Pre-treatment waveform for irreversible electroporation

Abstract

To provide an electroporation ablation system for treating targeted tissue in a patient.SOLUTION: The electroporation ablation system includes an ablation catheter and an electroporation generator. The ablation catheter includes a handle, a shaft having a distal end, and catheter electrodes situated at the distal end of the shaft and spatially arranged to generate electric fields in the targeted tissue in response to electrical pulses. The electroporation generator is operatively coupled to the catheter electrodes and configured to deliver the electrical pulses in an irreversible electroporation pulse sequence, which includes a preconditioning pulse sequence and an electroporation pulse sequence, to one or more catheter electrodes. The preconditioning pulse sequence includes multiple preconditioning electrical pulses configured to cause electrolysis near the targeted tissue and tetanizing skeletal muscle stimulation in the patient.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present disclosure relates to medical devices, systems, and methods for ablating a patient's tissue. More specifically, the present disclosure relates to medical devices, systems, and methods for ablating tissue by electroporation.

Background Art

[0002] Ablation procedures are used to treat many different conditions in patients. Ablation can be used to treat cardiac arrhythmias, benign tumors, cancerous tumors, and to control bleeding during surgery. Typically, ablation is achieved by thermal ablation techniques including radiofrequency (RF) ablation and cryoablation. In RF ablation, a probe is inserted into the patient and radiofrequency is transmitted through the probe to the surrounding tissue. The radiofrequency generates heat, which destroys the surrounding tissue and cauterizes blood vessels. In cryoablation, a hollow needle or cryoprobe is inserted into the patient, and a cold thermally conductive fluid is circulated through the probe to freeze and kill the surrounding tissue. The techniques of RF ablation and cryoablation kill tissue indiscriminately by necrosis, which can damage or kill otherwise healthy tissue such as tissue in the esophagus, phrenic nerve cells, and tissue in the coronary artery.

[0003] Another ablation technique uses electroporation. In electroporation or electropermeabilization, an electric field is applied to cells to increase the permeability of the cell membrane. Electroporation can be reversible or irreversible depending on the strength of the electric field. When electroporation is reversible, the increased permeability of the cell membrane can be used to introduce chemicals, drugs, and / or deoxyribonucleic acid (DNA) into the cells before the cells heal and recover. When electroporation is irreversible, the affected cells die by apoptosis.

[0004] Irreversible electroporation (IRE) can be used as a non-thermal ablation technique. In IRE, a short high-voltage pulse train is used to generate an electric field strong enough to kill cells by apoptosis. In cardiac tissue ablation, IRE may be a safe and effective alternative to the indiscriminate cell death of thermal ablation techniques such as RF ablation and cryoablation. IRE can be used to kill target tissues such as cardiomyocytes by using an electric field intensity and duration that kills the target tissue but does not permanently damage other cells or tissues that are not the target, such as cardiomyocytes, red blood cells, vascular smooth muscle tissue, endothelial tissue, and nerve cells.

[0005] In some IRE procedures, the electropermeabilizing electrical pulse causes undesirable side effects such as skeletal muscle stimulation (SMS) and engagement. One way to reduce SMS is to refine the IRE electrical pulse and optimize it to avoid SMS. Often, this results in a smaller ablation field and the creation of a smaller lesion. A method is needed to deliver effective IRE energy while avoiding SMS. [Overview of the project]

[0006] Example 1 describes an electropermeable ablation system for treating target tissue in a patient. The electropermeable ablation system includes an ablation catheter and an electropermeability generator. The ablation catheter includes a handle, a shaft having a distal end, and a catheter electrode located at the distal end of the shaft and spatially positioned to generate an electric field within the target tissue in response to an electrical pulse. The electropermeability generator is operably coupled to the catheter electrode and is configured to deliver electrical pulses to one or more catheter electrodes in an irreversible electropermeability pulse sequence including a preconditioning pulse sequence and an electropermeability pulse sequence. The preconditioning pulse sequence includes a plurality of preconditioning electrical pulses configured to induce electrolysis near the target tissue and tetany skeletal muscle stimulation in the patient.

[0007] Example 2 is the electroporation ablation system of Example 1, which includes a surface patch electrode that is attached to the patient and configured to generate an electric field within the patient in response to an electrical pulse.

[0008] Example 3 is the electroporation ablation system of Example 2, wherein the preconditioning pulse sequence includes multiple unipolar electrical pulses sourced from a surface patch electrode and sunk by one or more catheter electrodes.

[0009] Example 4 is the electroporation ablation system of Example 2, wherein the preconditioning pulse sequence includes multiple unipolar electrical pulses sourced from one or more catheter electrodes and sunk by a surface patch electrode.

[0010] Example 5 is an electroporation ablation system of any one of Examples 1 to 4, wherein the preconditioning pulse sequence includes multiple bipolar electrical pulses sourced from at least one of one or more catheter electrodes and sunk by at least one of one or more catheter electrodes.

[0011] In Example 6, the preconditioning pulse sequence is one of the electroporation ablation systems from Examples 1 to 5, comprising a plurality of preconditioning pulses delivered at a selected frequency.

