Patent Description:
Irreversible electroporation (IRE) is a soft tissue ablation technique that applies short pulses of strong electrical fields to create permanent and hence lethal nanopores in the cell membrane, thus disrupting the cellular homeostasis (internal physical and chemical conditions). Cell death following IRE results from apoptosis (programmed cell death) and not necrosis (cell injury, which results in the destruction of a cell through the action of its own enzymes) as in all other thermal or radiation based ablation techniques. IRE is commonly used in tumor ablation in regions where precision and conservation of the extracellular matrix, blood flow and nerves are of importance.

In <CIT>, there is described a method for ablating tissue by applying at least one pulse train of pulsed-field energy.

Exemplary embodiments of the present invention that are described hereinbelow provide improved devices for performing an IRE procedure.

There is therefore provided, in accordance with an exemplary embodiment of the invention, medical apparatus, including a probe configured for insertion into a body of a patient and including a plurality of electrodes configured to contact tissue within the body. An electrical signal generator is coupled to apply bipolar trains of pulses having a voltage amplitude of at least <NUM> V and having a duration of each of the bipolar pulses less than <NUM> between at least one pair of the electrodes in contact with the tissue, thereby causing irreversible electroporation of the tissue between the at least one pair of the electrodes. One or more electrical sensors are coupled to an output of the electrical signal generator and configured to sense the energy dissipated between the at least one pair of the electrodes during the trains of the pulses. A controller is coupled to control electrical and temporal parameters of the trains of the pulses applied by the electrical signal generator, responsively to the one or more electrical sensors, so that the dissipated energy satisfies a predefined criterion.

In one exemplary embodiment, the electrical parameters controlled by the controller include a voltage. Alternatively or additionally, the electrical parameters controlled by the controller include a current.

In some exemplary embodiments, the controller is configured to control the electrical parameters so that the dissipated energy between each pair of the electrodes meets a specified target value. In one exemplary embodiment, the controller is configured to adjust a peak amplitude of the pulses that are applied between the at least one pair of the electrodes so that the dissipated energy satisfies the predefined criterion.

Typically, the one or more electrical sensors are configured to measure a voltage and a current flowing between the at least one pair of the electrodes in a sequence of time intervals, and the controller is configured to measure the dissipated energy by computing a sum of a product of the voltage and the current over the sequence of the time intervals.

In further exemplary embodiments, the controller is configured to control the temporal parameters so that the dissipated energy between each pair of the electrodes meets a specified target value. In one exemplary embodiment, the controller is configured to adjust a number of the pulses that are applied between the at least one pair of the electrodes so that the dissipated energy satisfies the predefined criterion. Alternatively or additionally, the controller is configured to adjust a duration of the pulses that are applied between the at least one pair of the electrodes so that the dissipated energy satisfies the predefined criterion.

There is also provided, in accordance with an exemplary non-claimed embodiment of the disclosure, a method for ablating tissue within a body of a patient. The method includes inserting a probe into the body, wherein the probe includes a plurality of electrodes configured to contact the tissue. Bipolar trains of pulses having a voltage amplitude of at least <NUM> V and having a duration of each of the bipolar pulses less than <NUM> are applied between at least one pair of the electrodes in contact with the tissue, thereby causing irreversible electroporation of the tissue between the at least one pair of the electrodes. the energy dissipated between the at least one pair of the electrodes during the trains of the pulses is measured, and electrical and temporal parameters of the trains of the pulses applied by the electrical signal generator are controlled, responsively to the measured energy, so that the dissipated energy satisfies a predefined criterion.

IRE is a predominantly non-thermal process, which causes an increase of the tissue temperature by, at most, a few degrees for a few milliseconds. It thus differs from RF (radio frequency) ablation, which raises the tissue temperature by between <NUM> and <NUM> and destroys cells through heating. IRE utilizes bipolar pulses, i.e., combinations of positive and negative pulses, in order to avoid muscle contraction from a DC voltage. The pulses are applied, for example, between two bipolar electrodes of a catheter.

In order for the IRE-pulses to generate the required nanopores in tissue, the field strength E of the pulses must exceed a tissue-dependent threshold Eth. Thus, for example, for heart cells the threshold is approximately <NUM> V/cm, whereas for bone it is <NUM> V/cm. These differences in threshold field strengths enable IRE to be applied selectively to different tissues. In order to achieve the required field strength, the voltage to be applied to a pair of electrodes depends both on the targeted tissue and on the separation between the electrodes. The applied voltages may reach up to <NUM> V, which is much higher than the typical voltage of <NUM>-<NUM> V in thermal RF ablation.

