Patent Description:
Techniques that use a medical probe to perform irreversible electroporation (IRE) of an intra body tissue were previously proposed in the patent literature. For example, <CIT> describes a method, system, and device for electroporation. The system may include a medical device with a plurality of electrodes borne on an expandable element and an energy generator in communication with the electrodes. The energy generator may have processing circuitry configured to selectively deliver electroporation energy to at least one of the electrodes. The processing circuitry may determine whether an alert condition is present and, if so, cease the delivery of electroporation energy to one or more electrodes identified as the cause of the alert condition and/or prevent the delivery of electroporation energy to the one or more electrodes identified as the cause of the alert condition. The energy generator may also be configured to deliver electroporation energy in a sequence of a plurality of energy delivery patterns to enhance lesion formation. In an embodiment, bipolar signals are applied using all pairs of the plurality of electrodes simultaneously and, to prevent overheating of certain electrodes in some cases, these electrodes are disconnected from the energy generator.

As another example, <CIT> describes methods, systems, and devices for enhancing the efficiency and efficacy of energy delivery and tissue mapping. One system includes a treatment element having a plurality of electrodes and an energy generator that is configured to deliver electric energy pulses to the electrodes in a variety of patterns. For example, electrodes may be arranged in closely spaced pairs. The energy generator may deliver mapping energy to each electrode in each pair individually to map tissue and may deliver ablation energy to the electrodes in each pair together, such that each pair is treated like a single electrode, to deliver ablation energy, such as bipolar ablation energy between adjacent pairs. One system includes at least one concave electrode, the configuration of which concentrates the energy and drives it deeper into the tissue. One system includes neutral electrodes between active electrodes, the energy generator selectively coupling the neutral electrodes to alter the ablation pattern. In an embodiment, to prevent electrode overheating, effective electrode surface is increased by connecting several electrodes together. In another embodiment, overheated electrodes are disconnected to reduce heat.

<CIT> describes selective cellular ablation by electroporation, applicable, for example, to bulk tissue in the beating heart. Protocol parameters potentially induce tissue loss without thermal damage. Device and method are potentially applicable for myocardial tissue ablation to treat arrhythmias, obstructive hypertrophy, and/or to generate natural scaffolds for myocardial tissue engineering. In some embodiments of the invention, pulses are delivered alternately to different pairs of electrodes. In some embodiments, the intensity (pulse voltage, frequency, number, and/or duration) of the electroporation protocol is limited by a requirement to avoid localized heating leading to thermal damage. Thus, for example, electroporation potentials are alternately delivered (optionally with differences in potential corresponding to differences in an inter-electrode distance, to maintain a strength of the electroporating electric filed) between electrode-pairs. In such a configuration, each electrode potentially participates in only half of the activated pairings (e.g., used half of the time).

Chinese patent application publication <CIT> describes adjusting delivery of irreversible electroporation pulses according to transferred energy. A medical device is described that includes a probe configured for insertion into a patient and including a plurality of electrodes configured to contact tissue in the body. An electrical signal generator applies a bipolar pulse train having a voltage amplitude of at least 200V between at least one pair of the electrodes in contact with the tissue, the duration of each of the bipolar pulses is less than <NUM> microseconds, thereby causing irreversible electroporation of the tissue between the at least one pair of electrodes of the electrodes. One or more electrical sensors sense energy dissipated between the at least one pair of electrodes of the electrodes during the pulsetrain. A controller controls electrical and temporal parameters of the pulse train applied by the electrical signal generator in response to the one or more electrical sensors such that the dissipated energy meets predefined criteria.

US patent publication <CIT> describes systems, devices and methods for electroporation ablation therapy, with the system including a pulse waveform signal generator for medical ablation therapy that may be coupled to an ablation device including at least one electrode for ablation pulse delivery to tissue. The signal generator may generate and deliver voltage pulses to the ablation device in the form of a pulse waveform in a predetermined sequence where the signal generator may independently configure a set of electrodes of an ablation device. The signal generator may further perform active monitoring of a set of electrode channels and discharge excess energy using the set of electrode channels.