[0012] Example 7 is an electroporation ablation system from any one of Examples 1 to 6, wherein the preconditioning pulse sequence includes multiple preconditioning pulses in which the voltage increases from a lower voltage to a higher voltage over time.

[0013] Example 8 is one of the perforation ablation systems from Examples 1 to 7, wherein the preconditioning pulse sequence includes a plurality of preconditioning pulses, each containing a trailing waveform that decays exponentially, causing electrolysis near the target tissue.

[0014] In Example 9, the preconditioning pulse sequence is one of the electroporation ablation systems from Examples 1 to 8, comprising multiple single-phase preconditioning pulses.

[0015] Example 10 is an electroablation system from any one of Examples 1 to 9, in which an irreversible electropermeability pulse sequence, including a preconditioning pulse sequence and an electropermeability pulse sequence, is delivered to the patient within one or more of the following timeframes: the patient's cardiac refractory time, less than 330 milliseconds, and 100 to 250 milliseconds.

[0016] In Example 11, the electroporation pulse sequence is one of the electroporation ablation systems from Examples 1 to 10, delivered during the preconditioning pulse sequence.

[0017] Example 12 is an electropermeable ablation system from any one of Examples 1 to 11, wherein the electropermeable pulse sequence includes multiple bipolar electrical pulses delivered to one or more pairs of catheter electrodes of the catheter electrode.

[0018] Example 13 is an electroporation ablation system of any one of Examples 1 to 12, comprising an accelerometer configured to monitor the patient's skeletal muscle stimulation, wherein the electroporation generator is configured to deliver a preconditioning pulse sequence, detect tetany in the patient, and then deliver an electroporation pulse sequence, and local impedance is measured to calculate pre-ablation and post-ablation values ​​to evaluate lesion effectiveness.

[0019] Example 14 describes an electropermeable ablation system for treating target tissue in a patient. The electropermeable ablation system includes an ablation catheter and an electropermeability generator. The ablation catheter includes a handle, a shaft having a distal end, and a catheter electrode located at the distal end of the shaft and spatially positioned to generate an electric field within the target tissue in response to an electrical pulse. The electropermeability generator is operably coupled to a plurality of electrodes, including one or more of a surface patch electrode and one or more catheter electrodes, and is configured to deliver electrical pulses to the plurality of electrodes in an irreversible electropermeability pulse sequence including a preconditioning pulse sequence and an electropermeability pulse sequence, delivering the electropermeability pulse sequence during the preconditioning pulse sequence.

[0020] In Example 15, the preconditioning pulse sequence is the electroporation ablation system of Example 14, which includes multiple electrical pulses configured to induce electrolysis near the target tissue and tetany skeletal muscle stimulation in the patient.

[0021] Example 16 describes an electropermeable ablation system for treating target tissue in a patient. The electropermeable ablation system includes an ablation catheter and an electropermeability generator. The ablation catheter includes a handle, a shaft having a distal end, and a catheter electrode located at the distal end of the shaft and spatially positioned to generate an electric field within the target tissue in response to an electrical pulse. The electropermeability generator is operably coupled to the catheter electrode and configured to deliver electrical pulses to one or more catheter electrodes in an irreversible electropermeability pulse sequence including a preconditioning pulse sequence and an electropermeability pulse sequence, the preconditioning pulse sequence including a plurality of preconditioning electrical pulses configured to induce electrolysis near the target tissue and tetany skeletal muscle stimulation in the patient.

[0022] In Example 17, it is the electroporation ablation system of Example 16, which includes a surface patch electrode attached to a patient and configured to generate an electric field within the patient in response to an electric electric pulse pulse.

[0023] In Example 18, it is the electroporation ablation system of Example 16, in which the preconditioning pulse sequence includes a plurality of monopolar electric pulses sourced from a surface patch electrode and sunk by one or more catheter electrodes.

[0024] In Example 19, it is the electroporation ablation system of Example 16, in which the preconditioning pulse sequence includes a plurality of monopolar electric pulses sourced from one or more catheter electrodes and sunk by a surface patch electrode.

[0025] In Example 20, it is the electroporation ablation system of Example 16, in which the preconditioning pulse sequence includes a plurality of bipolar electric pulses sourced from at least one of one or more catheter electrodes and sunk by at least another one of one or more catheter electrodes.

[0026] In Example 21, it is the electroporation ablation system of Example 16, in which the preconditioning pulse sequence includes a plurality of preconditioning pulses delivered at a selected frequency.

[0027] In Example 22, it is the electroporation ablation system of Example 16, in which the preconditioning pulse sequence includes a plurality of preconditioning pulses whose voltage increases from a lower voltage to a higher voltage over time.

[0028] In Example 23, it is the ablation system of Example 16, in which the preconditioning pulse sequence includes a plurality of preconditioning pulses including a posterior waveform that exponentially decays and causes electrolysis near the target tissue.

[0029] In Example 24, the preconditioning pulse sequence is the electroporation ablation system of Example 16, which includes a plurality of preconditioning pulses that are single-phase.

[0030] In Example 25, the irreversible electroporation pulse sequence including the preconditioning pulse sequence and the electroporation pulse sequence is delivered to the patient within one or more of the refractory periods of the patient's heart, less than 330 milliseconds, and the time frame of 100 to 250 milliseconds, which is the electroporation ablation system of Example 16.