A bipolar IRE-pulse comprises a positive and a negative pulse applied between two electrodes with pulse widths of <NUM>-<NUM> and a separation between the positive and negative pulses of <NUM>-<NUM>. (Herein the terms "positive" and "negative" refer to an arbitrarily chosen polarity between the two electrodes. ) The bipolar pulses are assembled into pulse trains, each train comprising between one and a hundred bipolar pulses, with a pulse-to-pulse period of <NUM>-<NUM>. To perform IRE ablation at a given location, between one and a hundred pulse trains are applied between a pair of electrodes at the location, with a spacing between consecutive pulse trains of <NUM>-<NUM>. The total energy per channel (electrode-pair) delivered in one IRE ablation is typically less than <NUM> J, and an ablation may last up to <NUM>.

When a multi-electrode catheter is used in an IRE procedure, successive pairs of electrodes may be cycled through during the procedure. Taking as an example a <NUM>-electrode catheter, the electrode pairs may be energized in an adjacent fashion (<NUM>-<NUM>, <NUM>-<NUM>,. <NUM>-<NUM>) or in an interleaved fashion (<NUM>-<NUM>, <NUM>-<NUM>,. <NUM>-<NUM>). Energizing, for example, adjacent pairs is done in two stages, first energizing the odd-even electrodes <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM> and <NUM>-<NUM>, and then the even-odd electrodes <NUM>-<NUM>, <NUM>-<NUM>, <NUM>-<NUM>, and <NUM>-<NUM>.

Before starting the IRE procedure, the physician sets the parameters of the procedure based on, for example, the volume of the tissue to be ablated, required field strength within the tissue, catheter configuration, and the energy to be delivered during the procedure.

Once the procedure has started, the IRE ablation pulses may, in addition to the desired effect of electroporation itself, also affect the impedance of the tissue and/or the contact impedance between the electrodes and the tissue. For a fixed duration and amplitude of a pulse, a change in any of these impedances will affect the current delivered by the pulse, and thus the energy transferred from each pulse into the tissue. This, in turn, will cause the total energy dissipated in the tissue during the procedure to deviate from the amount of energy preset by the physician. Consequently, the effect of the IRE ablation may be different than expected. Moreover, two procedures that have the same energy settings for the IRE ablation may in reality have different amounts of energy transferred to the tissue, thus possibly affecting the repeatability of these kinds of procedures. Specifically, exceeding a preset level of energy may lead to unwanted thermal effects, such as formation of bubbles around the electrodes or charring of the tissue.

The exemplary embodiments of the present invention that are described herein address the problem of controlling the amount of energy that is delivered to the tissue in an IRE procedure by measuring the actual dissipation of energy between the electrodes. Based on this measurement, the pulses delivered by the catheter to the tissue are controlled so that the amount of dissipated energy satisfies a predefined criterion. For example, the criterion may specify that the amount of dissipated energy meets a certain target value (i.e., that the cumulative energy dissipated in each location in the tissue is equal to the target value to within a certain error bound, such as ±<NUM> percent or ±<NUM> percent). Alternatively or additionally, other criteria may be defined.

For these purposes, the exemplary embodiments that are described herein provide a medical apparatus comprising an electrical signal generator and a controller. The medical apparatus further comprises a probe, which is inserted into a body of a patient and which comprises multiple electrodes that contact tissue within the body and are used in applying the electrical signals for the IRE procedure to the tissue. The controller receives setup parameters for implementing an IRE ablation protocol. The parameters may be preset, or they may be adjusted by an operator of the apparatus, such as a physician. The controller transmits to the signal generator instructions to apply trains of bipolar pulses between selected electrodes on the probe. For IRE, these pulses typically have a voltage amplitude of at least <NUM> V and a duration of each bipolar pulse pair that is less than <NUM>, so as to cause irreversible electroporation of the tissue between the selected electrodes. Alternatively, other suitable pulse parameters may be chosen for this purpose.

To measure the pulse energy that is dissipated in the tissue, electrical sensors are coupled to the outputs of the electrical signal generator. These sensors continuously sense the energy dissipated between the bipolar pairs of electrodes, and convey the measured results to the controller. The controller computes the dissipated energy, and controls the electrical and temporal parameters of the trains of the pulses applied by the electrical signal generator, so that the dissipated energy meets a target value or satisfies some other criterion. The electrical signal generator may be configured either as a voltage source or a current source. In the former case, the electrical parameters controlled by the controller are primarily the voltages of the pulses, whereas in the latter case, the electrical parameters are primarily the currents of the pulses.

To measure the dissipated energy, the controller receives measurements of the voltages between the electrodes, as well as the currents passing through the electrodes, in successive intervals during the ablation procedure. From these measurements the controller estimates the instantaneous power delivered to the tissue, and thus finds the cumulative energy dissipated in the tissue during the IRE procedure. The controller computes possible adjustments required in the trains of the bipolar pulses so that the total energy dissipated in the procedure satisfies the applicable criteria. For this purpose, the controller typically adjusts one or more of the following parameters: pulse amplitude (either voltage amplitude or current amplitude, depending on whether the signal generator is a voltage source or a current source), pulse width (duration), number of pulses per pulse train, and number of pulse trains during the procedure. Alternatively or additionally, the controller may compute adjustments for individual bipolar pulses or pulse trains so that individual pulses or pulse trains will dissipate a preset amount of energy in the tissue.

