Waveform Generator and Control for Selective Cell Ablation

Abstract

Methods and apparatus for performing ablation. In some examples, an ablation delivery system is configured to allow access to individual voltage levels of a capacitor stack for therapy delivery. An ablation therapy system that can switch between current and voltage controlled outputs is described. Methods of treating a patient using an adjustable interphase or interpulse delay are also disclosed.

Description

[0001] Cross-reference to related patent documents

[0002] This application claims the benefit and priority of U.S. Provisional Patent Application No. 62 / 819,101, filed on March 15, 2019, entitled "WAVEFORM GENERATOR AND CONTROL FOR SELECTIVE CELL ABLATION", the disclosure of which is incorporated herein by reference. This application also relates to U.S. Provisional Patent Application No. 62 / 819,120, filed on March 15, 2019, entitled "TIME MULTIPLEXED WAVEFORM FOR SELECTIVE CELL ABLATION" and U.S. Provisional Patent Application No. 62 / 819,135, filed on March 15, 2019, entitled "SPATIALLY MULTIPLEXED WAVEFORM 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 treatment methods. Tumors can be surgically removed; however, less invasive methods have received much attention. Tissue ablation is a minimally invasive method of destroying unwanted tissue in the body. Ablation can be thermal or non-thermal.

[0004] Thermal ablation increases or removes heat to destroy unwanted cells. For example, cryoablation kills cells by freezing the extracellular compartment, causing cells to dehydrate starting at -15°C and resulting in membrane rupture at colder temperatures. Cryoablation is known to (beneficially) stimulate the patient's anti-tumor immune response.

[0005] Heat-based thermal ablation increases heat to destroy tissue. Radiofrequency (RF) heat, microwave, and high-intensity focused ultrasound ablation can all 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 and converts the vibrations into heat through friction. Once the cell temperature reaches 50 degrees Celsius, cell death occurs within just 30 seconds, and at higher temperatures, cell death is instantaneous. However, heat-based ablation may not promote the desirable immune response associated with cryoablation.

[0006] Both thermal ablation techniques using heat or cold have 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, reversible electroporation, and irreversible electroporation. Electroporation refers to the phenomenon where the cytoplasmic membrane exposed to a high-voltage pulsed electric field becomes temporarily permeable due to lipid bilayer instability. 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 affected by the electric field will absorb the chemicals and subsequently die, providing useful selectivity in the treatment area. Irreversible electroporation (IRE) omits the chemicals and instead uses an electric field, typically at an increasing amplitude, to expand the pores in the cell membrane beyond the point of recovery, 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, providing 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 and, among other problems, require the use of paralytic agents to facilitate the procedure. 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 poses a risk of causing thermal ablation. Improvements and alternatives to the existing technology are needed to allow the use of waveforms as effective as single-phase stimulation for IRE while avoiding muscle stimulation and thus obtaining the benefits of both single-phase and biphasic treatments. Summary of the Invention

[0009] The present inventors have recognized that one of the problems to be solved is to provide an ablation therapy that combines high performance and tissue selectivity while avoiding muscle stimulation. The multiple examples shown below provide illustrative signal generators, systems, and methods for such improvements.

[0010] The first non-limiting example takes the form of an apparatus for generating energy for the electrical ablation of tissue, the apparatus comprising: a voltage source; a capacitor bank having at least one first capacitor and one or more additional capacitors; and an output stage that couples the capacitor bank to a plurality of output nodes, the output stage comprising: a power selector switch pair coupled to a capacitor stack to enable defining a first output to include at least one of the first capacitor and one or more of the additional capacitors, or defining a second output to exclude the first capacitor but include at least one of the one or more additional capacitors, such that the first output is at a higher voltage than the second output; and a plurality of electrode selector switch pairs, each electrode selector switch pair associated with one of the plurality of output nodes, each electrode selector switch pair comprising a high-voltage side switch coupled to the power selector switch pair and a low-voltage side switch coupled to a reference.

[0011] As a supplement or alternative to the first non - limiting example, the device may further include: a feedback circuit coupled to a plurality of output nodes, the feedback circuit including one or more current sensors for sensing and quantifying the current passing through one or more output nodes; and a control node coupled to the feedback circuit, a power selector switch pair, and a plurality of electrode selector switch pairs to control electro - ablation using the one or more current sensors. Additionally or alternatively, the feedback circuit may be configured to detect the peak current of the output to prevent damage to the device components. Additionally or alternatively, the feedback circuit may be configured to detect the average current of the output to determine the characteristics of the delivered treatment.

[0012] As a supplement or alternative to the first non - limiting example, the device may further include: a feedback circuit coupled to a plurality of output nodes, the feedback circuit including one or more voltage sensors for sensing and quantifying the voltage at one or more output nodes; and a control node coupled to the feedback circuit, a power supply selector switch pair, and a plurality of electrode selector switch pairs to control electro - ablation using the one or more voltage sensors.

[0013] As a supplement or alternative to the first non - limiting example, the device may further include a feedback circuit including one or more voltage and / or current sensors for monitoring impedance to track tissue characteristics during treatment delivery.

[0014] The second non - limiting example takes the form of a device for generating energy for tissue electro - ablation, including: a voltage source; a capacitor bank having at least one first capacitor and one or more additional capacitors, the capacitor bank being accessible at multiple locations to serve as multiple output sources; and an output stage coupling the capacitor bank to a plurality of output nodes, the output stage including: a plurality of power selector switches coupled to the capacitor stack at multiple locations, the plurality of power selector switches allowing independent and simultaneous access to the capacitor bank to obtain multiple outputs at the same or different voltage levels; and a plurality of electrode selector switch pairs, each electrode selector switch pair being associated with one of the plurality of output nodes, each electrode selector switch pair including a high - voltage side switch coupled to the power selector switch pair and a low - voltage side switch coupled to a reference.

[0015] As a supplement or alternative to the second non - limiting example, the device may further include: a feedback circuit coupled to a plurality of output nodes, the feedback circuit including one or more current sensors for sensing and quantifying the current passing through one or more output nodes; and a control node coupled to the feedback circuit, a power selector switch pair, and a plurality of electrode selector switch pairs to control electro - ablation using the one or more current sensors.

[0016] As a supplement or alternative to the second non-limiting example, the device may further include: a feedback circuit coupled to a plurality of output nodes, the feedback circuit including one or more voltage sensors for sensing and quantifying the current at one or more of the output nodes; and a control node coupled to the feedback circuit, the power selector switch pair, and the plurality of electrode selector switch pairs to control the electroablation using one or more of the voltage sensors.

[0017] As a supplement or alternative to the second non-limiting example, the device may further include a feedback circuit including one or more voltage and / or current sensors for monitoring impedance to track tissue characteristics during treatment delivery.

[0018] As a supplement or alternative to the first or second non-limiting example, the output stage may define a plurality of paths from the capacitor bank to the output nodes, where at least one path includes a current control circuit that can be switched into and out of the path, and where switching one of the current control circuits into the path configures the device to use a constant current output.

[0019] As a supplement or alternative to the first or second non-limiting example, the output stage may define a plurality of paths from the output nodes to a reference, where at least one path includes a current control circuit that can be switched into and out of the path, and where switching one of the current control circuits into the path configures the device to use a constant current output.

[0020] As a supplement or alternative to the first or second non-limiting example, the control circuit may be configured to provide a constant power output or optionally a constant voltage output.

[0021] Another example takes the form of a system for ablating tissue, the system including a device as in the first or second non-limiting example, and a probe for insertion into, in contact with, or in proximity to the tissue to be ablated.

[0022] A third illustrative and non-limiting example takes the form of a method of treating a patient using ablation therapy, including: setting output parameters for a biphasic electrical output including a first phase of a first polarity and a second phase of a second polarity opposite the first polarity, with a pulse interval defined between the first and second phases; a) providing the biphasic electrical output to the patient using the output parameters and observing whether a muscle response occurs; b) if no muscle response is observed, modifying the output parameters by extending the interval; repeating steps a) and b) until a muscle response is observed or until a pre-defined maximum pulse interval is used; if a muscle response is observed, setting the treatment interval to a portion of the interval at which the muscle response was observed or reducing it; or if the maximum pulse period is used, setting the treatment pulse period to the maximum pulse period; and providing treatment to the patient using a set of treatment parameters including the treatment interval.

[0023] The fourth illustrative and non-limiting example takes the form of a method of treating a patient using ablation therapy, including: setting output parameters for an electrical output having a pulse width and amplitude; providing the electrical output to the patient using the output parameters; observing whether a muscle response occurs in response to the delivered output; and one of the following: a) if no muscle response is observed, modifying the output parameters by increasing at least one of the pulse width or amplitude of the electrical output; b) if a muscle response is observed, modifying the output parameters by decreasing at least one of the pulse width or amplitude of the circuit; and providing the electrical output to the patient again using the output parameters modified in one of steps a) or b).

[0024] The fifth illustrative and non-limiting example takes the form of a method of treating a patient using ablation therapy, including: setting output parameters for a biphasic electrical output that includes a first phase of a first polarity and a second phase of a second polarity opposite the first polarity, defining a pulse interval between the first and second phases; providing the biphasic electrical output to the patient using the output parameters; observing whether a muscle response occurs; a) if no muscle response is observed, modifying the output parameters by lengthening the interval; b) if a muscle response is observed, modifying the output parameters by decreasing the pulse interval; and providing the biphasic electrical output to the patient again using the output parameters modified in one of steps a) and b).

