as labels and are not intended to impose a numerical requirement on their objects.

[0154] The method examples described herein can be implemented, at least in part, by a machine or a computer. Some examples can include a computer-readable medium or a machine-readable medium encoded with instructions that are operable to configure an electronic device to perform the methods described in the above examples. The implementation of such methods can include code, such as microcode, assembly language code, high-level language code, etc. Such code can include computer-readable instructions for performing various methods. The code can form part of a computer program product. Additionally, in one example, the code can be tangibly stored on one or more volatile, non-transitory, or non-volatile tangible computer-readable media, such as during execution or at other times. Examples of such tangible computer-readable media can include, but are not limited to, hard disks, removable magnetic disks or optical disks, magnetic tape cartridges, memory cards or memory sticks, random access memory (RAM), read-only memory (ROM), etc.

[0155] The above description is intended to be illustrative and not restrictive. For example, the above examples (or one or more aspects thereof) can be used in combination with each other. After reviewing the above description, other embodiments can be used, such as those used by ordinary skilled artisans in the art.

[0156] A summary is provided to comply with 37 C.F.R.§1.72(b) so as to allow the reader to quickly ascertain the nature of the technical disclosure. It should be understood that the submitted summary will not be used to interpret or limit the scope or meaning of the claims.

[0157] Moreover, in the above detailed description, various features can be combined together to simplify the present invention. This should not be construed as meaning that the disclosed features not claimed are essential to any of the claims. On the contrary, the subject matter of the invention can lie in less than all of the features of a particular disclosed embodiment. Thus, the following claims are incorporated into the detailed description as examples or embodiments, where each claim stands on its own as a separate embodiment, and it is contemplated that these embodiments can be combined with each other in various combinations or permutations. The scope of the present invention should be determined with reference to the appended claims, along with the full scope of equivalents to which these claims are entitled.

Claims

1. A signal generator adapted to deliver tissue ablation energy, which comprises: A treatment output block, the treatment output block including a voltage conversion circuit, an energy storage circuit, and an output control circuit; An input / output circuit adapted to be coupled to a probe for delivering tissue ablation energy, the input / output circuit defining a plurality of output channels such that a probe coupled thereto and having at least three electrodes including a first electrode, a second electrode, and a third electrode can be used for individual activation of a subset of the at least three electrodes; A user interface that allows a user to control the signal generator and is adapted to display more than one parameter of the tissue ablation energy to be delivered by the signal generator; A controller coupled to the treatment output block and the user interface; A memory coupled to the controller and having stored instructions for delivering a treatment cycle, the treatment cycle including a pulse train, the pulse train including: A first single-phase pulse between a first pair of electrodes selected from the at least three electrodes; A second single-phase pulse between a second pair of electrodes selected from the at least three electrodes; and A third single-phase pulse between a third pair of electrodes selected from the at least three electrodes; Wherein each of the first single-phase pulse, the second single-phase pulse, and the third single-phase pulse uses a combination of an anode and a cathode, and the stored instructions include a definition of an output channel for each of the first single-phase pulse, the second single-phase pulse, and the third single-phase pulse; wherein in each of the first single-phase pulse, the second single-phase pulse, and the third single-phase pulse, each electrode for treatment delivery is used as an anode at least once and as a cathode at least once; Wherein, at the end of each treatment cycle, the amount of charge delivered through each output channel is balanced to be close to zero; and Wherein the stored instructions configure the pulse train to be completed within a time period of less than 1 millisecond to prevent muscle contraction.

2. The signal generator according to claim 1, wherein the stored instructions define an amplitude for each of the first single-phase pulse, the second single-phase pulse, and the third single-phase pulse, the amplitude exceeding the electroporation threshold of the tissue in or on which the probe is to be placed.

3. The signal generator according to claim 1, wherein the stored instructions define an amplitude for each of the first single-phase pulse, the second single-phase pulse, and the third single-phase pulse, the amplitude exceeding the irreversible electroporation threshold of the tissue in or on which the probe is to be placed.

4. The signal generator according to claim 1, wherein considering the probe, the stored instructions define an amplitude for each of the first single-phase pulse, the second single-phase pulse, and the third single-phase pulse to exceed 600 volts per centimeter.

5. The signal generator according to claim 1, wherein the stored instructions define the first single-phase pulse, the second single-phase pulse, and the third single-phase pulse to each have a pulse width of less than 10 microseconds.

6. The signal generator according to claim 1, wherein the stored instructions configure the pulse train such that charge balance cannot be achieved across all output channels until the final single-phase pulse of the pulse train is delivered.

7. The signal generator according to claim 1, further comprising a sensing circuit coupled to the input / output circuit and adapted to monitor at least one of current or voltage at each output channel, wherein the stored instructions further include monitoring impedance during a treatment output to facilitate calculation of charge balance.

8. The signal generator according to claim 7, wherein the stored instructions are adapted to cause the controller to monitor the charge delivered in each output channel to cause delivery of more than one single-phase pulse prior to completion of the pulse train to enhance charge balance, which would otherwise be non-zero due to one or more changes in current or impedance during ablation treatment delivery.

9. The signal generator according to claim 7, wherein the stored instructions are adapted to cause the controller to monitor the charge delivered in each delivery channel and to cause the controller to adjust the pulse width of more than one treatment pulse prior to completion of the pulse train to reduce charge imbalance.

10. The signal generator according to claim 7, wherein the stored instructions are adapted to cause the controller to monitor the charge delivered in each delivery channel and to cause the controller to adjust the voltage level of more than one treatment pulse prior to completion of the pulse train to reduce charge imbalance.

11. The signal generator according to any one of claims 1-6, wherein the stored instructions include delivering the pulse train at least twice.

12. A system comprising the signal generator according to any one of claims 1-6 and a LeVeen needle probe having a plurality of independently addressable electrodes thereon.

13. A system comprising the signal generator according to any one of claims 1-6 and a return electrode adapted to be placed on a patient's body during probe use.

14. An ablation system comprising the signal generator according to any one of claims 1-6 and a probe having a plurality of electrodes thereon for delivering ablation signals.

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