In some exemplary embodiments, the electrical signal generator used for the IRE procedure is capable of applying, in addition to bipolar pulses for IRE ablation, radio-frequency (RF) signals for thermal RF ablation of the tissue. The measurement of energy dissipation by the electrical sensors can also be used in monitoring and controller the thermal RF ablation process.

<FIG> is a schematic pictorial illustration of a multi-channel IRE system <NUM> used in an IRE ablation procedure, in accordance with exemplary embodiments of the present invention. In the following description, the IRE ablation procedure will also be referred to as "IRE ablation" or "IRE procedure. " In the illustrated exemplary embodiment, a physician <NUM> is performing a multi-channel IRE ablation procedure using IRE system <NUM>. Physician <NUM> is performing the procedure on a subject <NUM>, using an ablation catheter <NUM> whose distal end <NUM> comprises multiple ablation electrodes <NUM> arrayed along the length of the catheter <NUM>.

IRE system <NUM> comprises a processor <NUM> and an IRE module <NUM>, wherein the IRE module comprises an IRE generator <NUM> and an IRE controller <NUM>. As will be further detailed below, IRE generator <NUM> generates trains of electrical pulses, which are directed to selected electrodes <NUM> for performing an IRE procedure. The waveforms (timing and amplitude) of the trains of electrical pulses are controlled by IRE controller <NUM>. Processor <NUM>, as will also be detailed below, handles the input and output interface between IRE system <NUM> and physician <NUM>.

Processor <NUM> and IRE controller <NUM> each typically comprises a programmable processor, which is programmed in software and/or firmware to carry out the functions that are described herein. Alternatively or additionally, each of them may comprise hard-wired and/or programmable hardware logic circuits, which carry out at least some of these functions. Although processor <NUM> and IRE controller <NUM> are shown in the figures, for the sake of simplicity, as separate, monolithic functional blocks, in practice some of these functions may be combined in a single processing and control unit, with suitable interfaces for receiving and outputting the signals that are illustrated in the figures and are described in the text. In some exemplary embodiments, IRE controller <NUM> resides within IRE module <NUM>, as high-speed control signals are transmitted from the IRE controller to IRE generator <NUM>. However, provided that signals at sufficiently high speeds may be transmitted from processor <NUM> to IRE generator <NUM>, IRE controller <NUM> may reside within the processor.

Processor <NUM> and IRE module <NUM> typically reside within a console <NUM>. Console <NUM> comprises input devices <NUM>, such as a keyboard and a mouse. A display screen <NUM> is located in proximity to (or integral to) console <NUM>. Display screen <NUM> may optionally comprise a touch screen, thus providing another input device.

IRE system <NUM> may additionally comprise one or more of the following modules (typically residing within console <NUM>), connected to suitable interfaces and devices in system <NUM>:.

The above modules <NUM>, <NUM>, and <NUM> typically comprise both analog and digital components, and are configured to receive analog signals and transmit digital signals. Each module may additionally comprise hard-wired and/or programmable hardware logic circuits, which carry out at least some of the functions of the module.

Catheter <NUM> is coupled to console <NUM> via an electrical interface <NUM>, such as a port or socket. IRE signals are thus carried to distal end <NUM> via interface <NUM>. Similarly, signals for tracking the position of distal end <NUM>, and/or signals for tracking the temperature of tissue <NUM>, may be received by processor <NUM> via interface <NUM> and applied by IRE controller <NUM> in controlling the pulses generated by IRE generator <NUM>.

An external electrode <NUM>, or "return patch", may be additionally coupled externally between subject <NUM>, typically on the skin of the subject's torso, and IRE generator <NUM>.

Processor <NUM> receives from physician <NUM> (or from other user), prior to and/or during the IRE procedure, setup parameters <NUM> for the procedure. Using one or more suitable input devices <NUM>, physician <NUM> sets the parameters of the IRE pulse train, as explained below with reference to <FIG> and Table <NUM>. Physician <NUM> further selects pairs of ablation electrodes <NUM> for activation (for receiving the IRE pulse trains) and the order in which they are activated.

In setting up the IRE ablation, physician <NUM> may also choose the mode of synchronization of the burst of IRE pulses with respect to the cycle of heart <NUM>. A first option, which is called a "synchronous mode," is to synchronize the IRE pulse burst to take place during the refractory state of heart <NUM>, when the heart is recharging and will not respond to external electrical pulses. The burst is timed to take place after the QRS-complex of heart <NUM>, wherein the delay is approximately <NUM> percent of the cycle time of the heart, so that the burst takes place during the T-wave of heart <NUM>, before the P-wave. In order to implement synchronous mode, IRE controller <NUM> times the burst or bursts of IRE pulses based on ECG signals <NUM> from ECG module <NUM>, shown in <FIG>, below.