[0025] The sixth illustrative and non-limiting example takes the form of a method of treating a patient using ablation therapy, including: setting output parameters for a biphasic electrical output that includes a first phase of a first polarity and a second phase of a second polarity opposite the first polarity, defining a pulse interval between the first and second phases; providing the biphasic electrical output to the patient using the output parameters; observing whether a muscle response occurs; determining that no muscle response occurs and modifying the output parameters by lengthening the interval; and providing the biphasic electrical output to the patient again using the output parameters having the lengthened pulse interval.

[0026] The seventh illustrative and non-limiting example takes the form of a method of treating a patient using ablation therapy, including: setting output parameters for a biphasic electrical output that includes a first phase of a first polarity and a second phase of a second polarity opposite the first polarity, defining a pulse interval between the first and second phases; providing the biphasic electrical output to the patient using the output parameters; observing whether a muscle response occurs; determining that a muscle response occurs and modifying the output parameters by decreasing the pulse interval; and providing the biphasic electrical output to the patient again using the output parameters having the decreased pulse interval.

[0027] As a supplement to or alternative to the third to seventh non-limiting examples, the step of observing whether a muscle response occurs can be performed by a system user visually observing whether a visible movement or motion of the treatment probe occurs in response to the delivered biphasic electrical output.

[0028] As a supplement to or alternative to the third to seventh non-limiting examples, the step of observing whether a muscle response occurs can be performed by monitoring the output of an accelerometer placed within or on the patient.

[0029] As a supplement to or alternative to the third to seventh non-limiting examples, the step of observing whether a muscle response occurs can include sensing the electromyopotential of the patient's muscle tissue.

[0030] As a supplement to or alternative to the third to seventh non-limiting examples, the step of observing whether a muscle response occurs can include obtaining subjective feedback from the patient.

[0031] The eighth non-limiting example takes the form of a method of delivering an ablation treatment to a patient, including: delivering a train of treatment pulses over a predetermined period of time: delivering a first pulse having a first voltage and a first duration; sensing current during the first pulse; delivering a second pulse having a second voltage and duration, wherein the first voltage is not equal to the second voltage, and the first duration is not equal to the second duration, but the product of the first voltage and the first duration is substantially equal to the product of the second duration and the second voltage; sensing current during the second pulse; determining that the amount of charge delivered during the first pulse is not equal to the amount of charge delivered during the second pulse; and, prior to expiration of the predetermined period of time, delivering at least one additional pulse to eliminate a charge imbalance caused by the difference between the amount of charge of the first pulse and the amount of charge of the second pulse.

[0032] As a supplement to or alternative to the eighth non-limiting example, the at least one additional pulse can be a voltage-controlled pulse having a third voltage and a third duration, the third voltage and third duration being calculated by determining the impedance encountered by at least one of the first and second pulses.

[0033] As a supplement to or alternative to the eighth non-limiting example, the at least one additional pulse can be a current-controlled pulse, while the first and second pulses are voltage-controlled pulses.

[0034] The ninth illustrative and non-limiting example takes the form of an apparatus for generating energy for tissue electroablation, comprising: a voltage source; a capacitor bank for storing energy from the voltage source for delivering ablation energy; a voltage conversion circuit for transferring energy from the voltage source to the capacitor bank at a voltage higher than that which the voltage source can provide; an output stage that couples the capacitor bank to a plurality of output nodes; a sensing circuit for receiving a sensing signal from a probe suitable for use with the apparatus; and a control circuit configured to use feedback from the sensing circuit to control the capacitor bank, the voltage conversion circuit, and the output stage; wherein the control circuit is configured to perform the method in any one of the third to eighth non-limiting examples.

[0035] As a supplement or alternative to the ninth non-limiting example, the sensing circuit may be configured to be used with a probe having a thermal sensor, and the control circuit is configured to receive data related to the temperature sensed by the thermal sensor of the probe from the sensing circuit and modify one or more parameters of the treatment signal generated by the output stage.

[0036] As a supplement or alternative to the ninth non-limiting example, the sensing circuit may be configured to be used with a probe having optical capabilities, and the control circuit is configured to receive data related to a change in tissue color observed using the optical capabilities of the probe from the sensing circuit and modify one or more parameters of the treatment signal generated by the output stage. In another example, the sensing circuit may include a light source and a light detector such that the sensing circuit can direct an optical signal to the optical capabilities of the probe and receive an optical signal indicative of tissue reflectivity from the probe.

[0037] As a supplement or alternative to the ninth non-limiting example, the sensing circuit may be configured to be used with a probe having a transducer, and thus includes a driver circuit for driving the probe transducer and is further adapted to receive a signal from the probe transducer. In another example, the driver circuit may be configured to emit an ultrasonic frequency output to an ultrasonic transducer in the probe to detect a change in the fluid density of the tissue. In another example, the driver circuit may be configured to drive a MEMS-based accelerometer, and the sensing circuit is configured to receive a signal from the MEMS-based accelerometer to detect heart sounds. In another example, the driver circuit may be configured to drive a MEMS-based accelerometer, and the sensing circuit is configured to receive a signal from the MEMS-based accelerometer to detect muscle contractions. In another example, the driver circuit may be configured to drive a MEMS-based accelerometer, and the sensing circuit is configured to receive a signal from the MEMS-based accelerometer to detect an acoustic signal associated with ablation.

[0038] This summary is intended to provide an introduction to the subject matter of the present patent application. It is not intended to provide an exclusive or exhaustive explanation of the invention. The detailed description included in the present invention will provide further information regarding the present patent application.

[0039] Brief description of the drawings

[0040] In the drawings, which are not necessarily to scale, like numerals may describe like components in different views. Identical numerals with different letter suffixes may represent different instances of like components. The drawings generally illustrate, by way of example and not limitation, the various embodiments discussed in this document.

[0041] Figure 1 Shows approximations of different treatment modalities associated with combinations of electric field strength and pulse duration;

[0042] Figures 2-4 Shows various effects of applying an electric field to cells;

[0043] Figure 5 Shows the prior art "Leveen" needle;

[0044] Figures 6-8 Shows various waveform characteristics;

[0045] Figure 9 Shows a signal generator in block form;

[0046] Figure 10 Shows a target tissue surrounded by electrodes;

[0047] Figure 11 Shows an illustrative time multiplexed treatment output;

[0048] Figure 12 Shows a method for configuring and / or testing a treatment;

[0049] Figures 13A-13D Shows an illustrative output and feedback circuit of a signal generator;

[0050] Figures 14A-14B Shows an illustrative pulse generation circuit;

[0051] Figure 15 Shows an illustrative user interface; and

[0052] Figures 16A-16B Illustrates a method for treatment delivery using an unbalanced waveform and correcting detected charge imbalance, shown in block and graphical form. Detailed embodiments

[0053] Figure 1Shows approximations of different biophysical responses that depend on the amplitude-time relationship of the delivered electrical pulses. The thresholds (10, 20, 30) between cellular responses typically operate as a function of the applied field strength and pulse duration. Below the first threshold 10, there is no effect; between the first threshold 10 and the second threshold 20, reversible electroporation occurs. Above the second threshold 20 and below the third threshold 30, irreversible electroporation (IRE) predominantly occurs. Above the third threshold 30, the effects begin to be mainly thermal effects, driven by tissue heating. 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 can produce reversible electroporation (position 22), irreversible electroporation (position 32), and thermal ablation (position 40).

[0054] As described in U.S. Patent 6,010,613, a transmembrane potential in the range of about 1 volt is required to cause reversible electroporation, but the relationship between the pulse parameters (such as time and duration) and the transmembrane potential required for reversible electroporation remains an active area of research. The field required can vary depending on the characteristics of the cells to be treated. At the macroscopic level, reversible electroporation requires voltages in the hundreds of volts / cm, and irreversible electroporation requires higher voltages. For example, when considering in vivo electroporation of liver tissue, as described in U.S. Patent 8,048,067, the reversible electroporation threshold field strength can be about 360 V / cm, while the irreversible electroporation threshold field strength can be about 680 V / cm. Generally, multiple individual pulses are delivered to achieve such an effect across most of the treatment tissue; for example, 2, 4, 8, 16, or more pulses can be delivered. Some embodiments can deliver hundreds of pulses.

[0055] The electric field for electroporation is typically applied by delivering a series of individual pulses, each pulse having a duration in the range of one to hundreds of microseconds. For example, U.S. Patent 8,048,067 describes the analysis and experiments conducted to show that the region between lines 20 and 30 actually exists and that non-thermal IRE treatment can be achieved by delivering a series of 8 100-microsecond pulses at 1-second intervals in several experiments. Figure 1 The tissue membrane does not immediately return from the perforated state to the resting state. As a result, as described in, for example, U.S. Patent 8,926,606, applying pulses in close temporal proximity can have a cumulative effect. Additionally, as described in U.S. PG Patent Application 2007 / 0025919, a series of pulses can be used to first perforate the cell membrane and then move macromolecules through the generated reversible pores.