[0031] In Example 26, the electroporation pulse sequence is delivered within the preconditioning pulse sequence, which is the electroporation ablation system of Example 16. Example 27 is the electroporation ablation system of Example 16, in which the electroporation pulse sequence includes a plurality of bipolar electrical pulses delivered to one or more catheter electrode pairs of the catheter electrode.

[0032] In Example 28, an accelerometer configured to monitor the patient's skeletal muscle stimulation is provided, and the electroporation ablation system is a closed-loop system configured such that the electroporation generator delivers a preconditioning pulse sequence, detects tetany within the patient, and then delivers an electroporation pulse sequence, measures the local impedance to calculate the values before and after ablation, and evaluates the lesion effectiveness, which is the electroporation ablation system of Example 16.

[0033] Example 29 describes an electropermeabilization ablation system for treating target tissue in a patient. The electropermeabilization ablation system includes an ablation catheter and an electropermeabilization generator. The ablation catheter includes a handle, a shaft having a distal end, and catheter electrodes located at the distal end of the shaft and spatially positioned to generate an electric field within the target tissue in response to an electrical pulse. The electropermeabilization generator is operably coupled to a plurality of electrodes, including one or more surface patch electrodes and one or more catheter electrodes, and is configured to deliver electrical pulses to the plurality of electrodes in an irreversible electropermeabilization pulse sequence, including a preconditioning pulse sequence and an electropermeabilization pulse sequence, delivering the electropermeabilization pulse sequence during the preconditioning pulse sequence.

[0034] In Example 30, the preconditioning pulse sequence is the electroporation ablation system of Example 29, which includes multiple preconditioning electrical pulses configured to induce electrolysis near the target tissue and tetany skeletal muscle stimulation in the patient.

[0035] Example 31 is the electropermeabilization ablation system of Example 29, wherein the electropermeabilization pulse sequence includes multiple bipolar electrical pulses delivered to a selected catheter electrode pair. Example 32 describes a method for ablating a patient's target tissue by irreversible electroperforation. The method includes the steps of: delivering an irreversible electroperforation pulse sequence, which includes causing electrolysis near the target tissue and tetany skeletal muscle stimulation in the patient, by delivering a preconditioning pulse sequence between multiple electrodes, including one or more of surface patch electrodes and one or more catheter electrodes on a catheter; and delivering the electroperforation pulse sequence to the multiple electrodes to cause irreversible electroperforation ablation of the target tissue.

[0036] In Example 33, the step of delivering a preconditioning pulse sequence is the method of Example 32, comprising delivering a plurality of electrical pulses in which the voltage increases from lower to higher voltages over time, one or more of the electrical pulses including a trailing waveform that decays exponentially.

[0037] In Example 34, the electroporation pulse sequence is delivered during the preconditioning pulse sequence, as in Example 32. Example 35 is the method of Example 32, which includes the steps of monitoring an accelerometer on a patient, delivering a preconditioning pulse sequence in a closed-loop system to achieve tetany in the patient, detecting tetany in the patient by the accelerometer, and delivering an electroporation pulse sequence after tetany has been achieved.

[0038] While several embodiments are disclosed, further embodiments of this disclosure will become apparent to those skilled in the art from the following detailed description illustrating and describing exemplary embodiments of this disclosure. Therefore, the drawings and detailed description should be considered illustrative and not restrictive. [Brief explanation of the drawing]

[0039] [Figure 1] This figure shows an exemplary clinical setup for treating a patient and for treating a patient's heart using an electrophysiological system, according to embodiments of the subject matter of this disclosure. [Figure 2A] This figure shows the distal end of the shaft included in the catheter and the interaction between the electrode pair according to an embodiment of the subject matter of this disclosure. [Figure 2B] This figure shows the axial electric field generated by the interaction between electrode pairs according to an embodiment of the subject matter of this disclosure. [Figure 2C] This figure shows the circumferential electric field generated by the interaction between electrode pairs of a catheter according to an embodiment of the subject matter of this disclosure. [Figure 3]This figure shows an IRE pulse sequence, including a preconditioning pulse sequence and an electroporation pulse sequence, according to an embodiment of the subject matter of this disclosure. [Figure 4] This is a flowchart illustrating a method for ablating a patient's target tissue by irreversible electroporation according to embodiments of the subject matter of this disclosure.

[0040] This disclosure accepts various modifications and alternative forms, although certain embodiments are shown as examples in the drawings and described in detail below. However, the intent is not to limit this disclosure to the specific embodiments described. On the contrary, this disclosure is intended to encompass all modifications, equivalents, and alternative forms that fall within the scope of this disclosure as defined by the appended claims. [Modes for carrying out the invention]

[0041] The following detailed description is illustrative in nature and is not intended in any way to limit the scope, applicability, or configuration of the invention. Rather, the following description provides several practical examples for implementing exemplary embodiments of the invention. Examples of configurations, materials, and / or dimensions are provided for selected elements. Those skilled in the art will recognize that many of the examples described have various suitable alternative forms.