A second synchronization option is an asynchronous mode, wherein the burst of IRE pulses is launched independently of the timing of heart <NUM>. This option is possible, since the IRE burst, typically of a length of <NUM>, with a maximal length of <NUM>, is felt by the heart as one short pulse, to which the heart does not react. Asynchronous operation of this sort can be useful in simplifying and streamlining the IRE procedure.

In response to receiving setup parameters <NUM>, processor <NUM> communicates these parameters to IRE controller <NUM>, which commands IRE generator <NUM> to generate IRE signals in accordance with the setup requested by physician <NUM>. Additionally, processor <NUM> may display setup parameters <NUM> on display screen <NUM>.

In some exemplary embodiments, processor <NUM> displays on display <NUM>, based on signals received from tracking module <NUM>, a relevant image <NUM> of the subject's anatomy, annotated, for example, to show the current position and orientation of distal end <NUM>. Alternatively or additionally, based on signals received from temperature module <NUM> and ECG module <NUM>, processor <NUM> may display on display screen <NUM> the temperatures of tissue <NUM> at each electrode <NUM> and the electrical activity of heart <NUM>.

To begin the procedure, physician <NUM> inserts catheter <NUM> into subject <NUM>, and then navigates the catheter, using a control handle <NUM>, to an appropriate site within, or external to, heart <NUM>. Subsequently, physician <NUM> brings distal end <NUM> into contact with tissue <NUM>, such as myocardial or epicardial tissue, of heart <NUM>. Next, IRE generator <NUM> generates multiple IRE signals, as explained below with reference to <FIG>. The IRE signals are carried through catheter <NUM>, over different respective channels, to pairs of ablation electrodes <NUM>, such that currents <NUM> generated by the IRE pulses flow between the electrodes of each pair (bipolar ablation), and perform the requested irreversible electroporation on tissue <NUM>.

<FIG> is a schematic illustration of a bipolar IRE pulse <NUM>, in accordance with an exemplary embodiment of the invention.

A curve <NUM> depicts the voltage V of bipolar IRE pulse <NUM> as a function of time t in an IRE ablation procedure. The present exemplary embodiments relate to IRE generator <NUM>, which is configured as a voltage source. Consequently, IRE signals are here described in terms of their voltages. As will be described below, IRE generator <NUM> may alternatively be configured as a current source, in which case the IRE pulses would be described in terms of their currents. The bipolar IRE pulse comprises a positive pulse <NUM> and a negative pulse <NUM>, wherein the terms "positive" and "negative" refer to an arbitrarily chosen polarity of the two electrodes <NUM> between which the bipolar pulse is applied. The amplitude of positive pulse <NUM> is labeled as V+, and the temporal width of the pulse is labeled as t+. Similarly, the amplitude of negative pulse <NUM> is labeled as V-, and the temporal width of the pulse is labeled as t-. The temporal width between positive pulse <NUM> and negative pulse <NUM> is labeled as tSPACE. Typical values for the parameters of bipolar pulse <NUM> are given in Table <NUM>, below.

<FIG> is a schematic illustration of a burst <NUM> of bipolar pulses, in accordance with an embodiment of the invention.

In an IRE procedure, the IRE signals are delivered to electrodes <NUM> as one or more bursts <NUM>, depicted by a curve <NUM>. Burst <NUM> comprises NT pulse trains <NUM>, wherein each train comprises NP bipolar pulses <NUM>. The length of pulse train <NUM> is labeled as tT. The period of bipolar pulses <NUM> within a pulse train <NUM> is labeled as tPP, and the interval between consecutive trains is labeled as ΔT, during which the signals are not applied. Typical values for the parameters of burst <NUM> are given in Table <NUM>, below.

<FIG>are schematic illustrations of IRE signals <NUM> and <NUM> with an incorporated RF signal, in accordance with exemplary embodiments of the present invention. In the exemplary embodiments shown in <FIG>, RF ablation is combined with IRE ablation in order to benefit from both of these ablation modalities.

In <FIG>, a curve <NUM> depicts the voltage V as a function of time t of an RF signal <NUM> between two bipolar pulses <NUM> and <NUM>, similar to bipolar pulse <NUM> of <FIG>. The amplitude of RF signal <NUM> is labeled as VRF and its frequency is labeled as fRF, and the separation between bipolar pulses <NUM> and <NUM> is labeled as ΔRF. Typically the frequency fRF is between <NUM> and <NUM>, and the amplitude VRF is between <NUM> and <NUM> V, but higher or lower frequencies and amplitudes may alternatively be used.