[0056]

[0057] Figures 2-4 Figure 2 Shows the various effects of applying an electric field to cells. At an electric field strength below the reversible electroporation threshold, as Figure 2As shown, the cell membrane 62 of cell 60 remains intact and no pores appear. As Figure 3 shown, at higher electric field strengths, i.e., above the threshold of reversible electroporation and below the threshold of irreversible electroporation, the membrane 72 of cell 70 forms pores 74. 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 a longer or shorter duration.

[0058] As Figure 4 shown, at higher electric field strengths, above the threshold of 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 so 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, with few or no pores in the region 88 of the cell membrane parallel to the applied field (assuming here that the field is applied between electrodes arranged on the Figure 4 right and left sides of the cell as 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.

[0059] Figure 5 Shows a prior art "Leveen" needle. As described in U.S. Patent 5,855,576, the device includes an insertable portion 100 having a shaft 104 extending to a plurality of tissue piercing electrodes 102 that can be extended or retracted once in proximity to the target tissue 112 of a patient 110. The proximal end of the device is coupled to a power source 108 via an electrical connector 106, and the power source 108 can be used to provide RF energy.

[0060] Traditionally, the Leveen needle has been used to provide thermal ablation to target tissue. For example, as described in the '576 patent, one or more return electrodes in the form of plates can be provided on the patient's skin, the return electrode can be provided as another tissue piercing electrode, or the return electrode can be provided near the distal end of the shaft 104, close to the tissue piercing electrodes 102.

[0061] For example, improvements to the original design can be found in U.S. Patent 6,638,277, which discusses the independent actuation of the tissue piercing electrodes 102, both in terms of the movement of the electrodes and in terms of individual electrodes within the separately electrically activated electrodes. The 5,855,576 and 6,638,277 patents are incorporated herein by reference to show various probes. U.S. Provisional Patent Application 62 / 620,873, the disclosure of which is incorporated herein by reference to show various treatment delivery probes, discloses updates and improvements to the Leveen needle concept, allowing flexibility in the spacing, size, and selection of the electrodes.

[0062] Figures 6-8 shows various waveform characteristics. Refer to Figure 6 , the single-phase waveform is shown as 150. Waveform 150 is shown relative to the baseline or isopotential 152. The idealized square wave is shown as having an amplitude 154, a pulse width 156, and a period length 158. Waveform 150 is shown as an ideal square wave with 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 with a one-microsecond pulse width 156 is transmitted at two-microsecond intervals 158, the "frequency" of the waveform can be described as 500 kHz (the reciprocal of two microseconds). Waveform 150 can be a current-controlled or voltage-controlled waveform. As described further below, either method can be used in various examples.

[0063] In any practical application, the edges of the generated waveform will be rounded, and the rise amplitude from the baseline 152 will be greater, 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 also 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, which may include, for example, an overshoot in amplitude if the signal output is underdamped, or rounding of the edges for critically damped or overdamped signals.

[0064] In some examples, one or more 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 can 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.

[0065] Rise and fall times can be manipulated in several different ways. For example, process settings can be selected to modify the peak voltage target; higher targets can result in faster rise times because various components respond exponentially to turn-on or switching into 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 may switch the voltage source or use output regulation (e.g., by using a rectifier or by 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 user input requesting longer or shorter rise / fall times by selecting the appropriate output switch to use during a particular treatment output session. High-pass or low-pass filtering can also be switched into the output circuit to control the slew rate and can also be switched into the control signal circuit; for example, a slow turn-on of the output transistor will result in a slower rise time for the transistor itself and conversely, a fast turn-on of the output transistor will speed up the rise time. In another example, a digital-to-analog converter can be used as part of 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, thus manipulating the on / off signal to the output circuit itself. In yet another example, using a capacitor stack output as shown in several examples herein, 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 sequentially turning on less than the full capacitor stack and then subsequently adding more of the capacitor stack to the output; diodes placed appropriately in the output circuit will prevent reverse current or shorting of the newly added portions of the capacitor stack during such operation.

[0066] Figure 8 More details are shown, this time for a bipolar signal. Here, the waveform is shown at 180, the first positive pulse is at 182, followed by a negative pulse at 190. The positive pulse 182 has an amplitude of 184 and the negative pulse 190 has an amplitude of 192, which is typically equal to the voltage of 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, 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.

[0067] In typical applications or uses of biphasic signals, part of the purpose is to achieve charge balance at the end of each cycle. To this end, the pulse widths of the two phases are kept equal, and the amplitudes are also equal, but the polarities are opposite. Whether using a voltage control system or a current control system, as long as the pulse width and amplitude are controlled, charge balance can be reasonably maintained. For example, in a voltage control system, assuming the cycle length 196 is quite short, the current is more or less constant within one cycle. That is to say, although it is well known that during the ablation process, tissue impedance changes as cells are destroyed, thereby expelling the cellular medium that usually reduces impedance, the impedance does not change so fast that the charge balance of a simple biphasic waveform, even a biphasic waveform without current control, will become a problem. However, in some of the examples below, the energy delivered is not a "simple biphasic" waveform because the period between the two phases is extended to a duration that exceeds half of the duration of either phase. For example, in this case, it is more likely that impedance changes will cause charge imbalance, thereby triggering or risking muscle stimulation.

[0068] 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 the 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 expire after turning off the first switch and before turning on the second switch to avoid any possible internal short circuit. Faster switching can reduce the interphase time, and a great deal of engineering work has been invested in reducing this time period 188.

[0069] 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 Patent 10,154,869, 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. Closing the switch between the power supply and the load / inductor causes the current through the load to reverse almost immediately because the inductor draws current from the load after the power supply is disconnected.

[0070] From Figures 6-8The background collected 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 in the examples herein, the term "not causing muscle stimulation" allows some muscle stimulation, but only an amount that is tolerable within the relevant intervention and / or surgical field. For example, the stimulation that occurs does not make the patient uncomfortable. In another example, the stimulation that occurs is small enough that the surgery to ablate tissue is not disrupted by the stimulated patient movement. In another example, the muscle stimulation that occurs is inconsequential to the surgery and allows the surgery to be performed without the need to administer a paralytic agent. In some examples, the stimulation that occurs does not affect probe placement and fixation, or is small enough that probe migration does not occur. As used herein, a meaningful charge imbalance for ablation treatment purposes is triggering muscle stimulation that affects the surgery within a single cycle or over multiple cycles. In several embodiments, the aim is to provide an improved treatment - mimicking a single-phase treatment - while avoiding and / or preventing a meaningful charge imbalance.

[0071] Figure 9 A block diagram of a signal generator is shown. The signal generator 200 can be a stand-alone unit, or it can include several discrete components coupled together by wires and / or wireless connections. The control block is shown at 202 and can include multiple logic circuits in the form of a state machine, a microcontroller, a microprocessor, or even an off-the-shelf computing unit such as a laptop or desktop computer as needed, and can also include various associated analog and / or digital logic, application-specific integrated circuits (ASICs), dedicated hardware circuits, etc. The control block 202 having any one and / or a combination of these elements can be described herein as a control node. In one example, the output energy of the system can be transmitted at a much higher amplitude than that used by the operating logic (i.e., the output is hundreds or thousands of volts, and the logic and processing are performed at an amplitude typically below ten volts or even five volts). Thus, isolation circuits, voltage dividers, etc. can be included to reduce the system operating voltage to a level more easily handled by the control circuit. Dedicated circuits, such as ASIC circuits, can be used to handle high-speed operations or sample voltages or currents, etc. by including, for example, dedicated analog-to-digital conversion circuits, dedicated sampling circuits, and convert the measured voltage or current into a digital output. In addition, for example, opto-isolator elements are often used in the art to allow low-voltage control of high-voltage circuits.

[0072] Includes a memory 204 that may or may not be separate from the control block 202 to store an executable instruction set for operation and maintain a log of system activities and any sensor outputs 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. The UI or user interface 206 can also be integrated into the control block (e.g., when using a laptop for control 202, it will include each of the memory 204 and the UI 206). The UI 206 can include a mouse, keyboard, screen touchscreen, microphone, speaker, etc. as needed.

[0073] The power supply 208 can include one or more batteries and / or an electrical connection to plug into a wall socket to receive line power. The treatment block is shown at 210 and includes several stages. The isolation and voltage conversion circuit is shown at 212 and can include, for example, one or more transformers or other boost converters (such as a capacitive boost conversion circuit) to obtain the battery or line voltage and increase it to the high voltage output stored in the HV memory 214. The HV memory 214 can include batteries, inductors, or other circuit elements, but is typically a capacitive storage block, such as a capacitor stack. The HV storage 214 may help obtain the HV signal from block 212 and smooth it over time to provide a more stable high voltage output, which is then transmitted by the HV output circuit 216. Additionally, the HV storage 214 can enable a lower power voltage input to generate a very high power output by storing energy over a longer period of time for transmission in short bursts.

[0074] The HV output circuit 216 can include multiple switches and other elements, such as high voltage switches including thyristors, high power Mosfets, and other elements, to allow selective output of the high voltage signal to the IO block shown at 218. In some examples, one or more optoisolators or other isolation circuits or circuit elements can be used to drive the HV output circuit to allow isolation of the lower power logic and control circuits from the higher power / amplitude circuits. The IO block 218 can provide multiple sockets to receive plugs from one or more delivery probes 220, and one or more outputs for placing one or more indifferent electrodes on the patient's body, used as return electrodes or simply to ground the patient and the system. For illustrative purposes, the drawings show separate outputs as if each output had a separate plug, but the embodiments here also include composite plugs and / or ports that facilitate multiple electrical connections through a single mechanical coupling.