There is provided, in accordance with an embodiment of the present invention, an irreversible electroporation (IRE) system, including a catheter, an IRE ablation power source, and a processor. The catheter has multiple electrodes that are configured to be placed in contact with the tissue of an organ. The IRE ablation power source is configured to generate bipolar IRE pulses. The processor is configured to ablate the tissue over a continuous region by applying the bipolar IRE pulses to pairs of the electrodes, in accordance with an order in which successive activations of a given electrode-pair are interleaved with activation of at least one other electrode-pair, and are spaced in time by at least a predefined duration. The processor is configured to apply the bipolar IRE pulses between adjacent electrodes and successively activated electrode-pairs do not share any electrodes.

In some embodiments, the system further includes a switching assembly that is configured to switch the IRE ablation power source between the electrode-pairs, and the processor is configured to apply the bipolar IRE pulses in accordance with the order by controlling the switching assembly.

Irreversible electroporation (IRE), also called Pulsed Field Ablation (PFA), may be used as an invasive therapeutic modality to kill tissue cells by subjecting them to high-voltage pulses. Specifically, IRE pulses have a potential use to kill myocardium tissue cells in order to treat cardiac arrhythmia. Cellular destruction occurs when the transmembrane potential exceeds a threshold, leading to cell death and thus the development of a tissue lesion. Therefore, of particular interest is the use of high-voltage bipolar electric pulses (e.g., using a pair of electrodes in contact with tissue) to generate high electric fields (e.g., above a certain threshold) to kill tissue cells between the electrodes.

In the context of this disclosure, "bipolar" voltage pulse means a voltage pulse applied between two electrodes of a catheter (as opposed, for example, to unipolar pulses that are applied by a catheter electrode relative to some common ground electrode not located on the catheter).

To implement IRE ablation over a relatively large tissue region of an organ, such as a circumference of an ostium of a pulmonary vein (PV), it is necessary to use multiple pairs of electrodes of a multi-electrode catheter. To make the generated electric field as spatially uniform as possible over a large tissue region it is best to have pairs of electrodes selected with overlapping fields, or at least fields adjacent to each other. However, there is a Joule heating component that occurs with the IRE generated fields, and this heating may damage the electrodes when multiple pairs of electrodes are continuously used in delivering a sequence of IRE pulses.

The IRE pulse generator is configured to deliver peak power in the range of tens of kW. However, IRE pulses that are intense enough to ablate tissue may also cause unwanted effects of potential clinical hazard. For example, a pulse voltage of <NUM> kV across <NUM>Ω of tissue (both possible values) momentarily generates a local peak current of <NUM> A, i.e., <NUM> kW in the tissue between two electrodes. This voltage, when applied between the electrodes to form a sequence of bipolar IRE pulses, may also be high enough to generate enough Joule heating which, if not quickly dissipated, may generate char.

Embodiments of the present invention that are described hereinafter provide techniques to IRE ablate (i.e., apply the IRE pulses) over a relatively large continuous region of tissue without causing thermal damage to the electrodes and/or to tissue due to electrode overheating. In some embodiments, a system comprising a switching assembly energizes different pairs of electrodes of the multi-electrode catheter, and arranges the timing of the pairs so that no electrode overheats while IRE is applied to tissue, but which still provides continuous spatial ablation. Some embodiments provide a processor-controlled switching box (e.g., a "switching assembly"). During application of IRE ablative power by the electrodes, the processor can, by controlling the switching box, switch between electrode-pairs.

The energizing of the different electrode-pairs and the times needed for Joule heating to dissipate, are predetermined in a protocol (e.g., by an algorithm). In particular, no electrode pair is used successively. For example, the protocol may specify applying the bipolar IRE pulses to pairs of the electrodes, in accordance with an order in which successive activations of a given electrode-pair are interleaved. In other words, the activation of at least one other electrode-pair should occur between successive activations of a given electrode-pair. Such a protocol ensures that any two activations of a same electrode-pair are spaced in time (i.e., time gapped) by at least a predefined duration. The time gap may range between <NUM> microsecond to <NUM> mSec, typically being <NUM> mSec.

In yet another embodiment, a protocol is optimized to sequentially energize electrode-pairs (i.e., interleave activations) over an entire circumference of a loop head catheter to perform IRE ablation over an entire circumference of a lumen, such as an ostium of a PV.