In <FIG>, a curve <NUM> depicts the voltage V as a function of time t of an RF signal <NUM> between a positive IRE pulse <NUM> and a negative IRE pulse <NUM>. IRE pulses <NUM> and <NUM> are similar to pulses <NUM> and <NUM> of <FIG>. In this exemplary embodiment, the spacing tSPACE between positive and negative pulses <NUM> and <NUM> has been stretched, as indicated in Table <NUM>.

Typical values of the amplitude and frequency of RF signals <NUM> and <NUM> are given in Table <NUM>. When an RF signal is inserted into the IRE signal, as depicted either in <FIG>, the combination of the two signals is repeated to the end of the ablation procedure.

<FIG> is a block diagram that schematically shows details of IRE module <NUM> and its connections to other modules in system <NUM>, in accordance with an exemplary embodiment of the present invention.

With reference to <FIG>, IRE module <NUM> comprises IRE generator <NUM> and IRE controller <NUM>. IRE module <NUM> is delineated in <FIG> by an outer dotted-line frame <NUM>. Within frame <NUM>, IRE generator <NUM> is delineated by an inner dotted-line frame <NUM>. IRE generator <NUM> comprises a pulse generation assembly <NUM> and a pulse routing and metrology assembly <NUM>, which will both be further detailed in <FIG>, below.

IRE generator <NUM> may be configured either as a voltage source or as a current source. Typical voltages of the IRE pulses vary from <NUM> V to <NUM> V, with the ohmic loads for the pulses varying from <NUM>Ω to <NUM>Ω, and consequently the currents varying from <NUM> A to <NUM> A. In the present exemplary embodiments, IRE generator <NUM> is configured as a voltage source. Configuring IRE generator <NUM> as a current source will be apparent to those skilled in the art after reading the present description.

IRE controller <NUM> communicates with processor <NUM> through bi-directional signals <NUM>, wherein the processor communicates to the IRE controller commands reflecting setup parameters <NUM>. IRE controller <NUM> further receives digital voltage and current signals <NUM> from pulse routing and metrology assembly <NUM>. The controller utilizes these signals, inter alia, in computing the flow of energy dissipated in tissue <NUM>. Additionally, IRE controller <NUM> receives digital ECG signals <NUM> from ECG module <NUM>, and digital temperature signals <NUM> from temperature module <NUM>, and communicates these signals through bi-directional signals <NUM> to processor <NUM>.

IRE controller <NUM> communicates to pulse generation assembly <NUM> digital command signals <NUM>, derived from setup parameters <NUM>, as well as from the computed dissipation of energy. Command signals <NUM> cause IRE generator <NUM> to generate IRE pulses, such as those shown in <FIG>, while IRE controller <NUM> adjusts the properties of the IRE pulses based on the computed dissipation of energy and the required dissipated energy. (Further details of the control process are shown in <FIG>). These IRE pulses are sent to pulse routing and metrology assembly <NUM> as analog pulse signals <NUM>. Pulse routing and metrology assembly <NUM> is coupled to electrodes <NUM> through output channels <NUM>, as well as to return patch <NUM> through connection <NUM>. <FIG> shows ten output channels <NUM>, labelled CH1-CH10. In the following description, a specific electrode is called by the name of the specific channel coupled to it; for example electrode CH5 relates to the electrode that is coupled to CH5 of channels <NUM>. Although <FIG> refers to ten channels <NUM>, IRE generator <NUM> may alternatively comprise a different number of channels, for example <NUM>, <NUM>, or <NUM> channels, or any other suitable number of channels.

<FIG> is an electrical schematic diagram of pulse routing and metrology assembly <NUM> of <FIG>, in accordance with an exemplary embodiment of the invention. For the sake of clarity, the circuits involved in measuring currents and voltages, have been omitted. These circuits will be detailed in <FIG>, below. Output channels <NUM> and connection <NUM> are shown in <FIG> using the same labels as in <FIG>.

Pulse routing and metrology assembly <NUM> comprises modules <NUM>, with one module for each output channel <NUM>. A pair <NUM> of adjacent modules <NUM> is shown in detail in <FIG>, below.

Each module <NUM> comprises switches, labelled as FOi, SOi, Ni, and BPi for the ith module. Switches FOi are all fast switches for switching the IRE ablation from channel to channel, whereas switches SOi, Ni, and BPi are slower relays, used to set up pulse routing and metrology assembly <NUM> for a given mode of IRE ablation. A typical switching time for fast switches FOi is shorter than <NUM>, whereas slow relays SOi, Ni, and BPi require a switching time of only <NUM>. The examples that are given below demonstrate uses of the switches and relays.

Example <NUM> demonstrates the use of the switches and relays for IRE ablation between pairs of electrodes according to an odd-even scheme CH1-CH2, CH3-CH4, CH5-CH6, CH7-CH8, and CH9-CH10. (Here the bipolar pulses are applied between each electrode and a first neighbor. ) The settings of the switches and relays are shown in Table <NUM>, below.