[0075] In some alternative approaches to the treatment block 210, rather than using a switch bank to directly output the signal from the HV storage as HVOut216, a resonant circuit can be powered by the HV signal and the output of the resonant circuit can be 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 relying on the form of an extended H-bridge circuit, as shown in the additional figures and description below. Additional details that can be used in some embodiments are shown in the following additional figures. Certain user interface functions are also highlighted in the following additional figures and description.

[0076] 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 of 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 comparison, Wilkinson, integrating, delta encoding, pipelined, sigma-delta, 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) electrically or magnetically coupled to one or more transmission lines.

[0077] 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 treatment delivery. For example, a temperature sensor can be used to manage non-thermal therapies such as electroporation by observing whether the temperature in a certain area rises above a threshold temperature or shows an increasing trend, in which case one or more elements of the power output can be reduced to ensure that the desired type of treatment predominates. If the probe contains 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.

[0078] 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. Heart signals for identifying a therapeutic physiological window may be received from a clinical electrocardiogram monitor, an implantable medical device (such as a subcutaneous heart monitor, a pacemaker, or a defibrillator), or from various perceptible wearable products for the heart rhythm. Instead of using an ECG, heart sounds or pulse oximetry may be used to identify the cardiac cycle and select a treatment window.

[0079] In addition, as Figure 5 shown, the probe may include one or more imaging devices, such as lenses coupled to an optical fiber cable, to capture an image at or near the probe. For example, a combined lens and optical cable may be provided on one or more of the tissue piercing electrodes, at their distal end, or at their proximal end. The optical cable may have a single strand to simply receive the optical image. In some examples, the optical fiber cable may have more than one strand to allow two "channels", using one to illuminate near the lens and the other to receive the reflected light, or a splitter may be used at the proximal end to allow a pulsed light output to be provided into a single strand and direct the reflected light to a feedback channel, which is then routed to an optical sensor. As the ambient light or reflected light changes, one can observe a change in tissue color, indicating that blood perfusion is occurring or stopping, or indicating a change in the local tissue. In some illustrative examples, the sensing circuit 224 may be adapted for such use by having a light output generator (LED, VCSEL, or other suitable light generator) and a light receiver. A lens may or may not be required; providing an optical fiber bundle with a cutting end in contact with the tissue may be sufficient to allow light to exit.

[0080] In another example, one or more transducers may be placed as Figure 5on the probe shown for a variety of purposes. The accelerometer can be used to sense muscle movement as well as other vibrations, such as acoustic. By emitting an output sound wave ("ping") and receiving feedback, or simply "listening", the transducer can be used to determine if any sound indicating a physical change in the area of the treatment electrode is occurring. For example, if an arc occurs between two electrodes, this generates heat energy, which causes vaporization, which may generate sound waves that can be sensed. An ultrasonic transducer can also be provided, allowing the use of ultrasound to measure changes in tissue fluid density. For each such transducer, the sensing circuit 224 can include a driver circuit, such as an operational amplifier, to supply energy to the transducer via one or more electrical connections in the I / O circuit 218 and the probe 220. As described above, heart sounds can be obtained for timing treatment; such a transducer can also be used to obtain heart sounds. To observe sound energy and / or muscle movement, one, two, or three-axis microelectromechanical systems (MEMS) sensors can be used. Such transducers typically have a vibrating element that changes an electrical parameter when movement is observed. Filtering the output to different frequency ranges in one or more channels may be useful for separately observing patient movement, heart sounds, and / or the sound of a thermal ablation source. As needed, the voltage and / or current sensing circuits described for block 224 can be used to receive, sample, and / or condition the signal returned from the transducer.

[0081] Optionally, an "other treatment" block 222 can be included. "Other" treatments can include, for example, delivering a chemical or biological agent to provide additional treatment to enhance the delivered treatment or trigger an immune response to promote the body's own healing after ablation. Such other therapies 222 can include a reservoir (which can be refillable) of material to be delivered to the patient via, for example, a syringe or catheter or through the probe. "Other therapies" 222 can include introducing a substance that improves, enhances, synergizes with, or independently increases the ablation effect of the electrical delivery therapy. For example, a substance can be injected to alter or enhance the electric field effect, such as the substance disclosed in U.S. Patent Application 16 / 188,343, titled IRREVERSIBLE ELECTROPORATION THROUGH SUBSTANCE INJECTION AND ELECTRICAL FIELD APPLICATION, the disclosure of which is incorporated herein by reference.

[0082] In some examples, cryotherapy can be integrated into the system to allow cooling of tissue before, during, or after electroablation, thereby promoting an immune response as needed. Cryotherapy can be delivered, for example, using a balloon on the treatment probe 220, or provided separately through a nozzle in a balloon connected to a pressurized fluid source (such as nitrous oxide); for example, as disclosed in U.S. Patent 6,428,534, the pressurized fluid discharged through the nozzle expands or undergoes a phase change from liquid to gas, thereby causing local cooling. In another example, a fluid (gas or liquid) can be cooled externally and introduced through a catheter for cryogenic purposes, or, in an alternative, a fluid (gas or liquid) can be heated externally and introduced through a catheter for thermal ablation purposes.

[0083] In other examples, other therapies 222 can include delivering 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, or other laser source) coupled to an optical fiber extending through the probe, to allow delivery of laser energy to the target tissue. In some instances, as noted, a secondary or "other" therapy can be used to trigger an immune response, even if it is not used as the primary method of destroying the target tissue. The modality of "other therapy" 222 can overlap some features of the sensing circuit, so the same circuit elements can be considered part of each block. For example, the laser treatment output can be provided via the I / O as well as a connection for optical interrogation of tissue features via the associated probe. Each can use the same or different optical transducers. In one example, a VCSEL is provided for use in "other treatment" and reused as needed to provide a lower energy output for optical tissue interrogation by the sensing circuit 224.

[0084] For safety purposes, a current sensor on the output circuit can be used to limit short circuit or overcurrent situations. For example, the sensing input block 224 can detect an overcurrent at the I / O 218 and signal the control circuit 202, which can respond by cutting the power to the voltage conversion circuit 212 and / or disabling the HV output 216 to turn off the output circuit (e.g., opening a switch) in response to the detected overcurrent. In some embodiments, the sensing input block 224 can capture the peak current during any treatment output to sense transient events or trends that pose a risk of component damage. At the same time, the sensed current for other purposes (such as determining impedance) can be the peak sensed current during the stimulation output, or can be defined as the average current during the stimulation (more specifically, during a particular one or more of the output phases in the output stage). If the average current is taken, the sensing circuit can determine the start and end time points relative to the system clock, so that the control circuit can align the sensed current with the phase and other characteristics of the output excitation.

[0085] Additionally or alternatively, if desired, the output circuits in the I / O block 218 and / or the HV output 216 may include fuses. Additional safety features may include providing temperature sensors associated with the voltage conversion circuit 212, the HV storage 214, the HV output 216, and / or the I / O 218; an over-temperature condition may cause the system to shut down. In other examples, if the signal generator 200 is too cold, such as when stored or transported in a vehicle in cold weather prior to use, one or more temperature sensors may be used to prevent operation. One or more temperature sensors may be provided on the probe for use with the system to enable or disable operation. For example, a too-cold temperature (e.g., well below body temperature) may indicate that the probe 220 has not been applied to tissue, and the control circuit 202 may prevent stimulation delivery or may provide a warning to the user on the UI 206 that the probe 220 does not indicate a body temperature condition. An over-temperature condition at the probe 220 may indicate thermal damage occurring in a poorly controlled manner, such as may occur when the two contacts of the probe are too close together or shorted; again, the control circuit 202 may be configured to shut down or modulate the intensity. The temperature sensors on the probe 220 may also be used for active feedback, as the control circuit 202 may modulate the treatment amplitude and / or pulse width to obtain a desired temperature range during treatment. For example, for non-thermal or thermal effects, the temperature may be maintained within a predetermined range, such as by keeping the temperature above or below a temperature within the range of 50 to 60 degrees Celsius.

[0086] Figure 10 Depicted is target tissue surrounded by electrodes. As Figure 10 shown, the target tissue 300 may be surrounded by a plurality of electrodes 1-6. A probe such as Figure 5 shown may be readily used to place a plurality of electrodes around the target tissue 300, where the individual electrodes 1-6 pierce and advance through the tissue surrounding the target. In traditional biphasic applications, the electrodes may be used in pairs or groups, or as a complete set relative to a remote return electrode, with a positive phase signal immediately followed by a negative phase signal of generally equal but opposite voltage or current. Contrary to such uses, the present invention uses spatial multiplexing of the treatment output to deliver a treatment with the effectiveness of a single-phase output while taking advantage of the reduced side effects (particularly muscle stimulation) of biphasic treatment. To this end, in one example, the electrodes may be used to provide a single-phase therapy in a cyclic type manner as follows:

[0087] Step Cathode Anode A 1 4 B 2 5 C 3 6 D 4 1 E 5 2 F 6 3

[0088] For this example, each output can be a single-phase waveform. If desired, the pulse width and amplitude during the sequence can remain 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 a distance while exceeding the IRE threshold of the target tissue 300. In one example, electrodes 1 and 4 can be estimated to be 2 centimeters apart, which can be calculated using radiography or other visualization, or can be determined by assuming the impedance per unit distance of the tissue in the probe deployment area, measuring the impedance between electrodes 1 and 4, and then calculating the distance.