As used herein, the term "approximately" for any numerical values or ranges indicate a suitable dimensional tolerance that allows the part or collection of components to function for its intended purpose as described herein. More specifically, "approximately" may refer to the range of values ±<NUM>% of the recited value, e.g. "approximately <NUM>%" may refer to the range of values from <NUM>% to <NUM>%.

In another embodiment, the distance between the electrodes in each pair is the same across all the pairs. By keeping the same inter-electrode distance in each electrode-pair, the processor maintains applying a uniform electric field strength across the lesion as long as the pulses are the same. Inter-electrode distance of an electrode-pair can range from <NUM> to <NUM> typically being <NUM>.

The disclosed sequential IRE ablation method applies to many types of multi-electrode catheters, including expendable-frame catheters such as balloon or basket catheters. The technique is also applicable to loop catheters, such as the Lasso™ catheter, and to multi-arm catheters such as the PentaRay™ catheter (both made by Biosense Webster, Irvine, California). Catheters of other shapes can also be used with the disclosed technique, such those having deflectable tips disposed with a one-dimensional array of electrodes, or flat catheters disposed with a two-dimensional array of electrodes. The electrodes themselves may have any shape suitable for bipolar IRE ablation, e.g. flat or ring.

Typically, the processor is programmed in software containing a particular algorithm that enables the processor to conduct each of the processor-related steps and functions outlined above.

By sequencing electrode-pair bipolar IRE ablation according to a prespecified protocol (e.g., algorithm), the disclosed sequenced multi-electrode IRE ablation technique can provide safer and more effective IRE ablation treatments.

<FIG> is a schematic, pictorial illustration of a catheter <NUM> based position-tracking and irreversible electroporation (IRE) ablation system <NUM>, in accordance with an embodiment of the present invention. System <NUM> comprises a deflectable tip section <NUM>, illustrated in inset <NUM>, that is fitted at a distal end 22a of a shaft <NUM> of catheter <NUM> with deflectable tip section <NUM> comprising multiple electrodes <NUM> (seen in detail in <FIG>). In the embodiment described herein, electrodes <NUM> are used for IRE ablation of tissue of the left atrium of heart <NUM>, such as IRE ablation of an ostium <NUM> of a pulmonary vein in heart <NUM>.

The proximal end of catheter <NUM> is connected to a control console <NUM> comprising an ablative power source <NUM>. Console <NUM> includes a switching box <NUM> (also referred to as a switching assembly) that can switch to energize any one or more electrode-pairs among electrodes <NUM>. A sequenced IRE ablation protocol utilizing an embodiment of the disclosed method, such as shown in <FIG>, is stored in a memory <NUM> of console <NUM>.

Physician <NUM> inserts distal end 22a of shaft <NUM> through a sheath <NUM> into heart <NUM> of a patient <NUM> lying on a table <NUM>. Physician <NUM> navigates the distal end of shaft <NUM> to a target location in heart <NUM> by manipulating shaft <NUM> using a manipulator <NUM> near the proximal end of the catheter and/or deflection from the sheath <NUM>. During the insertion of distal end 22a, deflectable tip section <NUM> is maintained in a straightened and constrained configuration by sheath <NUM>. By containing tip section <NUM> in a straightened configuration, sheath <NUM> also serves to minimize vascular trauma along the way to target location.

Once distal end 22a of shaft <NUM> has reached the target location, physician <NUM> retracts sheath <NUM> and deflects tip section <NUM>, and further manipulates shaft <NUM> to place electrodes <NUM> disposed over tip section <NUM> in contact with ostium <NUM> the pulmonary vein.

Electrodes <NUM> are connected by wires running through shaft <NUM> to processor <NUM> controlling switching box <NUM> of interface circuits <NUM> in a console <NUM>.

In an embodiment, processor <NUM> receives electrical impedance signals, measured between electrodes <NUM> and surface electrodes <NUM>, which are seen in the exemplified system as attached by wires running through a cable <NUM> to the chest of patient <NUM>. A method for tracking the positions of electrodes <NUM> using the measured impedances is implemented in various medical applications, for example in the CARTO™ system, produced by Biosense-Webster (Irvine, California) and is described in detail in <CIT>, <CIT>, <CIT>, and<CIT>. This method is sometimes called Advanced Catheter Location (ACL). Console <NUM> drives a display <NUM>, which shows the tracked position and/or shape of deflectable tip section <NUM> inside heart <NUM>.