Example <NUM> demonstrates the use of the switches and relays for IRE ablation between pairs of electrodes according to an even-odd scheme CH2-CH3, CH4-CH5, CH6-CH7, and CH8-CH9 (in which the bipolar pulses are applied between each electrode and its second neighbor). For a circular catheter <NUM>, wherein the first and last of electrodes lie side-by-side, the pair CH10-CH1 may be added to the even-odd pairs. The settings of the switches and relays are shown in Table <NUM>, below.

Combining Examples <NUM> and <NUM>, a fast IRE ablation between all pairs of electrodes <NUM> may be accomplished by first ablating with the even-odd scheme of Example <NUM>, then switching each fast switch FOi to an opposite state (from ON to OFF and from OFF to ON), and then ablating with the odd-even scheme of Example <NUM>. As slow relays SOi, Ni, and BPi are not required to switch their states, the switching takes place at the speed of the FOi switches.

Example <NUM> demonstrates IRE ablation between non-adjacent electrodes <NUM>, in this example CH1-CH3, CH4-CH6, and CH7-CH9. Such a configuration may be utilized to cause deeper lesions in tissue <NUM>. The settings of the switches and relays are shown in Table <NUM>, below.

Again, other pairs of electrodes may be rapidly chosen by reconfiguring switches FOi.

Example <NUM> demonstrates an alternative way to perform an ablation between channels CH1 and CH3. In this example, a BP line <NUM> is utilized to close the ablation circuit. The settings of the switches and relays are shown in Table <NUM>, below.

In Example <NUM>, the electrical path in pulse routing and metrology assembly <NUM> couples transformer secondaries <NUM> and <NUM> in series. As the distance between electrodes CH1 and CH3 is double to that between adjacent electrodes (for example CH1 and CH2), the voltage between CH1 and CH3 has to be double the voltage between adjacent electrodes so as to have the same electrical field strength between the respective electrodes. This is accomplished by driving the primaries for these two secondaries in opposite phases. Slow switches SOi are all left in the ON-state in preparation for the next ablation between another pair of electrodes, for example between CH2 and CH4.

As shown in the above examples, the implementation of pulse routing and metrology assembly <NUM> using relays and fast switches enables a flexible and fast distribution of IRE pulses to electrodes <NUM>, as well as a flexible reconfiguration of the applied IRE pulse amplitudes.

<FIG> is an electrical schematic diagram of two adjacent modules <NUM> and <NUM> of pulse routing and metrology assembly <NUM>, in accordance with an exemplary embodiment of the invention.

Modules <NUM> and <NUM> make up pair <NUM> of <FIG>, as is shown by dash-dot frame with the same label (<NUM>). Modules <NUM> and <NUM> are fed by pulse generating circuits <NUM> and <NUM>, respectively, which comprise, with reference to <FIG>, parts of pulse generation assembly <NUM>. Modules <NUM> and <NUM>, in turn, feed channels CH1 and CH2, respectively, similarly to modules <NUM> of pair <NUM> in <FIG>. Two modules <NUM> and <NUM> are shown in <FIG> in order to show a connection <NUM> between the modules. As the two modules are identical (and identical to the additional modules in pulse routing and metrology assembly <NUM>), only module <NUM> is described in detail below.

Further details of pulse generating circuits <NUM> and <NUM> are shown in <FIG>, below. Pulse generation assembly <NUM> comprises one pulse generating circuit similar to circuits <NUM> and <NUM> for each channel of IRE generator <NUM>. Pulse generation assembly <NUM> further comprises a high-voltage supply <NUM>, detailed in <FIG>.

Pulse generating circuit <NUM> is coupled to module <NUM> by a transformer <NUM>. Fast switch FO<NUM> and slow relays SO<NUM>, N<NUM>, and BP<NUM> are labelled similarly to <FIG>. A low-pass filter <NUM> converts a pulse train transmitted by pulse generating circuit <NUM> via transformer <NUM> and switch FO<NUM> to a sinusoidal signal, allowing CH1 to be used for RF ablation. Similarly, each channel of IRE generator <NUM> may be independently used for RF ablation. The engagement of filter <NUM> is controlled by a relay <NUM>. An RF signal having a given frequency fRF and amplitude VRF is produced by pulse generating circuit <NUM> emitting a train of bipolar pulses at the frequency fRF through low-pass filter <NUM>, which converts this pulse train to a sinusoidal signal with the frequency fRF. The amplitude of the train of bipolar pulses is adjusted so that the amplitude of the sinusoidal signal is VRF.

A voltage V<NUM> and current I<NUM> coupled to CH1 are shown in <FIG> as a voltage between channels CH1 and CH2, and a current flowing to CH1 and returning from CH2.