[0089] Treatment can be delivered in any order in reference to the above table - that is, it can be in the order of A - B - C - D - E - F. In some examples, the sequence A - D can be avoided because, even nominally not, this is essentially a biphasic output in form and may thus be less effective than a single-phase output. In some examples, to avoid back-to-back or immediate reversal of electrode pairings, rules can be set that require for any given pulse delivery, at least one electrode to be different from the immediately preceding pulse delivery.

[0090] In some examples, the completed sequence is delivered as a train of pulses completed within a time period that satisfies each of the following two rules:

[0091] - Charge balance rule: The train of pulses is completed such that a charge balance or an approximation of charge balance within the following ranges is provided:

[0092] o 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 is determined by its complex impedance; in a simplified model, the time constant is the capacitance multiplied by the resistance of the tissue (including cells) within the electric field generated between the two electrodes. Polarized cells or tissue may have a larger or smaller effective time constant.

[0093] o A time period less than about one millisecond

[0094] o The longest time period tolerable by the patient, determined by testing the patient. For example, to test the patient, the treatment output can include a first part and a second part separated by a period of time, and the period 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 the application of one or more first single-phase pulses with a charge imbalance, and the second part of the treatment is configured to eliminate the charge imbalance. For example, by the interphase period (Figure 8 , 188) By controlling and extending to multiples of a single pulse width, the biphasic output can be divided into two parts - for example, using 5 - microsecond pulses with intervals of tens or hundreds of microseconds, or even more, not exceeding a few milliseconds, tolerated by the patient while still remaining within the treatment completion rules mentioned below.

[0095] - Treatment Completion Rule: The pulse train will be delivered within a physiological window determined by observing non - treatment factors (such as the patient's heart rhythm).

[0096] Regarding the treatment completion rule, with the heart as the driving force, the heart rhythm contains various components known conventionally, such as the R - wave, QRS complex, P - wave, and T - wave. The stimulation for ablation purposes should not interfere with the heart rhythm, and the heart may be less vulnerable 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 called the S - T interval (S - wave ending the QRS complex); the S - T interval for a given patient may last for tens of milliseconds, with a range that may be from 5 to 100 milliseconds. Approximately 60 milliseconds is typical for a healthy individual, but it should be noted that the therapies discussed here may not necessarily apply to healthy or typical individuals, and thus, the S - T interval may not be "typical". In any case, in some examples, the treatment starts and ends within the S - T interval window. The cardiac signals used to identify the ST 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 cardiac signals from electrodes placed in or on the patient. Other sources may be drivers; for example, detecting diaphragmatic movement may also be useful to deliver treatment in a timely manner when the patient inhales or exhales.

[0097] In other examples, one, the other, or both of these timing rules can be omitted. In some examples, the window can be approximate, for example, by setting a rule that the pulse train must return to a balanced charge state within less than one millisecond, or 800 microseconds, or 500 microseconds.

[0098] In another example, multiple electrodes can be combined together as the cathode:

[0099] 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

[0100] In another example, multiple electrodes can be combined together as the anode:

[0101] 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

[0102] Both the anode and the cathode can be combined:

[0103] 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

[0104] A variety of such pairings can be used. As described above, the treatment can be delivered according to a ruleset. As needed, the device for providing the treatment can incorporate such a ruleset into a stored instruction set or hardwire it.

[0105] In view of the foregoing, an illustrative example takes the form of a treatment delivery method that includes delivering a plurality of single-phase outputs between selected electrode pairs or groups of electrodes in a burst. Additionally, a first rule can be used to deliver the treatment delivery and the burst, which first rule requires that each successive pulse in the burst use at least one electrode different from the immediately preceding pulse. The use of the first rule to deliver the treatment delivery and the burst requires that each successive pulse in the burst use at least one different electrode (whether by omitting a previously used electrode, adding an electrode, or replacing one or more electrodes with one or more other electrodes). A second rule requires that the burst 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 that the burst be delivered within a specified physiological window, where the physiological window corresponds to the time during the cardiac cycle when the heart is insensitive or at least relatively insensitive to electrical interference. Another illustrative example can take the form of a signal generator as shown above Figure 9 that stores in executable form or is configured to incorporate the first, second, and third rules. For each of these illustrative examples, the output treatment pulses can be in the range of, for example, about 0.1 to 10 microseconds per pulse, with a burst of any suitable length, such as about 4 to about 100 pulses, and the burst may repeat.

[0106] In some examples, when delivering treatment using various electrodes, the output current of each electrode can be tracked for input or output. At the end of a burst or a series of bursts, the sum of the currents through each electrode can be determined, and one or more corrective outputs can be generated by providing a predetermined amount of current or voltage that may cancel any accumulated charge at any one electrode interface. Various illustrative examples can include a combination of monitoring the delivered charge and then providing a "corrective" pulse to cancel any accumulated charge on any one or more electrode surfaces. The corrective pulse is particularly useful when using voltage-controlled outputs rather than current-controlled outputs. In Figure 10 Other examples that build on or show alternatives thereto can be found in U.S. Provisional Patent Application 62 / 819,135, filed on March 15, 2019, entitled SPATIALLY MULTIPLEXED WAVEFORM FOR SELECTIVE CELL ABLATION, the disclosure of which is incorporated herein by reference.

[0107] Figure 11Shows an illustrative treatment waveform. The example illustrates a method of delivering a multi-phase ablation waveform that includes generating a first pulse train 430 that includes a first pulse 410 of a first polarity (negative in the illustration) having a first amplitude 414 and a first pulse width 412, which alternates with a second pulse 420 of a second polarity opposite the first polarity having a second amplitude 424 and a second pulse width 422 that is less than the first pulse width 412. The example also includes generating a second pulse train 460 that includes a third pulse 440 of the first polarity having a third amplitude 444 and a third pulse width 442, which alternates with a fourth pulse 450 of the second polarity having a fourth amplitude 454 and a fourth pulse width 452 that is greater than the third pulse width 442. The example method can be performed such that the first pulse train 430 creates a first charge imbalance and the second pulse train 460 creates a second charge imbalance that cancels the first charge imbalance to prevent muscle stimulation. The charge imbalance of the first pulse train 430 will be proportional to the difference between the product of the amplitude 414, the pulse width 412, and the number of first pulses 410 of the first pulse train 430 and the product of the amplitude 424, the pulse width 422, and the number of second pulses 420 of the first pulse train 430.

[0108] In some examples, the first and second amplitudes 414, 424 are the same, and the third and fourth amplitudes 444, 454 are the same. Additionally, the method can be performed such that the time 470 from the start of the first pulse train 430 to the end of the second pulse train 460 is short enough to avoid muscle stimulation due to the charge imbalance of the first pulse train 430. For example, as needed, the time 470 can be less than one millisecond, or less than two milliseconds, or less than some other duration.

[0109] In some examples, the durations of the first and fourth pulse widths 412, 452 are equal, and the durations of the second and third pulse widths 422, 442 are equal. For example, the first and fourth pulse widths 412, 452 can be in the range of about 1 to about 20 microseconds, and the second and third pulse widths 422, 442 can be in the range of about 0.1 to about 10 microseconds. In some examples, the first pulse width 412 is approximately twice the second pulse width 422, and the fourth pulse width 452 is approximately twice the third pulse width 442. In other examples, the first, second, third, and fourth pulse widths are all in the range of about 0.1 to 50 microseconds and can have other suitable ratios.

[0110] Generally, Figure 11The concept is to provide two pulse trains that, if delivered individually, each would be unbalanced, and the delivery occurs in a short enough time to achieve charge balance without muscle stimulation. In other examples, a single pulse train with asymmetric output within the pulse train can alternatively be used.

[0111] In some examples, the first pulse train 430 includes a first number of first pulses 410 and a second number of second pulses 420, and the second pulse train 460 includes a third number of third pulses 440 and a fourth number of fourth pulses 450, where the first, second, third, and fourth amounts are all equal. In some examples, the first, second, third, and fourth amplitudes each exceed the irreversible electroporation threshold. As noted above, the "threshold" can depend in part on the pulse width and the distance between the electrodes. In other examples, the first, second, third, and fourth pulse widths are all in the range of about 0.1 to 50 microseconds.

[0112] In an alternative formulation, the pulse train 430 can include an odd number of pulses, such as pulses p1 to p5, each having the same amplitude, where pulses p1, p3, and p5 have the same polarity and each has a pulse width PW, while pulses p2 and p4 have opposite polarities, each with a pulse width of 1.5×PW, which will result in a charge-balanced output even though the pulse charge content delivered for each polarity is different. In another example, the pulse train 430 can include an odd number of pulses, each having the same pulse width, such as pulses p1 to p5, where pulses p1, p3, and p5 have the same polarity and each has an amplitude V, while pulses p2 and p4 have opposite polarities, each with an amplitude of 1.5×V, and the asymmetric output provided is also charge-balanced at the end of the pulse sequence. Other examples based on Figure 11 constructing or showing alternatives thereof can be found in U.S. Provisional Patent Application 62 / 819,120, entitled "TIME MULTIPLEXED WAVEFORM FOR SELECTIVE CELL ABLATION," filed on March 15, 2019, the disclosure of which is incorporated herein by reference.