[0042] Figure 1 shows an exemplary clinical setup 10 for treating a patient 20 and the patient 20's heart 30 using an electrophysiology system 50, according to embodiments of the subject matter of this disclosure. The electrophysiology system 50 includes an electropermeabilization system 60 and an electroanatomical mapping (EAM) system 70, the EAM system 70 including a localization field generator 80, a mapping and navigation controller 90, and a display 92. The clinical setup 10 also includes additional equipment such as an imaging device 94 (represented by a C-arm) and various controller elements such as a foot controller 96 configured to allow an operator to control various aspects of the electrophysiology system 50. As will be understood by those skilled in the art, the clinical setup 10 may have other components and configurations not shown in Figure 1.

[0043] The electroporation system 60 includes an electroporation catheter 105, an introduction sheath 110, a surface patch electrode 115, and an electroporation generator 130. In some embodiments, the electroporation system 60 also includes an accelerometer 117, which may be a separate sensor or part of the surface electrode patch 115. In addition, the electroporation system 60 includes various connecting elements (e.g., cables, umbilicals, etc.) that work to functionally connect the components of the electroporation system 60 to each other and to the components of the EAM system 70. This arrangement of connecting elements is not critically important to the disclosure, and those skilled in the art will recognize that the various components described herein can be interconnected in various ways.

[0044] In one embodiment, the electroporation system 60 is configured to deliver electric field energy to target tissue within the patient's heart 30 to induce tissue apoptosis, thereby preventing the tissue from conducting electrical signals. The electroporation generator 130 is configured to control the functional aspects of the electroporation system 60. In one embodiment, the electroporation generator 130 is operable as a pulse generator for generating pulse sequences and supplying them to the electroporation catheter 105 and surface patch electrode 115, as will be described in more detail herein. In another embodiment, the electroporation generator 130 is operable to receive a sensing signal from an accelerometer 117 and, based on the received sensing signal, functions as a pulse generator for generating pulse sequences and supplying them to the electroporation catheter 105 and surface patch electrode 115, as will be described in more detail herein.

[0045] In the embodiment, the electroporation generator 130 includes one or more controllers, microprocessors, and / or computers that execute code from memory to control and / or perform functional aspects of the electroporation catheter system 60. In the embodiment, the memory may be part of one or more controllers, microprocessors, and / or computers, and / or part of a memory capacity accessible through a network such as the World Wide Web.

[0046] In the embodiment, the introducer sheath 110 is operable to provide a delivery conduit from which the electroporation catheter 105 can be deployed to a specific target site within the patient's heart 30. However, it will be understood that although the introducer sheath 110 is illustrated and described herein to provide context for the entire electrophysiology system 50, it is not essential for novel aspects of the various embodiments described herein.

[0047] The EAM system 70 is capable of tracking the locations of various functional components of the electroporation system 60 and producing high-fidelity three-dimensional anatomical and electroanatomical maps of the target cardiac chambers. In embodiments, the EAM system 70 may be the RHYTHMIA® HDx mapping system sold by Boston Scientific Corporation. Also in embodiments, the mapping and navigation controller 90 of the EAM system 70 includes one or more controllers, microprocessors, and / or computers that execute code from memory to control and / or perform functional aspects of the EAM system 70, and the memory may, in embodiments, be part of one or more controllers, microprocessors, and / or computers, and / or part of a memory capacity accessible via a network such as the World Wide Web.

[0048] As will be understood by those skilled in the art, the diagram of the electrophysiological system 50 shown in Figure 1 is intended to provide a general overview of the various components of the system 50 and is not intended in any way to imply that this disclosure is limited to any set of components or arrangement of components. For example, those skilled in the art will readily recognize that additional hardware components, such as breakout boxes, workstations, etc., may and likely be included in the electrophysiological system 50.

[0049] The EAM system 70 defines a location-specific volume around the heart 30 by generating a location-specific field via a field generator 80, and one or more location sensors or sensing elements on a device to be tracked, such as an electroporation catheter 105, track the position of the sensor within the location-specific volume, and therefore the position of the corresponding device, by generating an output that can be processed by a mapping and navigation controller 90. In the shown embodiment, device tracking is achieved using magnetic tracking technology, so the field generator 80 is a magnetic field generator that generates a magnetic field that defines the location-specific volume, and the location sensors on the device to be tracked are magnetic field sensors.

[0050] In other embodiments, impedance tracking methods may be employed to track the positions of various devices. In such embodiments, the positioning field is an electric field generated, for example, by an external field generator arrangement such as surface electrodes, or by an internal or intracardiac device such as an intracardiac catheter, or both. In these embodiments, the position-sensing elements may constitute electrodes on the device being tracked that generate outputs received and processed by a mapping and navigation controller 90 to track the positions of various position-sensing electrodes within a positioning volume.

[0051] In some embodiments, the EAM system 70 has both magnetic tracking and impedance tracking capabilities. In such embodiments, the accuracy of impedance tracking can be improved by first creating a map of the electric field induced by an electric field generator in the target cardiac chamber using a probe equipped with a magnetic position sensor, as is possible in some cases with the aforementioned RHYTHMIA HDx® mapping system. One exemplary probe is the INTELLAMAP ORION® mapping catheter, marketed by Boston Scientific Corporation.