V<NUM> and I<NUM> are measured by a metrology module <NUM>, comprising an operational amplifier <NUM> for measuring the voltage and a differential amplifier <NUM> measuring the current across a current sense resistor <NUM>. Voltage V<NUM> is measured from a voltage divider <NUM>, comprising resistors R<NUM>, R<NUM>, and R<NUM>, and an analog multiplexer <NUM>. Analog multiplexer <NUM> couples in either resistor R<NUM> or R<NUM>, so that the voltage dividing ratio of voltage divider <NUM> is either R<NUM>/R<NUM> or R<NUM>/R<NUM>. Metrology module <NUM> further comprises an analog-to-digital converter (ADC) <NUM> for converting the measured analog voltage V<NUM> and current I<NUM> to digital signals DV<NUM> and DI<NUM>. These digital signals are sent through a digital isolator <NUM> to IRE controller <NUM> as signals <NUM> (<FIG>). As further detailed in <FIG>, IRE controller <NUM> utilizes digital signals DV<NUM> and DI<NUM>, as well as the corresponding digital signals from the other modules, to compute the energy dissipated in tissue <NUM>. Digital isolator <NUM> protects subject <NUM> (<FIG>) from unwanted electrical voltages and currents.

Switch FO<NUM>, relays SO<NUM>, BP<NUM>, N<NUM> and <NUM>, and analog multiplexer <NUM> are driven by IRE controller <NUM>. For the sake of simplicity, the respective control lines are not shown in <FIG>.

<FIG> is an electrical schematic diagram of pulse generating circuit <NUM>, transformer <NUM>, and high-voltage supply <NUM>, in accordance with an exemplary embodiment of the invention.

Pulse generating circuit <NUM> (<FIG>) comprises two switches <NUM> and <NUM>, whose internal details are further shown in <FIG>, below. Switch <NUM> comprises a command input <NUM>, a source <NUM>, and a drain <NUM>. Switch <NUM> comprises a command input <NUM>, a source <NUM>, and a drain <NUM>. Together switches <NUM> and <NUM> form a half of an H-bridge (as is known in the art), also called a "half bridge.

High-voltage supply <NUM> supplies to respective outputs <NUM> and <NUM> a positive voltage V+ and a negative voltage V-, adjustable within respective positive and negative ranges of ±(<NUM>-<NUM>) V responsively to a signal received by a high-voltage command input <NUM> from IRE controller <NUM>. High-voltage supply <NUM> also provides a ground connection <NUM>. A single high-voltage supply <NUM> is coupled to all pulse generating circuits of pulse generation assembly <NUM>. Alternatively, each pulse generating circuit may be coupled to a separate high-voltage supply.

Drain <NUM> of switch <NUM> is coupled to positive voltage output <NUM>, and source <NUM> of the switch is coupled to an input <NUM> of transformer <NUM>. When command input <NUM> receives a command signal CMD+, positive voltage V+ is coupled from positive voltage output <NUM> to transformer input <NUM> via switch <NUM>. Source <NUM> of switch <NUM> is coupled to negative voltage output <NUM>, and drain <NUM> of the switch is coupled to transformer input <NUM>. When command input <NUM> receives a command signal CMD-, negative voltage V- is coupled from negative voltage output <NUM> to transformer input <NUM> via switch <NUM>. Thus, by alternately activating the two command signals CMD+ and CMD-, positive and negative pulses, respectively, are coupled to transformer input <NUM>, and then transmitted by transformer <NUM> to its output <NUM>. The timing of the pulses (their widths and separation) are controlled by command signals CMD+ and CMD-, and the amplitudes of the pulses are controlled by a high-voltage command signal CMDHV to high-voltage command input <NUM>. All three command signals CMD+, CMD-, and CMDHV are received from IRE controller <NUM>, which thus controls the pulses fed into the respective channel of pulse routing and metrology assembly <NUM>.

In an alternative exemplary embodiment (not shown in the figures), a full H-bridge is utilized, with a single-polarity high-voltage supply. This configuration may also be used to produce both positive and negative pulses from the single-polarity source, in response to signals controlling the full H-bridge. An advantage of this exemplary embodiment is that it can use a simpler high-voltage supply, whereas the advantage of a half bridge and a dual high-voltage power supply is that it provides a fixed ground potential, as well as independently adjustable positive and negative voltages.

<FIG> is an electrical schematic diagram of switch <NUM>, in accordance with an embodiment of the invention. Switch <NUM> is implemented in a similar fashion to switch <NUM>.

The switching function of switch <NUM> is implemented by a field-effect transistor (FET) <NUM>, comprising a gate <NUM>, source <NUM>, and drain <NUM>. Command input <NUM> is coupled to gate <NUM>, with source <NUM> and drain <NUM> coupled as shown in <FIG>. Additional components <NUM>, comprising Zener diodes, a diode, a resistor, and a capacitor, function as circuit protectors.