[0113] Figure 12 A method for configuring and / or testing a therapy is shown. An output configuration is set at 502. The output configuration can be, for example, a definition of a therapeutic or non-therapeutic waveform to be delivered to a patient. For example, a non-therapeutic waveform can be a waveform using a lower or different pulse width than might be used during therapy. For Figure 12The method, a non-therapeutic waveform or a therapeutic waveform can be defined with a pulse width longer than the pulse width used in treatment, so as to amplify the impact of the waveform on the patient's muscle tissue (if needed). In this example, the output configuration 502 includes at least a first and a second signal portion separated by a pulse interval. As part of the output configuration, a pulse interval can be set between two signals of opposite or different polarities.

[0114] Next, the pulse interval is tested as shown at 504. The test includes delivering or outputting the waveform configured at 502, as shown at 506, and then determining or observing whether a muscle response 508 occurs. If no muscle response occurs, the method increases the duration of the inter-pulse delay, as shown at 510, and returns to block 506 to deliver or output the waveform again. This process is repeated in this example until one of two conditions is met - using the maximum or upper threshold pulse interval and no muscle response is observed, or a muscle response is observed. The aim is to maximize the pulse interval to provide a therapeutic waveform that mimics a single-phase waveform, preferentially enhancing the efficacy of causing cell death while avoiding the side effect of muscle stimulation.

[0115] Then the inter-pulse delay can be set, as shown at 512. For example, the inter-pulse delay can be set by reducing a certain margin or percentage of the last tested inter-pulse delay, such as reducing by 1 to 50 microseconds or a percentage of 5% to 25%. In some examples, the interval setting at 512 is performed differently according to the nature of the end of the test at block 508, that is, if the test ends due to reaching the maximum inter-pulse but no muscle response, the inter-pulse delay can be set to the maximum value, or if the test ends due to an observed muscle response, the inter-pulse delay is set to a duration reduced based on the last tested inter-pulse using a margin or percentage.

[0116] After setting the inter-pulse delay at block 512, the method then proceeds to treatment delivery at 514. The treatment delivery can use the same or different parameters in terms of waveform shape, duration, amplitude or type as those tested in blocks 506 / 508. For example, since the goal in blocks 502 to 508 is to select an inter-pulse delay which is mainly a function of the surrounding tissue and not necessarily a function of the ablation target, it may not be necessary to use the parameters required for ablation to perform the test, which may confound the test results. In other examples, the inter-pulse delay is tested as part of the treatment delivery itself by adjusting the inter-pulse delay while using the actual ablation parameters in a repeating series. In a further example, when applying treatment at block 514, for example, in a series of repeated pulse trains, the muscle response can be monitored over time, and if a muscle response is observed, the inter-pulse delay parameter can be modified, such as by reducing the inter-pulse delay.

[0117] The step of monitoring muscle response at 508 can use subjective and / or objective measurements or observations. For example, subjective monitoring 520 can include asking the patient 522 if they feel any muscle tightening, twitching, etc., and / or asking the patient if they have any other sensations, such as tingling, buzzing, burning, paresthesia, etc. Subjective monitoring 520 can also be based on the observation of the user or doctor, as shown at 524, asking the user to indicate if they have witnessed movement, tightening, or other physical responses. In other examples, objective measurements 530 can be used, including, for example, placing a motion sensor 532 on the probe or at relevant locations inside or on the patient to determine if any movement is occurring - whether or not it is perceptible to the user or patient.

[0118] In some examples, muscle response can be observed by capturing electrical signals from the muscle itself (electromyogram 534); when the muscle exhibits an electrical response, it can be understood that movement is about to occur or may occur. In other examples, during treatment, gross observations (i.e., patient sensation or movement) may be used during the setup of the inter-pulse delay, and electromyogram is used to provide feedback during treatment by determining if the electrical signals from the muscle change over time; an increase in the magnitude of the sensed muscle electrical response can be used to reduce the inter-pulse delay, or some other characteristic, such as amplitude, to avoid triggering muscle movement; conversely, a decrease in the electrical response may indicate that changes in the ablated tissue (e.g., as cells are destroyed) are reducing the likelihood of muscle response, thus allowing a longer inter-pulse delay and / or a higher amplitude output.

[0119] Figures 13A-13D An illustrative output and feedback circuit of a signal generator is shown. Now refer to Figure 13A , illustrative examples can include multiple sources 550, which are connected to multiple switches 552 that allow the delivery of multiple independent channels for ablation treatment. The multiple sources can include current sources (e.g., a set of current mirrors that can be added together as needed), or can include multiple voltage sources, such as capacitor stacks, as further illustrated below in Figures 14A-14B . Depending on the nature of the source 550, for example, if a current source that can be independently disabled is used, the switch 552 can be omitted.

[0120] In some examples, the wire between the source 550 and the output block 556 can be considered the "high voltage side" of the output circuit. If desired, the feedback connection indicated at 554 can be used to monitor the high voltage side wire. For example, the feedback connection 554 can be a current sensor for measuring the current through the wire or a voltage sensor for measuring the voltage. A voltage or current sensor from the list of examples mentioned above can be used. If desired, both a current sensor and a voltage sensor can be provided. The feedback connection 554 is coupled to a feedback monitoring circuit 570, which can include, for example, various conditioning, filtering, comparing, sampling, and / or storage circuits or circuit elements to capture what occurs during the therapy output.

[0121] The output block 556 can include one or more mechanical ports, plugs, or other connectors for making mechanical and electrical connections to a therapy delivery probe. Although four outputs are shown at 556, it should be understood that the present invention is not limited thereto and any number of outputs can be provided. If desired, two or more output blocks 556 can be provided alternatively.

[0122] Another set of wires couples the output block 556 to another set of switches 560. The switches 560 can enable or disable the output and can link the output to the reference voltage or ground of the system, or can be coupled to multiple sources 562. In some examples, the ablation stimulation output can simply be coupled to the system ground for return purposes. In other examples, if desired, one or more voltage sources or current sources can be used as the negative source or sink for the output energy.

[0123] In some examples, the wire between the block 556 and the switches 560 can be considered the low voltage side wire. An additional set of feedback connections 558 can be provided on the low voltage side wire. The feedback connections 558 can include a voltage or current sensor or both as needed, and are again coupled to a feedback monitoring circuit 572, which can be similar to block 570. The high voltage side source 550 and switches 552, feedback circuits 570, 572, and the low voltage side sources 562 and switches 560 are all shown coupled to a control block 580, which can include various control elements discussed above with respect to Figure 9 block 202.

[0124] Feedback monitoring circuits 570, 572 can be used to monitor the peak current of the delivered stimulus to identify overcurrent conditions and prevent components inside the device from being damaged by overcurrent. Alternatively, the peak or average current can be monitored to determine what the output might do in the tissue, such as causing thermal or non-thermal ablation. In an example, the average current is monitored with reference to time blocks, such as with reference to the start and end points of a treatment phase, multiple phases, or a burst. The average current can be used to monitor physiological changes, for example, which may be related to determining that electroporation has occurred and cell contents have been expelled into the interstitial fluid. In other examples, current feedback can be used to provide a current control output.

[0125] As described above, additional feedback can also be obtained from the probe used for stimulation / therapy delivery, including, for example, thermal sensing, acoustic sensing, visual observation / sensing, ultrasound, and impedance monitoring. Such feedback loops can be used to identify hazards and / or monitor the progress and / or success or failure of the treatment output of the ablated tissue.

[0126] Figure 13B Another example of coupling a power source to a set of voltage sources (capacitor stack) is shown, where independent outputs are available at multiple different levels. Example 600 uses a voltage or power input 610 coupled to a boost converter 612 that is used to charge the capacitor stack 614. Block 612 can be similar to Figure 9 block 212.

[0127] This example shows four capacitors 616 in the capacitor stack 614; any suitable number of capacitors can be used in examples using a capacitor stack. For example, depending on the need, 2 to 20 capacitors or more can be used. The size of the capacitor 616 and the capacitor stack 614 will be jointly designed to allow a high-voltage (kilovolts or higher) output with a duration up to the millisecond range to be delivered to a load as small as a few tens of ohms without significant voltage drop. For example, a typical output voltage range can be between 200 volts and 10 kV, or lower or higher, and a representative load may be less than 10 ohms, such as 5 ohms or 2 ohms, or lower or higher. For a single capacitor or the entire stack, a representative capacitor size can be in the range of 10 to 10,000 microfarads or lower or higher. A reconfigurable capacitor stack can include capacitors that can be charged in parallel and discharged in series or charged and discharged in series or parallel using any suitable number and arrangement of switches and diodes to couple the capacitors together.

[0128] In an illustrative numerical example, considering an output circuit impedance of approximately 25 ohms (including the patient), the time constant of the output circuit is preferably greater than 1 millisecond, and more preferably greater than 10 milliseconds. Thus, for example, a set of four 1600 microfarad capacitors can be used to provide a stacked capacitance of 400 microfarads, which will produce a 10 millisecond time constant when used with a 25 ohm load. Reducing the load to 10 ohms will still provide a 4 millisecond time constant. Larger loads will of course provide longer time constants. Other design parameters can be used, including different capacitor numbers and sizes, different patient load estimates, and different target minimum time constants.

