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 other thermal and 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.

International Patent Application Pulication <CIT> describes selective cellular ablation by electroporation. In one example, a radially expandable electrode array is pressed into position for electroporating ablation of myocardial tissue by expansion of a frame.

International Patent Application Publication <CIT> describes catheter systems and methods for the selective and rapid application of DC voltage to drive irreversible electroporation. In one example, a basket ablation catheter for electroporation energy delivery is described.

Embodiments of the present invention that are described hereinbelow provide improved systems for ablation of tissue in the body.

There is therefore provided, in accordance with an embodiment of the present invention, a medical apparatus, which includes a probe. The probe includes an insertion tube configured for insertion into a body cavity of a patient, a basket assembly connected distally to the insertion tube, and a plurality of resilient, conductive spines, which are configured to contact tissue within the body and to allow current to flow between the conductive spines along the entire length of the conductive spines. The apparatus further includes an electrical signal generator configured to apply between one or more pairs of the spines bipolar pulses having an amplitude sufficient to cause irreversible electroporation (IRE) in the tissue contacted by the spines.

In a disclosed embodiment, the spines have respective proximal and distal tips, wherein the proximal tips of the spines are joined mechanically at a proximal end of the basket assembly, and the distal tips of the spines are joined mechanically at a distal end of the basket assembly, and the spines bow radially outward when the basket assembly is deployed in the body cavity, thereby contacting the tissue in the body cavity.

In a further disclosed embodiment, the basket assembly has a stable collapsed state, and the apparatus includes a puller attached to the distal end of the basket assembly and slidably disposed within the insertion tube, so that the spines bow radially outward in response to pulling the puller in a proximal direction through the insertion tube. Additionally or alternatively, the puller includes a reinforced polymer tube.

In some embodiments, the insertion tube includes a flexible catheter configured for insertion into a chamber of a heart of the patient, and the spines are configured to contact and apply the electrical signals to myocardial tissue within the chamber.

In additional embodiments, the spines include drawn metal ribbons, which may be fabricated from a nickel-titanium alloy. Additionally or alternatively, the spines include flexible printed circuit boards bonded to structural members.

In disclosed embodiments, the bipolar pulses applied by the electrical signal generator include a sequence of bipolar pulses having an amplitude of at least <NUM> V, and a duration of each of the bipolar pulses is less than <NUM>. Additionally or alternatively, the sequence of the bipolar pulses includes pairs of pulses, wherein each pair includes a positive pulse and a negative pulse.

In some embodiments, the electrical signal generator is configured to apply the bipolar pulses between first and second sets of the spines, wherein at least one of the sets includes two or more of the spines.

In further embodiments, the apparatus includes a controller configured to transmit control signals to the electrical signal generator, wherein the electrical signal generator includes a pulse generation assembly, configured to receive the control signals from the controller and to transmit sequences of bipolar pulses with an amplitude and duration responsive to the control signals. The electrical signal generator further includes a pulse routing assembly, which includes a configurable network of switches, which are configured to receive the control signals from the controller, to receive the sequences of bipolar pulses from the pulse generation assembly, and to select sets of the spines responsively to the received control signals, each set including one or more of the spines, so as to the transmit the sequences of bipolar pulses through the selected sets.

IRE is a predominantly non-thermal process, which causes an increase of the tissue temperature by, at most, a few degrees for a few seconds. 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. Typically the electrodes are relatively small, for achieving a localized IRE in the tissue. However, the use of small electrodes reduces the size of the electroporated area.

The embodiments of the present invention that are described herein address the problem of increasing the area of electroporation by providing a basket-type catheter with conductive spines, which contact tissue in a body cavity, such as myocardial tissue in the heart. Each spine acts as an electrode, and an electrical signal generator applies bipolar pulses between one or more pairs of the spines with an amplitude sufficient to cause IRE in the tissue contacted by the spines. The pairs of spines through which the pulses are applied are selected according to the region to be electroporated. Using complete spines as electrodes in this manner allows relatively large areas to be electroporated simultaneously.