As further shown in inset <NUM>, distal end 22a comprises a magnetic position sensor <NUM> contained within distal end 22a just proximally to tip section <NUM>. During navigation of distal end 22a in heart <NUM>, console <NUM> receives signals from magnetic sensor <NUM> in response to magnetic fields from external field generators <NUM>, for example, for the purpose of measuring the position of tip section <NUM> in the heart and, optionally, presenting the tracked position on a display <NUM>. Magnetic field generators <NUM> are placed at known positions external to patient <NUM>, e.g., below patient table <NUM>. Console <NUM> also comprises a driver circuit <NUM>, configured to drive magnetic field generators <NUM>.

The method of position sensing using external magnetic fields is implemented in various medical applications, for example, in the CARTO™ system, produced by Biosense-Webster and is described in detail in <CIT>, <CIT>,<CIT>,<CIT>, <CIT>and <CIT>, in <CIT>, and in <CIT>, <CIT> and <CIT>.

Processor <NUM>, shown comprised in control console <NUM>, is typically a general-purpose computer, with suitable front end and interface circuits <NUM> for receiving signals from catheter <NUM>, as well as for applying RF energy treatment via catheter <NUM> in a left atrium of heart <NUM> and for controlling the other components of system <NUM>. Processor <NUM> typically comprises a software in a memory <NUM> of system <NUM>, that is programmed to carry out the functions described herein. The software may be downloaded to the computer in electronic form, over a network, for example, or it may, alternatively or additionally, be provided and/or stored on non-transitory tangible media, such as magnetic, optical, or electronic memory. In particular, processor <NUM> runs a dedicated algorithm as disclosed herein, included in <FIG>, that enables processor <NUM> to perform the disclosed steps, as further described below.

<FIG> is a schematic, pictorial side view of multi-electrode deflectable tip section <NUM> of catheter <NUM> of <FIG>, in accordance with an exemplary embodiment of the invention. Deflectable tip section <NUM>, which is shown straight but can take a bent shape or even a loop shape, has ten electrodes <NUM> disposed over section <NUM> and designated e1-e10.

Using switching assembly <NUM> of system <NUM>, one or more IRE pulses can be delivered from IRE ablation power source <NUM> of system <NUM> independently to each electrode-pair selected of the ten electrodes, as prespecified, for example, by an algorithm, such as one schematically illustrated by <FIG>. In the illustrated exemplary embodiment, electrode-pairs e1-e2 (50a), e4-e5 (50b) and e6-e7 (50c) are selected to be energized to deliver IRE pulses. Thus, rather than activating pairs e1-e2, e2-e3, e3-e4, e4-e5, e5-e6, e6-e7 sequentially where electrodes e2, e3, e4, e5, e6 have electrical current passing with no time to cool in between, the pairs may be sequenced e1-e2, e4-e5, e6-e7, and, subsequently, e2-e3, e5-e6, e3-e4, so that each electrode <NUM> has time to cool before being used again for IRE ablation. The pairs may be energized sequentially, or groups of electrodes may be energized together (e.g. e1-e2 and e6-e7; e4-e5 and e2-e3; e5-e6 and e3-e4).

<FIG> is a schematic front view of sequenced energization of electrode-pairs of a multi-electrode deflectable tip section <NUM> of a catheter deployed in a form of a loop <NUM>, in accordance with an exemplary embodiment of the present invention. <FIG> may schematically represent a front view of the aforementioned Lasso™ catheter, being deployed at an ostium of a PV.

In <FIG>, each concentric ring <NUM> represents a duration, e.g., during a refractory period of a heart cycle, at which selected electrodes are energized to deliver IRE bipolar pulses.

In an embodiment, the pulses are gated to be applied synchronously with the beating of the heart, i.e., to be applied during a refractory period of the tissue. Ventricular and atrial electrograms at ventricular or atrial tissue locations are usually acquired by electrodes in contact with tissue at the location catheter, e.g., during electrophysiological mapping of wall tissue portions of each of the respective cardiac chambers. A ventricular or an atrial refractory period is a duration of a pause in neural activity at the tissue location, after an activation occurred in tissue of either of the above cardiac chambers. Typically, a refractory period largely coincides with the QRST interval portion of a cardiac cycle demonstrated in a ventricular or an atrial electrogram taken at the location. A refractory period can be deliberately induced at a tissue portion of the heart, for example, using a pacing catheter to pace the tissue at the tissue location.