[0129] Multiple sets of switch arrays 620 are connected to nodes within capacitor stack 614 at several different levels, including at the top 622, between the top two capacitors 624, between the middle two capacitors 626, and between the bottom two capacitors 628. Each switch array defines paths A, B, and C respectively as alternative outputs, each output being capable of tapping the stack at different power / voltage levels; each set 620 has a switch dedicated to each output path. As shown at 630, each output path can include current monitors I1, I2, I3; in other examples, voltage monitors can be on each path, or both voltage and current can be monitored. The switches can be, for example, relays, high power Mosfets, silicon controlled rectifiers (SCRs), other transistors, or can include multi-part switches such as SCRs in combination to enable a signal to turn off a signal with a Mosfet. The ground or reference node G is also highlighted.

[0130] Those skilled in the art will understand that Figure 13B An example with multiple independently operable channels is shown. Given appropriately sized capacitors, each channel can generally operate without affecting the other channels. The capacitor size can be reflected in the rating of the system output, since the capacitor size combined with the output impedance (including the patient) can be used in combination to determine the maximum pulse width and voltage / amplitude ratings. For example, if the capacitor stack is tapped at position 626, the maximum output current (or minimum impedance) may be relatively greater than when the capacitor stack is tapped at the top 622.

[0131] The topology shown omits various diodes and current control devices that can be used to allow the capacitor stack to charge without directly linking the boost voltage from block 612 to the actual output. In some examples, voltage conversion can use a multi-tap transformer rather than being single-connected to the top of the capacitor stack at 612, where each tap is connected to nodes 622, 624, 626, 628, effectively charging the capacitor stack in parallel while allowing series discharge. For charging, the primary stage loads energy from voltage source 610 into the transformer, while the secondary stage releases the loaded energy into capacitor stack 614. Whichever capacitor carries the lowest voltage will be charged to the greatest extent during the secondary stage. Appropriate timing of the secondary stage will allow the charging of the capacitor stack to occur intermittently with the therapeutic output. By using a multi-tap charging circuit, the capacitor stack can be updated and rebalanced as current is drawn from its selected portions.

[0132] Figure 13C An illustrative output configuration is shown. Reusing the Figure 13B names A, B, C from , a set of output nodes O1, O2, O3 are shown as being coupled to outputs A, B, C. Switch 654 couples Figure 13B node A of the circuit in to output node O1658. Switch 654 is somewhat redundant, note that the Figure 13B switches shown in each group 620 can be the only switches. While two switches may increase complexity, they may also limit leakage current that could be harmful to the patient. In fact, in some examples, one switch can be an enabling switch while the other is used to assist with waveform shaping and / or cutting off the current. Current and / or voltage can be measured using node 660. A ground switch is shown at 656. During operation, the ground switch 656 can be used to define the return electrode for the output - that is, any output current can be delivered relative to ground. As previously mentioned, if needed, the return can be to a negative voltage source or current sink rather than ground or reference.

[0133] Figure 13DShows another configuration that allows the output node to be placed in voltage or current control operation. Circuit 680 is shown for connecting a single node A 682 to output O1 686, but can be replicated for multiple output nodes. The first switch 696 connects output O1 to resistor 694 and bypass switch 690. For voltage-controlled output, switches 690 and transistor 696 are closed simultaneously. Opening switch 690 while driving transistor 696 allows current to pass through resistor 694. By controlling VDrive, which powers transistor 696, the current through the circuit can be controlled because the current through resistor 694 is limited by the equation: VDrive > I × R(694), where R(694) is the resistance of resistor 694 and I is the current. This configuration is somewhat similar to the configuration shown in U.S. Patent 6,952,608, where it is used to deliver a constant current pacing stimulus in an implantable defibrillator. Other configurations known in the art can be used.

[0134] In some examples, a current control circuit such as Figure 13D can be used to perform current control. In other examples, a monitoring circuit, whether on the high-voltage side, low-voltage side, or in the input / output circuit, can be used to monitor voltage and / or current. Then, an analog-to-digital conversion circuit or other regulator can be used to modify the returned reference voltage or the output voltage obtained from the capacitor stack to change the voltage output and provide a constant current, constant voltage, or constant power (power is the product of voltage and current) output. For example, as the current change is measured and monitored, the voltage output can be increased or decreased to maintain a constant power. In another example, a constant power circuit can control the current as Figure 13D shown, while monitoring the output voltage, and can modify the current by adjusting the VDrive signal to ensure that the product of the current and voltage delivered to the probe is constant.

[0135] Figures 14A-14B Shows an illustrative pulse generation circuit. Now refer to Figure 14A , circuit 700 includes a capacitor bank or stack shown at 710, having multiple capacitors and multiple circuit paths, including at least paths 712, 714 leading away from it. The capacitor stack 710 can be charged using a voltage source (not shown), which can be a battery or line voltage connected to a voltage converter to generate a voltage in the range of one to several thousand volts as needed; voltages of 2, 4, 6, and up to 10 kV or higher can be used.

[0136] Then an output stage including at least one power selector switch pair is provided, as shown at 720. The power selector switch pair 720 is shown as having first and second switches 722, 724 that can select all or only a portion of the capacitor stack to power the output signal. If desired, more than two switches can be included to enable selection of multiple different power levels. If switch 722 is closed and switch 724 is open, the entire capacitor stack 710 can be used to select a higher voltage output, while if switch 722 is open and switch 724 is closed, a lower voltage output capacitor stack can be selected by using less than the entire capacitor stack 710, thereby excluding at least one capacitor of the capacitor stack.

[0137] The output circuit further includes a plurality of output arms 730, 740, 742, 744, each output arm including an electrode selector switch pair. The electrode selector switch pair controls which of the output nodes (here labeled Elec1, Elec2, Elec3, and Elec4) act as anodes or cathodes. Two or more such nodes can act as anodes or cathodes simultaneously; for example, there can be one anode, one cathode, two open nodes, or two anodes and one cathode, one open node, or two cathodes and one anode, one open node, or two cathodes and two anodes, etc., etc., various combinations. Each electrode selector switch pair includes a high-side switch coupled to the power selector switch pair and a low-side switch coupled to a reference. For example, electrode switch pair 732 has a high-side switch 734 for coupling to power selector 720 and a low-side switch 736 for coupling to a reference or system ground. If desired, additional branches can include discharge and / or leakage resistors (not shown) to allow active or passive discharging of the circuit when not in use.

[0138] Figure 14B Another topology is shown. This time, the capacitor stack or capacitor bank 760 is connected to the power selector 766 via at least two output paths 762, 764, as Figure 14A shown. The electrode switch pair in this example includes at least first and second main branches 768, 770. While switch pair 770 is similar to the switch pair Figure 14A shown, switch branch 768 is different. The first switch pair 780 allows access to multiple low-level branches, where switch pairs 782, 784 allow selective connection to a set of four output nodes 786, 788, 790, 792. Thus, multiple topologies with different complexities can be used to allow individual selection of the power level (via block 766) and the outputs to be used (via branches 768, 770).

[0139] Figure 15Shows an illustrative user interface. The user interface can be generated on a display screen, such as on a standalone screen, laptop computer, tablet computer, or any other suitable device. The display screen can be a touch screen. The display 800 shows the user a variety of features and diagnostics. A slider is shown at 802 for displaying the maximum amplitude of the current output relative to the maximum voltage (VH); the user can modify the maximum amplitude of the current output via the touch screen, trackball, mouse, touchpad, keyboard, etc. A number of current settings are shown at 804, including the positive pulse width (PPW), negative pulse width (NPW), and interpulse duration (IPD). Each of the PPW, NPW, and IPD can be modified using the various embodiments shown herein as well as the embodiments shown in the related U.S. Provisional Patent Applications 62 / 819,120 and 62 / 819,135, the disclosures of which are incorporated herein by reference.

[0140] Other modifiable parameters include the number of pulses per burst (PPB), which controls the number of pulses delivered in a single ablation energy burst. The intercycle delay (ICD) defines the time elapsed between two sets of pulses. The number of bursts to be delivered (#Bursts) can also be set, as well as the delay between bursts (BRD). In the example shown, the output energy will be delivered as a four-microsecond positive and negative square wave, with a four-microsecond delay between the two square waves, and the delivery of five pairs of positive and negative square waves having a four-microsecond delay between the end of the negative square wave and the start of the subsequent positive square wave. Each burst of five cycles is separated from the next burst by 1000 milliseconds, and one hundred bursts are to be delivered.

[0141] Additional control features are shown at 808, with the trigger set to off. If the trigger is on, biometrics (such as a reference point identified in the cardiac cycle) can be used instead of the BRD to trigger each burst. In an alternative, having the trigger on while the BRD is set can indicate that each burst is to be separated from the next by at least the BRD, and the new burst is triggered by a sensed biometric such as a cardiac cycle reference point. The cardiac cycle reference point can be, for example, the identification of the R wave or QRS complex, followed by some post-event delay. For example, the trigger output can be delivered by sensing the R wave and waiting 5 to 100 milliseconds after the end of the R wave before treatment delivery, with the goal of completing the burst before the T wave occurs. If desired, the system can be set to automatically calculate the delay by subtracting the length of time required to complete the burst from the known, tested, or estimated S-T duration.