[0052] Regardless of the tracking method used, the EAM system 70 utilizes the positional information of various tracked devices, along with the electrical activity of the heart acquired, for example, by an electroperforation catheter 105 or another catheter or probe equipped with a sensing electrode, to create a detailed three-dimensional geometric anatomical map or representation of the cardiac chambers, as well as an electroanatomical map in which the electrical activity of the target heart is superimposed on the geometric anatomical map, and displays it on the display 92. Furthermore, the EAM system 70 may create graphical representations of various tracked devices within the geometric anatomical map and / or electroanatomical map.

[0053] Although the EAM system 70 is shown in combination with the electroporation system 60 to provide a comprehensive diagram of the exemplary clinical equipment 10, the EAM system 70 is not essential for the operation and function of the electroporation system 60. That is, in the embodiment, the electroporation system 60 can be used independently of the EAM system 70 or any equivalent electroanatomical mapping system.

[0054] In the embodiment shown, the electroperforation catheter 105 includes a handle 105a, a shaft 105b, and an electroperforation electrode assembly 150, which will be further described below. The handle 105a is configured to be operated by the user to position the electroperforation electrode assembly 150 at a desired anatomical location. The shaft 105b has a distal end 105c and generally defines the longitudinal axis of the electroperforation catheter 105. As shown, the electroperforation electrode assembly 150 is located at or proximal to the distal end 105c of the shaft 105b. In the embodiment, the electroperforation electrode assembly 150 is electrically coupled to an electroperforation generator 130 to receive an electric pulse sequence or pulse train, thereby selectively generating an electric field for ablation of target tissue by irreversible electroperforation.

[0055] In the embodiment, the surface patch electrode 115 includes a conductive electrode that can be attached to the patient's body, such as the patient's chest. The surface patch electrode 115, including the conductive electrode, is electrically coupled to the electroporation generator 130 to act as a return path or sink for electrical energy in the system and to receive an electrical pulse sequence or pulse train from the electroporation generator 130, thereby acting as a source of electrical energy and selectively generating an electric field for ablation of target tissue by irreversible electroporation. In the embodiment, the surface patch electrode 115 acts as a return or sink for electrical energy received by the electroporation catheter 105 and the electroporation electrode assembly 150. In the embodiment, the surface patch electrode 115 acts as a source of electrical energy, and the electroporation catheter 105, including the electroporation electrode assembly 150, acts as a return or sink for the sourced electrical energy.

[0056] The electroporation system 60 is operable to generate an IRE pulse sequence, which includes a preconditioning pulse sequence and an electroporation pulse sequence. The IRE pulse sequence is configured to ablate the target tissue. In embodiments, the preconditioning pulse sequence is a series of electrical pulses that increase in magnitude to induce tetany in the skeletal muscle tissue and to provide electrolysis near the target tissue. In embodiments, the electroporation pulse sequence is a series of electrical pulses configured to cause irreversible damage to the target tissue.

[0057] In the embodiment, the electroporation system 60 includes an accelerometer 117 that can be attached to the patient's body, such as the patient's chest, and electrically coupled to an electroporation generator 130. The accelerometer 117 is configured to detect tetany by sensing the contraction of the patient's skeletal muscle system. The signal from the accelerometer 117 is received by the electroporation generator 130, which processes the signal to determine whether the patient's skeletal muscle system is contracting and whether tetany has been achieved. In the embodiment, the electroporation generator 130 is configured to provide an electroporation pulse sequence only after tetany has been achieved in the patient.

[0058] In the embodiment, the electroporation system 60 operates as a closed system in which a surface accelerometer 117 monitors chest vibrations, an electroporation generator 130 modulates pulses until tetany is achieved, and then the electroporation generator 130 delivers electroporation pulses. In the embodiment, the local impedance of the target tissue and the surrounding tissue can be measured during this time to calculate pre-ablation and post-ablation values ​​and evaluate the effectiveness of the lesion.

[0059] Figures 2A to 2C illustrate the features of an electropermeable catheter 105 including an electropermeable electrode assembly 150 according to an exemplary embodiment. In the embodiment shown in Figure 2A, the electropermeable electrode assembly 150 includes a plurality of electrodes 201a, 201b, 201c, 201d, 201e, and 201f arranged in a three-dimensional electrode array, where each of the electrodes 201a, 201b, 201c, 201d, 201e, and 201f is spaced apart from one another axially (i.e., in the direction of the longitudinal axis LA), circumferentially around the longitudinal axis LA, and / or radially with respect to the longitudinal axis LA. In some embodiments, electrodes 201a, 201b, 201c, 201d, 201e, and 201f are individually and selectively addressable via an electroporation generator 130 (Figure 1) to define a plurality of anode-cathode electrode pairs, and each anode-cathode electrode pair can receive an electrical pulse sequence from the electroporation generator 130, thereby generating an electric field that can selectively target tissue by electroporation, including ablation of target tissue by IRE. Figure 2A schematically illustrates the interaction between electrode pairs (e.g., current flow that forms an electric field) formed between electrodes 201 (e.g., 201a, 201b, 201c, 201d, 201e, and 201f) contained in the electroporation catheter 105. In this figure, the interaction is shown as paired arrows (e.g., ad, be, and df) indicating the current flow between electrodes 201. Furthermore, electrode pairs (e.g., 201a and 201d, 201b and 201e, and 201d and 201f) are labeled and indicated with their respective current flows (e.g., ad, be, and df).