Additionally or alternatively, a set of multiple spines may be electrically connected together to create a larger "virtual electrode". IRE signals may be applied between one or more pairs of these "virtual electrodes" or sets.

Catheters having an expandable basket assembly in accordance with embodiments of the invention are typically inserted into the heart through a narrow sheath, with the basket assembly in a collapsed state. For deployment in the body cavity, the basket assembly emerges out of the sheath and expands into its operational state. In some embodiments, the spines are made of a resilient material, which is fabricated so as to curve outward into the form of the basket when released from the sheath. The catheter may include a pusher tube within the insertion tube of the catheter. This pusher tube can be pushed distally at the conclusion of the ablation procedure in order to straighten the spines and thus collapse the basket assembly so that it may be pulled back into the sheath, thus facilitating the removal of the catheter from the subject.

In other embodiments, the spines are fabricated so that the basket assembly is stable in a collapsed state rather than in an expanded state. A puller passing through the insertion tube is connected to the distal end of the basket assembly. After the basket assembly emerges from the sheath within a body cavity, pulling on the puller expands the assembly from its stable collapsed state to an expanded state and thus enables its deployment. By releasing the puller, the basket assembly reverts back to its collapsed state, and enables it to be pulled back into the insertion tube for the extraction of the catheter from the subject. This configuration is advantageous in that the puller is typically thinner and more flexible than a pusher tube, thus enabling the catheter to be made thinner and more flexible. The puller may comprise, for example, either a simple wire or alternatively a more complex assembly, such as a polymer tube with braiding or embedded wires to minimize its elongation.

<FIG> is a schematic pictorial illustration of a system <NUM> used in an IRE ablation procedure, in accordance with embodiments of the invention. (In the following description, the IRE ablation procedure will also be referred to as "IRE ablation" or "IRE procedure. ") In the pictured embodiment, a physician <NUM> is performing an IRE ablation procedure in a heart <NUM> of subject <NUM> using system <NUM>. Physician <NUM> is performing the procedure using an ablation catheter <NUM> comprising an insertion tube <NUM> with a longitudinal axis <NUM>, wherein a distal end <NUM> of the insertion tube is connected to a basket assembly <NUM> comprising multiple conductive spines <NUM> (shown in more detail in <FIG>).

IRE system <NUM> comprises a processor <NUM> and an IRE module <NUM>. IRE module <NUM> comprises an IRE generator <NUM> and an IRE controller <NUM>, wherein the IRE generator comprises a dedicated pulse generator, as described further hereinbelow. IRE generator <NUM> generates, under the control of IRE controller <NUM>, IRE signals, which comprise trains of bipolar electrical pulses. The pulses are directed to selected spines <NUM>, which serve as electrodes for performing an IRE procedure. Processor <NUM> handles the input and output interfaces between IRE system <NUM> and physician <NUM>, as well as the communication to IRE controller <NUM>. The bipolar electrical pulses and IRE module <NUM> are further described below with reference to <FIG>.

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. IRE generator <NUM> comprises analog and digital components and assemblies, for generating the IRE signals that are directed to spines <NUM>. Although processor <NUM>, IRE generator <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.

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 both of the following modules (typically residing within console <NUM>), connected to suitable interfaces and devices in system <NUM>:.

The above modules <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 from IRE generator <NUM> via interface <NUM> and wiring inside insertion tube <NUM> to spines <NUM> in basket assembly <NUM>. Similarly, signals for tracking the position and orientation of distal end <NUM> may be received by tracking module <NUM> via interface <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 module <NUM>. External electrode <NUM> may be used for coupling IRE signals between one of spines <NUM> and the external electrode, thus achieving electroporation that is localized deeper in tissue <NUM>.