<FIG> is a flowchart <NUM> that schematically illustrates a method for controlling an IRE procedure, in accordance with an exemplary non-claimed embodiment of the present disclosure.

In flowchart <NUM>, a dotted-line frame <NUM> indicates schematically the steps of the process that take place within IRE generator <NUM>, and a dotted-line frame <NUM> indicates schematically the steps of the process that take place within IRE controller <NUM>. This particular functional division is described here solely by way of example, however, and the principles of the present method may alternatively be applied in other sorts of IRE module configurations, as well as in other systems for IRE, as will be apparent to those skilled in the art after reading the present description.

The IRE procedure starts in a start step <NUM>. In a setup definition step <NUM>, physician <NUM> defines, through input devices <NUM>, the setup parameters for the procedure. These setup parameters are based, for example, on the required tissue volume, field strength within the tissue, catheter configuration, and the energy to be delivered into the tissue during the procedure. Processor <NUM> transmits these setup parameters to IRE controller <NUM> in a parameter transmission step <NUM>. IRE controller <NUM> extracts or computes from the setup parameters a requested total dissipated energy in a requested energy step <NUM>. This step defines a target value (for example in Joules) of the energy that is to be dissipated from the IRE pulses into the tissue at each location where ablation is to take place.

In a setup step <NUM>, IRE controller <NUM> sets up the IRE ablation parameters for IRE generator <NUM>, and transmits them to the generator in a modify/transmit step <NUM>. Once the ablation parameters have been set up in IRE generator <NUM>, IRE controller <NUM> initiates the ablation by sending an appropriate command to IRE generator <NUM> in an ablation start/continue step <NUM>. In response to the command, IRE generator <NUM> applies IRE pulses to electrodes <NUM> in an IRE pulse step <NUM>. At the same time, metrology module <NUM> (<FIG>) within IRE generator <NUM> measures the voltage Vi and current Ii within each channel i in a V/I measurement step <NUM>, and transmits their values to IRE controller <NUM>.

Based on the received values of Vi and Ii, IRE controller <NUM> computes continuously, in a dissipated energy step <NUM>, the energy dissipated in tissue <NUM>. The computation of the dissipated energy is based on a multiplication of the received values Vi and Ii in each of a sequence of time intervals, and a cumulative summation of the products. In a first comparison step <NUM>, IRE controller <NUM> checks whether the cumulative dissipated energy from the start of the procedure computed in dissipated energy step <NUM> is already equal to (or perhaps exceeds) the requested total dissipated energy recorded in requested energy step <NUM>. If the result is affirmative, the IRE ablation is terminated in an end step <NUM>.

When the requested total dissipated energy has not yet been reached at step <NUM>, IRE controller <NUM> computes, in a prediction step <NUM>, a predicted total dissipated energy assuming the ablation is continued using the current parameters (such as bipolar pulse amplitudes, pulse widths, and number of remaining pulses) of IRE generator <NUM>. In a second comparison step <NUM>, IRE controller <NUM> compares the predicted total dissipated energy (from step <NUM>) to the requested total dissipated energy (from step <NUM>). When these two are equal, the ablation continues using the current ablation parameters, and the ablation continues through step <NUM>.

When the predicted total dissipated energy deviates from the requested total dissipated energy at step <NUM>, IRE controller <NUM> modifies the IRE ablation parameters in modify/transmit step <NUM>, and the cycle of <FIG> continues. Thus, the feedback provided by the measurement of ablation voltages Vi and currents Ii by metrology module <NUM> to IRE controller <NUM> enables the controller to adjust the ablation parameters of IRE generator <NUM> so as to achieve the requested total dissipated energy for the ablation procedure.

Alternatively or additionally, when the setup parameters specify an energy per pulse or pulse train, the process flow described by flow chart <NUM> is modified accordingly.

Claim 1:
A medical apparatus (<NUM>) for regulating delivery of irreversible electroporation pulses, the apparatus comprising:
a probe (<NUM>) configured for insertion into a body of a patient and comprising a plurality of electrodes (<NUM>) configured to contact tissue within the body;
an electrical signal generator (<NUM>) coupled to apply bipolar trains of pulses having a voltage amplitude of at least <NUM> V and having a duration of each of the bipolar pulses less than <NUM> between at least one pair of the electrodes in contact with the tissue, thereby causing irreversible electroporation of the tissue between the at least one pair of the electrodes;
one or more electrical sensors coupled to an output of the electrical signal generator and configured to sense a cumulative energy dissipated between each pair of the electrodes during the trains of the pulses; and
a controller (<NUM>) coupled to control electrical and temporal parameters of the trains of the pulses applied by the electrical signal generator, responsively to the one or more electrical sensors, so that the dissipated energy satisfies a predefined criterion.