[0060] Figure 2B shows the electric field 210 generated by the interaction between electrode pairs within the electroporation catheter 105. In this figure, an axially oriented electric field 210 is shown, located in a small opening 221 between the left atrium 223 and the left inferior pulmonary vein 225. In the embodiment, the axially oriented electric field 210 is generated by delivering electrical pulses to axially spaced anodes and cathodes.

[0061] Figure 2C also shows the electric field 210 generated by the interaction between electrode pairs within the electroporation catheter 105. However, here the electric field 210 is circumferentially oriented. In this embodiment, the circumferentially oriented electric field 210 is generated by delivering electrical pulses to circumferentially spaced anodes ("A") and cathodes ("C").

[0062] Figures 2A to 2C illustrate that multiple electric fields 210 may be generated simultaneously and / or sequentially in axial and circumferential orientations. For example, in embodiments, axially and circumferentially oriented electric fields 210 may be generated non-simultaneously in a predetermined sequence by selectively controlling the timing of the delivery of electrical pulses to each electrode 201. In addition, it is understood that intermittently generated electric fields 210 caused by staggered interactions between sets of electrode pairs, as well as electric field orientations other than axial and circumferential, are not beyond the scope of this disclosure.

[0063] As can be seen in Figure 2A, the electroporation electrode configuration 150 may include a plurality of individually addressable electrodes 201 (e.g., anodes or cathodes) arranged to selectively define a plurality of electrode pairs (e.g., anode-cathode pairs). Each anode-cathode pair may be configured to generate an electric field when a pulse sequence is delivered thereto. The plurality of anode-cathode pairs may include at least two of a first anode-cathode pair, a second anode-cathode pair, and a third anode-cathode pair. The first anode-cathode pair may be configured to generate a first electric field when a first pulse sequence is delivered thereto, which is oriented generally circumferentially with respect to the longitudinal axis. The second anode-cathode pair may be configured to generate a second electric field when a second pulse sequence is delivered thereto, which is oriented generally in the same direction as the longitudinal axis. A third anode-cathode pair may be arranged to generate a third electric field that is generally oriented transversely to the longitudinal axis when a third pulse sequence is delivered thereto. In embodiments, any combination of the first, second, and third pulse sequences may be delivered simultaneously or intermittently, and may take various forms.

[0064] In embodiments, the electroporation electrode structure 150 may be configured to structurally arrange electrodes 201a, 201b, 201c, 201d, 201e, and 201f in a distal first region and a more proximal second region. Thus, electrode pairs may be formed across various electrodes 201 within the electroporation electrode structure 150 between the first and second regions. For example, electrodes 201d and 201f may be configured to form an electrode pair. Similarly, electrodes 201a and 201d, or electrodes 201b and 201e, or combinations thereof, may be selected to form each electrode pair. Thus, electrode pairs may include electrodes spaced axially, electrodes spaced laterally, or electrodes spaced circumferentially. In addition, in embodiments, a given electrode (e.g., 201d) may function as a common electrode in at least two electrode pairs to generate an electric field 210.

[0065] Figure 2B shows an exemplary electric field 210 that may be generated by the electroporation electrode configuration 150. The electroporation electrode configuration 150 may be configured to generate a multidirectional electric field 210 when at least one pulse sequence is delivered thereto. The multidirectional electric field 210 may include at least two of the following directions with respect to the longitudinal axis: substantially axial, circumferential, and transverse. As used herein, the transverse direction may mean any non-parallel angle with respect to the longitudinal axis. As described elsewhere herein, the electroporation electrode configuration 150 may be configured to be operably coupled to an electroporation generator configured to generate at least one pulse sequence. The electroporation electrode configuration 150 may be configured to receive at least one pulse sequence from the electroporation generator. Thus, the electroporation electrode configuration 150 and the electroporation generator may be operably communicating with each other. In this disclosure, such communication can be used to generate an electric field 210 that is at least substantially gapless.

[0066] Undesirable gaps in the electric field 210 generated by the electroporating electrode configuration 150 can be limited or at least substantially eliminated. Such gaps may potentially lead to lesion gaps and therefore, for example, require multiple repositioning of the catheter. By overlapping the electric fields 210, the number of such gaps can be limited at least substantially. In embodiments, at least some of the electric fields 210 generated in a first pulse sequence set may overlap each other at least partially. For example, multiple adjacent electric fields 210 in a composite electric field 211 (e.g., axial, transverse, and / or circumferential) may intersect each other so as to limit the gaps within the composite electric field 211. The overlap may occur around or near multiple adjacent electric fields 210, or over an overwhelming majority or majority of one or more adjacent electric fields 210. In this disclosure, adjacent means adjacent electrodes 201, or electrodes 201 that are otherwise close to each other. The electroporation generator may be configured to generate a pulse sequence used to create overlapping electric fields.