[0142] The additional feature 808 can also define a time limit for completing the treatment, which can time out to prevent system hang-up. The current threshold is also set as indicated and can be provided to ensure that the current does not exceed a threshold that may pose a risk of harm to the patient. For example, it is well known that when cells are ablated, the local impedance may decrease; excessive current may cause tissue heating or component damage, so setting limits may help ensure safety or control the spatial characteristics of the ablation effect.

[0143] As shown at 810, a remaining time indicator and a measurement of impedance 812 can be provided. The impedance can be reported as the total impedance of the system output, including the impedance of the probe being used, or it can be more specifically for the impedance of the patient tissue being treated. A graph can be shown to display the sensed output voltage waveform 814, the overall or specific or most recent cycle or burst of the treatment output. The sensed current can be similarly shown in graphical form 816. A disable signal button 820 can be provided to allow pre-treatment or post-treatment display of one or more patient signals; during treatment delivery, this button 820 can be grayed out, hidden, or inaccessible if needed. A stop button is prominently shown at 824 to allow the treatment to be turned off if needed. The current setting for the level of the capacitor stack being used can be displayed at 826. Further diagnostics and status are shown on the right side of the display, including the current capacitor stack voltage at 830, the history of the capacitor stack voltage at 832, and the peak sensed voltage and peak current (indicated as positive but can also be negative) of the positive and negative phases of the output signal, and the peak impedance calculation can be shown in block 834. The history of the impedance can be shown in a graph in block 836 versus time. The specific set of parameters and diagnostics shown is merely exemplary, and more, fewer, or different parameters and diagnostics can be shown. The displayed tissue can also be modified if needed.

[0144] Figures 16A-16B A treatment delivery method using an unbalanced waveform and correcting detected charge imbalance is shown. Figure 16A The method is shown in block form, while Figure 16B the method is shown in graphical format. Starting from Figure 16A the figure shows a method of delivering an ablation treatment to a patient, including delivering a train of treatment pulses over a predetermined period of time. The method includes delivering a first output at 910. The first output can be a first pulse having a first voltage and a first duration. The method includes sensing at least the current during the first pulse, as shown at 920.

[0145] Next, the method includes delivering a second output as indicated at 912. The second output can include a second pulse having a second voltage and duration. In one example, the first voltage is not equal to the second voltage, and the first duration is not equal to the second duration, but the product of the first voltage and the first duration is substantially equal to the product of the second voltage and the second duration. Additionally, the method includes sensing current during the second pulse, as shown at 922.

[0146] Then, the method includes adjusting the charge balance produced by the first and second outputs 910, 912, as shown at 924. In one example, the adjustment 924 includes determining that the amount of charge delivered during the first pulse is not equal to the amount of charge delivered during the second pulse. The adjustment includes delivering at least one additional pulse before the expiration of a predetermined time period to eliminate a charge imbalance caused by a difference between the amount of charge of the first pulse and the amount of charge of the second pulse. As shown at 914, an additional pulse can include a single output or more than one output.

[0147] Figure 16B The method is shown graphically as delivering a first pulse 910 having a first amplitude and a first pulse width, and delivering a second pulse 912 having a second amplitude and a second pulse width. It can be seen that the height and width of the two pulses 910, 912 are different, but the area under the line of the two pulses is approximately equal - that is, generally, equal within about + / - 10%, or + / - 5% or + / - 2%. Although the combination of voltage and duration may provide a balanced output in terms of charge, this may not be the case in the real world. Therefore, one or more adjustment pulses are delivered at 914.

[0148] In a further example, at least one additional pulse is a voltage-controlled pulse having a third voltage and a third duration, which are calculated by determining the impedance encountered by at least one of the first and second pulses. Alternatively, the total charge delivered during the first and second pulses or the net charge delivered in the first and second pulses can be calculated. In another example, the adjustment pulse 914 can be delivered as a current-controlled output, while the initially delivered pulses 910, 912 can be delivered as voltage-controlled outputs. If desired, the adjustment pulse can be delivered at a non-therapeutic amplitude or duration.

[0149] The operation can be a burst of any number of pulses rather than a single pulse, while tracking the total charge delivered, followed by one or more corrective outputs to eliminate charge imbalance. Although significant charge imbalance may not necessarily occur in a single cycle within a burst, or even in a single burst, it may accumulate over time as the cycles are repeated within the burst and the bursts are repeated within a treatment plan to an extent sufficient to affect the patient or the treatment, e.g., causing muscle stimulation. Thus, the adjustment can be made after the output pair, after a cycle, after a burst, or occasionally within a series of bursts. For example, the correction can be periodic and provided after a set number of cycles or bursts or after a set period of time, or can be occasional and provided when the sensed or calculated imbalance reaches or exceeds a threshold.

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

[0151] The above detailed description includes references 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 other than those shown or described. However, the inventors also contemplate examples that provide only those elements shown or described. Additionally, the inventors also contemplate examples using any combination or arrangement of those elements (or one or more aspects thereof) shown or described with respect to a particular example (or one or more aspects thereof) or with respect to other examples (or one or more aspects thereof) shown or described herein.

[0152] If there is an inconsistency in usage between this document and any document incorporated by reference, the usage in this document shall govern. In this document, the term "a" is used, as is common in patent documents, to include one or more, independent of any other instance or usage of "at least one" or "one or more". Additionally, in the appended claims, the terms "first", "second", "third", etc. are used only as labels and are not intended to impose numerical requirements on their objects.

[0153] The method examples described herein can be at least partially machine or computer-implemented. Some examples can include a computer-readable medium or a machine-readable medium encoded with instructions operable to configure an electronic device to perform the methods as described in the above examples. Implementations 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 disks, memory cards or sticks, random access memory (RAM), read-only memory (ROM), etc.

[0154] 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. Other embodiments can be used, such as by one of ordinary skill in the art after reading the above description. The abstract is provided to comply with 37 C.F.R. § 1.72(b), allowing the reader to quickly ascertain the nature of the technical disclosure. It is submitted with the understanding that it will not be used to interpret or limit the scope or meaning of the claims.

[0155] Furthermore, in the above detailed description, various features can be combined together to simplify the disclosure. This should not be construed as intending that the disclosed features that are not claimed are essential to any claim. On the contrary, the subject matter of the present invention may lie in less than all of the features of a particular disclosed embodiment. Accordingly, the following claims are hereby incorporated into the detailed description as examples or embodiments, with each claim standing on its own as a separate embodiment, and it is anticipated 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 and the full scope of equivalents to which such claims are entitled.

Claims

1. An apparatus (600) for generating energy for use in tissue electroablation, comprising: a voltage source (610); a capacitor bank (614) having at least one first capacitor and more than one additional capacitor, the capacitor bank being accessible at multiple locations for use as multiple output sources; and an output stage that couples the capacitor bank (614) to a plurality of output nodes (632), each output node (O1, O2, O3) having an output path (A, B, C), the output stage comprising: a plurality of power selector switches coupled to the capacitor stack at multiple locations, the plurality of power selector switches arranged in a switch array (620), each group of the switch array including switches dedicated to each output path, allowing independent and simultaneous access to the capacitor bank to derive multiple outputs at the same or different voltage levels; and a plurality of electrode selector switch pairs (654, 656), each of the electrode selector switch pairs being associated with a corresponding one of the plurality of output nodes, each of the electrode selector switch pairs including a high-side switch (654) coupled to the corresponding one of the output nodes and a low-side switch (656) coupled to a reference.

2. The apparatus according to claim 1, further comprising a feedback circuit coupled to the plurality of output nodes, the feedback circuit including one or more current sensors for sensing and quantifying current passing through more than one output node, and a control node coupled to the feedback circuit, the power selector switch pairs, and the plurality of electrode selector switch pairs, the control node being adapted to control electroablation using the one or more current sensors.

3. The apparatus according to claim 1, further comprising a feedback circuit coupled to the plurality of output nodes, the feedback circuit including one or more voltage sensors for sensing and quantifying current at more than one output node, and a control node coupled to the feedback circuit, the power selector switch pairs, and the plurality of electrode selector switch pairs, the control node being adapted to control electroablation using the one or more voltage sensors.

4. The apparatus as claimed in claim 1, further comprising a feedback circuit including one or more voltage and / or current sensors for monitoring impedance to track tissue characteristics during treatment delivery.

5. The apparatus according to any one of claims 1-4, wherein the output stage defines a plurality of paths from the capacitor bank to the output nodes, wherein at least one path includes a current control circuit that can be switched into and out of the path, and switching one of the current control circuits into the path configures the apparatus to use a constant current output.

6. The apparatus according to any one of claims 1-4, wherein the output stage defines a plurality of paths from the output nodes to the reference, wherein at least one path includes a current control circuit that can be switched into and out of the path, and switching one of the current control circuits into the path configures the apparatus to use a constant current output.

7. The device according to any one of claims 1-4, wherein the control circuit is configured to provide a constant power output.

8. The device according to any one of claims 1-4, wherein, the control circuit is configured to provide a constant voltage output.

9. A system for ablating tissue, comprising the device according to any one of claims 1-8, and a probe for insertion into the tissue to be ablated or placed in contact with or near the tissue to be ablated.

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