Processor <NUM> receives from physician <NUM> (or from another 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 setup parameters <NUM>, selecting one or more pairs of spines <NUM> to serve as electrodes for activation (for receiving the IRE signals) and the order in which the electrodes are activated, as well as defining the characteristics (timing and amplitude) of the IRE signals. Additionally, processor <NUM> may display setup parameters <NUM> on display screen <NUM>. As used herein the pairs of spines are not limited to adjacent spines but in all possible configurations that allow for delivery of biphasic energy between (a) two singular spines acting as two separate electrodes or (b) between two groups of multiple spines. For case (a) one example of two singular spines acting as an electrode "pair" in (a) is spine 30a in <FIG> adjacent with spine 30b to define a "pair of electrodes" when biphasic voltage is delivered to these spines 30a and 30b. Alternatively, spine 30a can be paired with a non-neighobring spine 30c as "another pair"; spine 30a with non-neighboring spine 30d as yet another "pair"; spine 30a with distant spine 30f as a further "pair"; spine 30b with distant spine 30d as yet a "pair". In a further variation, spines 30a and 30c can be energized as one an "electrode pair" with spines 30b and 30d energized as a different "electrode pair" and so on in various permutations. For case (b) relating to a group of spines acting as one electrode in concert with another group of different spines acting as another electrode to arrive at a "pair of electrodes", two or more spines (e.g., 30a and 30b) can act as one electrode to operate with two or more spines (30c and 30d) grouped together as another electrode define an electrode "pair" for delivery of biphasic energy to the electrodes (i.e., spines 30a and 30b as one electrode and spines 30c and 30d as the other electrode to define an "electrode pair). Various permutations of single spines acting as a pair of electrodes can be combined with groups of spines acting as electrode pairs can be utilized and are considered to be within the scope of the present invention. For example, the spines of shown in <FIG> can be utilized to define two electrode pairs: spines 30a and 30b define one electrode pair, a group of spines 30c+30d (one electrode) and another group of spines 30e+30f (as another electrode) to define the second electrode pair in <FIG> (i.e., 30a+30b as the first pair of electrodes; 30c and 30d + 30e and 30f as the second pair of electrodes).

In some embodiments, processor <NUM> displays on display <NUM>, based on signals received from tracking module <NUM>, a relevant image <NUM> of the subject's anatomy, such as a map of a chamber of heart <NUM>, which is annotated, for example, to show the current position and orientation of basket assembly <NUM>. Alternatively or additionally, based on signals received from ECG module <NUM>, processor <NUM> may display on display screen <NUM> the electrical activity of heart <NUM>.

To begin the procedure, physician <NUM> inserts catheter <NUM> into subject <NUM>, for example through the subject's vascular system, and then navigates insertion tube <NUM>, using a control handle <NUM>, to an appropriate site within, or external to, heart <NUM>. At the insertion and navigation stage, basket assembly <NUM> is in a collapsed form, generally inside a sheath (not shown), in order to provide for an easy insertion into subject <NUM>.

Once insertion tube <NUM> is positioned in the required area within heart <NUM>, basket assembly <NUM> is advanced from the sheath, assuming an expanded form. A further detailed description of basket assembly <NUM> is given in <FIG>, below. As shown schematically in an inset <NUM>, physician <NUM> now brings basket assembly <NUM> into contact with tissue <NUM> of heart <NUM>, such as myocardial or epicardial tissue. Next, IRE generator <NUM>, under the control of IRE controller <NUM>, generates IRE signals comprising trains of pulses (shown in detail in <FIG>). The IRE signals are carried through catheter <NUM>, over different respective electrical conductors (not shown), to pairs of spines <NUM>, such that currents <NUM> generated by the IRE signals flow between the spines in each pair (bipolar ablation), and perform the desired irreversible electroporation of tissue <NUM> over the extended area between the spines.

<FIG> is a schematic side view of basket assembly <NUM>, in accordance with an embodiment of the invention. Basket assembly <NUM> comprises spines <NUM>, which are in <FIG> labelled individually as 30a, 30b, 30c, 30d, 30e, and 30f. Spines 30a-30f comprise long segments of a resilient material, which is conductive or has a conductive coating or a conductive member attached to it. For example, spines 30a-30f may comprise a nickel-titanium alloy, known as nitinol.