The duration number one to six (e.g., heart cycle numbers <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>) and respective identity of electrode-pairs that are energized thereon during a refractory period of each heart cycle are listed in Table I below:.

As seen, each electrode is energized four times over the six durations, with a pause every two successive energizations (i.e., pauses <NUM> of e1, pauses <NUM> of e2, pauses <NUM> of e3, pauses <NUM> of e4, pauses <NUM> of e5, pauses <NUM> of e6, pauses <NUM> of e7, pauses <NUM> of e8, pauses <NUM> of e9, pauses <NUM> of e10).

The dark circular sections (<NUM>) represent arc regions of tissue over a circumference of an ostium that received IRE ablation. As seen, the entire ostium was IRE ablated twice during the six-period (heartbeat) IRE treatment.

By way of example, the pulse applied at each heartbeat cycle may be specified by the following Table II:.

The pictorial side view shown in <FIG> is chosen by way of example, where other exemplary embodiments are possible. For example, in another embodiment, arc sections <NUM> are longer, e.g., representing bipolar voltages applied between two next-adjacent electrodes (e.g., every third electrode), such as e1-e3, e2-e4, e3-e5, and so on, that generate partially spatially overlapping electrical fields.

In another exemplary embodiment, no more than a single electrode-pair is activated at any given time. In this case the protocol of Table I can be replaced by a protocol given in table III below, in which each cycle specifies a single electrode pair that is activated alone:.

In still another exemplary embodiment, at least some of the bipolar IRE pulses are applied between groups of electrodes shorted together (e.g., between e1,e2,e3 shorted to one another and e6,e7,e8 shorted to one another, or between e1,e2,e3,e4 shorted to one another and e9), as opposed to pairs of individual electrodes such as between e2 and e3.

<FIG> is a flow chart that schematically illustrates a method for using electrode-pairs of the catheter head of <FIG> for sequential irreversible electroporation (IRE) ablation, in accordance with an exemplary embodiment of the present invention. The algorithm, according to the presented exemplary embodiment, carries out a process that begins at an IRE protocol selection step <NUM>, when physician <NUM> selects an IRE protocol comprising sequenced activation of electrode-pairs of a multi-electrode catheter, such as pairs of electrodes <NUM> of catheter <NUM>. An example protocol is provided above by Tables I and II.

Next, physician <NUM> inserts, navigates, and positions the catheter at a target location within a lumen of a patient, such as at ostium <NUM>, at a balloon catheter positioning step <NUM>.

Finally, physician <NUM> uses system <NUM>, using the IRE protocol, to apply IRE pulses according to the sequence specified in the protocol (e.g., according to the sequence of Table I), to non-successively energize each of the electrode-pairs, at a sequenced IRE ablation step <NUM>.

The example flow chart shown in <FIG> is chosen purely for the sake of conceptual clarity. In alternative embodiments, additional steps may be performed, such as processor <NUM> monitoring measured temperature of electrodes, and acting according to measured temperatures, if required, such as disconnecting an overheated electrode pair from further use in the specified protocol.

Although the embodiments described herein mainly address pulmonary vein isolation, the methods and systems described herein can also be used in other applications that may require a sequenced ablation, such as, for example, in renal denervation, and generally, in ablating other organs, such as in treatment of lung or liver cancers.

Claim 1:
An irreversible electroporation (IRE) system, comprising:
a catheter (<NUM>) having multiple electrodes (<NUM>) that are configured to be placed in contact with a tissue of an organ;
an IRE ablation power source (<NUM>) configured to generate bipolar IRE pulses; and
a processor (<NUM>), which is configured to ablate the tissue over a continuous region by applying the bipolar IRE pulses to pairs of the electrodes (<NUM>), in accordance with an order in which successive activations of a given electrode-pair are interleaved with activation of at least one other electrode-pair, and are spaced in time by at least a predefined duration, wherein the processor (<NUM>) is configured to apply the bipolar IRE pulses between adjacent electrodes (<NUM>) and successively activated electrode-pairs do not share any electrodes (<NUM>).