[0067] The configuration of the electroporation electrode structure 150 in various embodiments can take any form suitable for a three-dimensional electrode structure, whether currently known or to be developed later. In exemplary embodiments, the electroporation electrode structure 150 may be in the form of a spline basket catheter, where each electrode 201a, 201b, 201c, 201d, 201e, and 201f is arranged on a plurality of splines in any manner known in the art. In embodiments, the electroporation electrode structure 150 may be formed on an expandable balloon, for example, where the electrodes are formed on flexible circuit branches or individual traces arranged on the balloon surface. In other embodiments, the electroporation electrode structure 150 may be in the form of an expandable mesh. In short, the specific structure used to form the electroporation electrode structure 150 is not essential for embodiments of the present disclosure.

[0068] Figure 3 shows an ablation energy application sequence 300, also referred to herein as the IRE pulse sequence 300, which includes a preconditioning pulse sequence 302 and an electroporation pulse sequence 304, according to an exemplary embodiment. The preconditioning pulse sequence 302 is a series of pulses 306 whose magnitude increases from lower voltages to higher voltages. The electroporation pulse sequence 304 is a series of high-energy electroporation pulses 308 having large positive and / or negative voltage values.

[0069] The electroporation system 60 is configured to deliver a preconditioning pulse sequence 302 which delivers a series of pulses 306 or a sequence of pulses 306 to achieve tetany and generate electrolysis. In Figure 3, only three pulses 306 of the preconditioning pulse sequence 302 are pointed to for clarity in the figure, but in embodiments, the sequence of pulses 306 includes all pulses in the preconditioning pulse sequence 302. The electroporation system 60 is further configured to deliver an electroporation pulse sequence 304, i.e., electroporation ablation energy, in a series of electroporation pulses 308 to ablate the target tissue. In embodiments, all pulses in the IRE pulse sequence 300 are delivered within the refractory period of the heart, such as within 250-330 milliseconds.

[0070] The pulse sequence 306 is a series of single-phase pulses whose magnitude increases over time from lower voltage to higher voltage. The voltage gradient causes relatively slow recruitment of skeletal muscle, ultimately leading to tetany skeletal muscle contraction, preceding the higher-voltage electroporation pulse 308 in the electroporation pulse sequence 304. Each of the pulses 306, or at least some of the pulses 306, also has features that promote electrolysis, such as including a single-phase exponentially decaying waveform 310 (or drooping waveform) behind the pulse 306. In Figure 3, only three of the exponentially decaying waveforms 310 in the preconditioning pulse sequence 302 are pointed to for clarity in the figure, but in embodiments, all pulses in the preconditioning pulse sequence 302 include an exponentially decaying waveform 310. In embodiments, the pulses 306 do not have to be entirely single-phase, but may include at least some asymmetric phases that are charge-equalized in both positive and negative components. In some embodiments, the duration of pulse 306 is from 1 millisecond (ms) to 60 ms, and in some embodiments, the slope / droop / exponential decay of the waveform is in the range of 20 to 80% of the leading edge.

[0071] The pulse 306 may have several different characteristics. In some embodiments, the pulse 306 in the preconditioning pulse sequence 302 is provided at a selected frequency, such as 1 kilohertz. In some embodiments, this frequency is in the range of 200 to 1000 Hz. In some embodiments, the pulse 306 is increased in voltage from 0 volts to 5 to 100 volts, and in some embodiments, the amplitude reaches 100 to 1000 volts. In some embodiments, the rate of increase can be an increment of 1% to 30% of the preceding pulse. In some embodiments, the preconditioning pulse sequence 302 is applied with a sequence duration of 100 to 250 milliseconds.

[0072] The preconditioning pulse sequence 302 preconditions the body for electroporation in at least two ways. Firstly, the preconditioning pulse sequence 302 acts as a series of tetany skeletal muscle pulses 306 that induce tetany, i.e., contraction of the skeletal muscles of the patient's body, before receiving the higher voltage electroporation pulse sequence 304. Increasing the magnitude of the pulses 306 over time from lower voltage to higher voltage will induce or contribute to inducing tetany. This SMS prepares the patient for the higher voltage electroporation pulses 308 in the electroporation pulse sequence 304, otherwise it could shock or be a painful experience for the patient. Secondly, the preconditioning pulse sequence 302 acts as a series of electrolysis-inducing pulses 306 that induce electrolysis near the target tissue. This creates a cytotoxic environment near the target tissue, which in turn allows for the use of smaller electroporation pulses to permeate the target tissue and induce cell death, thus enabling the creation of larger lesions with smaller electroporation pulses.

[0073] This synergistic electrolysis is triggered by applying relatively long, low-voltage pulses, such as the preconditioning pulse sequence 302, to the target region. In particular, the exponentially decaying waveform 310 (or drooping waveform) following pulse 306 of the preconditioning pulse sequence 302 causes electrolysis near the electrode. To elaborate further, synergistic electrolysis occurs when new chemical species are generated at the electrode interface as a result of electron transfer between the electrode and ions in the solution. These new chemical species diffuse from the electrode into the tissue in a process driven by the electrochemical potential. In physiological solutions, the pH changes due to the electrolytic reaction create an acidic region near the anode and a basic region near the cathode. The cytotoxic environment resulting from the local pH change, and the presence of several new chemical species formed during the electrolysis of the solution, work together with the permeabilization of electroporation to cause cell death.

