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.

<CIT> discusses systems, methods and computer-accessible mediums that can establish particular parameters for electric pulses based on a characteristic(s) of the tissue(s), and control an application of the electric pulses to tissue(s) for a plurality of automatically controlled and separated time periods to ablate the tissue(s) through mediation of membrane potential and through inducing the cells through a plurality of charge-discharge cycles.

Exemplary embodiments of the present invention that are described hereinbelow provide improved systems for irreversible electroporation.

The invention provides an apparatus according to claim <NUM>.

There is further disclosed a non-claimed method, not forming part of the invention, 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 disposed along the probe and configured to contact the tissue. The method further includes applying during a first period of time while the probe contacts a locus in the tissue, between each electrode and a first neighboring electrode on a first side of the electrode in the array, a first sequence of bipolar pulses having an amplitude sufficient to cause irreversible electrophoresis (IRE) in the tissue between each electrode and the first neighboring electrode. During a second period of time while the probe remains in contact with the locus in the tissue, a second sequence of bipolar pulses capable of causing IRE in the tissue is applied between each electrode and a second neighboring electrode on a second side of the electrode, opposite the first side, in the array.

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>). However, energizing, for example, adjacent pairs must be 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>. Using commonly available sources, such as signal generators or defibrillators, to drive the electrodes, the required switching from one set of electrodes (odd-even) to another set of electrodes (even-odd) is done either manually or using slow switches.

The exemplary embodiments of the present invention that are described herein address the requirements for switching between sets of electrodes by providing a medical apparatus comprising a versatile electrical signal generator for IRE, with capabilities of fast switching and generation of a variety of therapeutic signals. The signal generator operates in conjunction with a probe, comprising a catheter with multiple electrodes arrayed along the catheter, which is inserted into the body of the patient so that the electrodes contact tissue within the body.

Each electrode along the catheter (except the first and last electrodes in the array) has neighboring electrodes on both sides. In some exemplary embodiments, during a first period of time, the signal generator applies IRE pulses between each electrode and a first of its two neighbors, for example between pairs <NUM>-<NUM>, <NUM>-<NUM>,. <NUM>-<NUM>. Then, during a second period of time it applies the IRE pulses between each electrode and its second neighbor, for example, pairs <NUM>-<NUM>, <NUM>-<NUM>,. <NUM>-<NUM>. In other words, by defining the labels "first neighbor" and "second neighbor" appropriately, the above application of IRE pulses energizes the odd-even electrodes during the first period of time and the even-odd electrodes during the second period of time.

In the disclosed exemplary embodiments, the signal generator, configured as an IRE generator, comprises a network of fast switches, enabling switching between the odd-even and even-odd electrodes in a matter of milliseconds or less. By incorporating additional relays in the network, it may be configured for applying the IRE pulses to other configurations of electrodes, such as, for example, interleaved electrodes, with a concomitant fast switching between sets of interleaved electrodes.

As noted earlier, the two commonly used methods of ablation, IRE ablation and RF ablation, implement different modalities: IRE ablation destroys cells by punching holes in the cell membranes, whereas RF ablation destroys the cells by heating. It can be advantageous to combine these two methods in treating the same tissue.

Thus, according to the invention, the electrical signal generator is capable of switching rapidly between the two modalities of IRE ablation and RF ablation. The electrical signal generator thus applies an alternating sequence of IRE pulses and a RF signal between one or more pairs of the electrodes.

In the disclosed exemplary embodiments, the signal generator, configured as an IRE generator, functions in two rapidly switchable modalities: In an IRE modality, it generates IRE pulses for IRE ablation; in an RF modality, the signal generator generates a pulse train at a frequency suitable for RF ablation and with a lower amplitude than IRE pulses. This pulse train is converted to a sinusoidal RF ablation signal by filtering it through a low-pass filter. Rapid switching between these two modalities, while coupling both the IRE and the RF ablation signals to the same electrodes, is accomplished by alternatingly closing and opening a bypass switch in parallel with the low-pass filter. The RF ablation signal may be inserted either between two consecutive bipolar IRE pulses or between the positive and negative pulses of a single bipolar IRE pulse. In the latter case, the spacing between the positive and negative pulse is stretched to <NUM>-<NUM>.

The IRE generator is controlled by an IRE controller implementing an ablation protocol. The protocol defines the values for all of the parameters of the IRE ablation, including an additionally incorporated RF ablation in some cases, to suit the targeted tissue and the electrode configuration of the catheter. These parameter values are set at the start of the IRE procedure by a medical professional, such as a physician, controlling the procedure. The physician sets the parameters based on the required tissue volume, field strength, catheter configuration, and the energy per pulse or pulse train, as well as the energy to be delivered over the entire procedure.

<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.

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> 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 present 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 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 exemplary embodiment of the present 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 the present invention. 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.

According to the invention the frequency fRF is between <NUM> and <NUM>, and the amplitude VRF is between <NUM> and <NUM> V.

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 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>, 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>, commanding IRE generator <NUM> to generate IRE pulses, such as those shown in <FIG>, above. 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 present 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 present 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 SOi, 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>). Digital isolator <NUM> protects subject <NUM> (<FIG>) from unwanted electrical voltages and currents.

Switch FO<NUM>, relays SOi, 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 present 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 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 exemplary embodiment of the present 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.

Claim 1:
A medical apparatus for tissue ablation, comprising:
a probe configured for insertion into a body of a patient and comprising a plurality of electrodes (<NUM>) configured to contact tissue within the body; and
an electrical signal generator (<NUM>) configured to apply between one or more pairs of the electrodes (<NUM>) signals of first and second types in alternation, the signals of the first type comprising a sequence of bipolar pulses (<NUM>, <NUM>, <NUM>, <NUM>) having an amplitude of at least <NUM> V, and a duration of each of the bipolar pulses less than <NUM>, the amplitude being sufficient to cause irreversible electrophoresis (IRE) in the tissue contacted by the electrodes (<NUM>), and the signals of the second type comprising a radio-frequency (RF) signal (<NUM>, <NUM>) having a frequency between <NUM> and <NUM>, an amplitude between <NUM> and <NUM> V and a power sufficient to thermally ablate the tissue contacted by the electrodes (<NUM>);
wherein the signals of the first type comprise pairs of pulses (<NUM>, <NUM>, <NUM>, <NUM>), wherein each pair comprises a positive pulse and a negative pulse, and wherein the signals of the second type (<NUM>, <NUM>) are either interleaved between the positive (<NUM>) and negative pulses (<NUM>) of the pairs or between successive pairs of pulses (<NUM>, <NUM>).