Proximal tips <NUM> of spines 30a-30f are joined mechanically at proximal end <NUM> of basket assembly <NUM>, and distal tips <NUM> of the spines are joined mechanically at a distal end <NUM> of the basket assembly. (Proximal and distal tips <NUM> and <NUM>, respectively, of spines 30a-30f, however, are insulated electrically from one another so that the spines can serve as separate electrodes. ) Spines 30a-30f are fabricated so that basket assembly <NUM> has an expanded state as its stable state. Thus, spines 30a-30f bow radially outward when the basket assembly is deployed in a body cavity, thereby contacting tissue <NUM> in the body cavity. Spines 30a-30f are electrically coupled via conductors within catheter <NUM> to IRE generator <NUM> (<FIG>) for receiving IRE ablation signals.

The IRE signals received from IRE generator <NUM> are coupled, for example, between spines 30a and 30b, causing the electroporation to take place between these two spines. Due to the applied IRE signals, currents <NUM> (<FIG>) flow between spines 30a and 30b along their entire length, thus causing electroporation over a large area in tissue <NUM>. For example, applying basket assembly <NUM> to pulmonary vein ablation will cause electroporation over a <NUM>-<NUM> wide ring around the pulmonary vein.

The IRE signals may be coupled between any pair of spines 30a-30f, although typically the signals will be applied between pairs of adjacent spines. Additionally or alternatively, the signals may be applied simultaneously or in alternation between several pairs of spines. Although basket assembly <NUM> is depicted in <FIG> to comprise six spines, other numbers of spines, both smaller and larger than six, may be used. Additionally or alternatively, a set of multiple spines <NUM> may be electrically connected together to form a larger "virtual electrode" comprising multiple spines. IRE signals may be applied between one or more pairs of these "virtual electrodes" or sets.

<FIG> are schematic sectional views of spines <NUM>, in accordance with two embodiments of the invention.

<FIG> is a schematic sectional view of spine <NUM>, wherein the spine comprises a drawn nitinol ribbon <NUM>. Nitinol ribbon <NUM> serves both as a structural member of spine <NUM> and as an electrical conductor for currents <NUM> (<FIG>). Forming nitinol ribbon <NUM> by the process of drawing is advantageous in that resulting edges <NUM> of the ribbon are rounded (as opposed to sharp edges formed in a ribbon cut from a sheet of nitinol), thus avoiding damage to tissue <NUM> touched by spines <NUM>.

<FIG> is a schematic sectional view of spine <NUM> in an alternative embodiment, wherein spine <NUM> comprises a composite of a structural member <NUM> and a conductive member <NUM>. Structural member <NUM> comprises, for example, as in <FIG>, a drawn nitinol ribbon. Conductive member <NUM> comprises a conductive film, such as gold, which is disposed on a flexible printed circuit board (PCB) <NUM>, which in turn is bonded to structural member <NUM> with suitable bonding and insulating materials <NUM>, such as a biocompatible epoxy or other adhesive. Thus, structural member <NUM> is insulated from tissue <NUM>, and currents <NUM> are conducted to the tissue by conductive member <NUM>, which is exposed to the tissue.

Alternatively, spine <NUM> may comprise a conductive or non-conductive structural member with a conductive coating (not shown).

<FIG> are schematic side views of a basket assembly <NUM> in its collapsed and expanded states, respectively, in accordance with an alternative embodiment of the invention. The same numerical labels as in <FIG> and <FIG> are used for similar items in <FIG>. As in <FIG>, <FIG>, spines <NUM> comprise long segments of a resilient material, which is conductive, or has a conductive coating or a conductive member attached to it.

<FIG> shows basket assembly <NUM> in its collapsed state, in which spines <NUM> are straight and aligned parallel to longitudinal axis <NUM>. This is the stable state of basket assembly <NUM>: When it is pushed out of the sheath, assembly <NUM> remains in the collapsed state, unless forced into an expanded state. Ablation catheter <NUM> contains a puller <NUM>, which extends through and is able to move longitudinally within insertion tube <NUM>. Puller <NUM> has a distal end <NUM> attached to distal end <NUM> of basket assembly <NUM>, and a proximal end (not shown) attached to control handle <NUM>. Since proximal ends <NUM> of spines <NUM> are secured to insertion tube <NUM>, pulling puller <NUM> from its proximal end shortens the distance between the respective distal and proximal ends <NUM> and <NUM> of spines <NUM>, and thereby causes the spines to bow outward for deployment, as shown in <FIG>. Releasing puller <NUM> allows basket assembly <NUM> to collapse back to its stable state (<FIG>), due to the resilience of spines <NUM>, for extracting catheter <NUM> from subject <NUM>.

Puller <NUM> may comprise any suitable elongated component having sufficient tensile strength and bending flexibility. For example, puller <NUM> may comprise a simple wire. Alternatively, puller <NUM> may comprise a more complex structure, such as a polymer tube with reinforcement in the form of braiding or embedded wires to minimize its elongation.

<FIG> is a schematic illustration of a bipolar IRE pulse <NUM>, in accordance with an 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. Bipolar IRE pulse <NUM> 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 spines <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 spacing 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 spines <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> is a block diagram that schematically shows details of IRE module <NUM>, in accordance with an embodiment of the invention. As explained above in regard to <FIG>, IRE module <NUM> comprises IRE generator <NUM> and IRE controller <NUM>. IRE generator <NUM> comprises a pulse generation assembly <NUM> and a pulse routing assembly <NUM>. Pulse generation assembly <NUM> is configured to receive control signals from IRE controller <NUM> (as described below) and to transmit sequences of bipolar pulses with an amplitude and duration responsive to the control signals. Pulse routing assembly <NUM> comprises a configurable network of switches, which are configured to receive control signals from IRE controller <NUM>, to receive sequences of bipolar pulses from pulse generation assembly <NUM>, and to select pairs of spines <NUM> responsively to the received control signals so as to the transmit the sequences of bipolar pulses through the selected pairs.

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 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 assembly <NUM> as analog pulse signals <NUM>, as directed by IRE controller <NUM>.

Pulse routing assembly <NUM> is coupled to spines <NUM> through output channels <NUM>, as well as (optionally) to return patch <NUM> through a connection <NUM>. For example, when pulse routing assembly <NUM> is coupled to six spines 30a-30f of basket assembly <NUM> (<FIG>), six of output channels <NUM> are coupled to the spines. Pulse routing assembly <NUM> is driven by IRE controller <NUM> to couple the IRE pulses into spines <NUM> as defined by setup parameters <NUM>. Specifically, IRE controller <NUM> drives pulse routing assembly <NUM> to couple the IRE pulses to one or more selected pairs of spines <NUM>. Routing assembly <NUM> may also electrically couple multiple spines <NUM> together to form a set that can serve as a "virtual electrode". Thus IRE controller <NUM> controls both the generation and the routing of the IRE pulses into spines <NUM>.

Although <FIG> shows 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.

Claim 1:
A medical apparatus, comprising:
a probe, comprising:
an insertion tube (<NUM>) configured for insertion into a body cavity of a patient; and
a basket assembly (<NUM>) connected distally to the insertion tube (<NUM>) and comprising a plurality of conductive spines (<NUM>), which are configured to contact tissue within the body and to allow current to flow between the conductive spines (<NUM>) along the entire length of the conductive spines (<NUM>); and
an electrical signal generator (<NUM>) configured to apply between one or more pairs of the spines (<NUM>) bipolar pulses having an amplitude sufficient to cause irreversible electroporation (IRE) in the tissue contacted by the spines (<NUM>).