[0074] In an exemplary embodiment, the preconditioning pulse sequence 302 is delivered as a series of unipolar electrical pulses 306. A surface patch electrode 115 attached to the chest of the patient 20 receives electrical pulses from the electroporation generator 130 and sources electrical energy, with the surface patch electrode 115 acting as the source electrode for the electrical pulses. One or more electrodes on the electroporation catheter 105 sink the electrical energy sourced by the surface patch electrode 115, with one or more electrodes on the electroporation catheter 105 acting as sinks for the electrical pulses. This causes the patient's skeletal muscles to contract to reach tetany, generating synergistic electrolysis near the target tissue where the electrodes of the electroporation catheter 105 are located close to the target tissue.

[0075] In other embodiments, one or more electrodes on the electropermeating catheter 105 receive pulses 306 from the electropermeating generator 130 and source electrical energy, so one or more electrodes on the electropermeating catheter 105 act as source electrodes for the electrical pulses 306. A surface patch electrode 115 attached to the chest of the patient 20 sinks the electrical energy sourced by one or more electrodes on the electropermeating catheter 105, so the surface patch electrode 115 acts as a sink for the electrical pulses.

[0076] After delivering at least some of the preconditioning pulse sequences 302, the electroporation system 60 is configured to deliver the electroporation pulse sequence 304, i.e., electroporation ablation energy, to ablate the target tissue. The electroporation pulse sequence 304 includes short-duration, high-energy electroporation pulses 308. As shown in the figure, the electroporation pulses 308 of the electroporation pulse sequence 304 are biphasic, for example, including both positive and negative pulses. In an embodiment, the electroporation pulses 308 may be positive 1000 volts and negative 1000 volts. In other embodiments, the electroporation pulses 308 may be single-phase, for example, including all positive pulses or all negative pulses.

[0077] If at least some of the pulses 206 of the preconditioning pulse sequence 302 are applied before the electroporation pulse 308 is applied, electrolysis near or in the target tissue can be performed using electroporation pulses 308 with a lower amplitude than what is normally or required (500 V / cm to 2,500 V / cm) when using only the electroporation pulse, for example, 250 volts / cm (V / cm) to 1000 V / cm.

[0078] As shown in the figure, the electroporation pulse 308 of the electroporation pulse sequence 304 is delivered within a series of pulses 306 of the preconditioning pulse sequence 302. In another embodiment, the electroporation generator 130 may be configured to deliver the electroporation pulse 308 of the electroporation pulse sequence 304 after all the pulses 306 of the preconditioning pulse sequence 302 have been delivered.

[0079] The electroporation pulse 308 of the electroporation pulse sequence 304 may be either a unipolar or bipolar pulse. In embodiments, the electrode pair (or electrode set) on the electroporation catheter 105 is selected to deliver a bipolar pulse between the selected electrode pair. Each electrode in the electrode pair may act as a source electrode, or each electrode in the electrode pair may act as a sink to deliver electroablation energy to the target tissue.

[0080] In other embodiments, one or more electrodes on the electropermeating catheter 105 act as source electrodes for the electrical pulses, since they receive the electropermeating pulses 308 of the electropermeating pulse sequence 304 from the electropermeating generator 130 and source electrical energy in order to provide a unipolar pulse. A surface patch electrode 115 attached to the chest of the patient 20 acts as a sink for the electrical pulses, since it sinks the electrical energy sourced by one or more electrodes on the electropermeating catheter 105.

[0081] In one embodiment, the electroporation system 60 includes an accelerometer 117 configured to detect tetany by sensing the contraction of the patient's skeletal muscles, such as the contraction of the patient's pectoral muscles. The signal from the accelerometer 117 is received by an electroporation generator 130, which processes the signal to determine whether the patient's skeletal muscular system is contracting and whether tetany has been achieved. In one embodiment, the electroporation generator 130 is configured to provide an electroporation pulse sequence 304 only after tetany has been achieved in the patient. The electroporation generator 130 may provide the electroporation pulse sequence 304 during or after a preconditioning pulse sequence 302.

[0082] Therefore, the electroporation system 60 acts as a closed system in which a surface accelerometer 117 monitors chest vibrations, and an electroporation generator 130 modulates pulse 306 until tetany is achieved, after which electroporation pulse 308 is delivered. In the embodiment, the local impedance of the target tissue and the surrounding tissue can also be measured during this time to calculate pre-ablation and post-ablation values ​​and evaluate the effectiveness of the lesion.

[0083] By applying at least some pulses 306 within the preconditioning pulse sequence 302 before delivering the electropermeating pulse 308 of the electropermeating pulse sequence 304, tetany or contraction of the patient's skeletal muscle can be achieved, and by electrolysis, a cytotoxic environment can be established near or adjacent to the target tissue before delivering the electropermeating pulse 308 of the electropermeating pulse sequence 304. This results in the possibility of creating lesions of the same size as those that can be created using much more energy or much more electropermeating pulses 308 without the preconditioning pulse sequence 302, but using lower energy electropermeating pulses 308 and / or fewer electropermeating pulses 308.

[0084] Figure 4 is a flowchart illustrating a method for ablating a patient's target tissue by irreversible electroporation according to an embodiment of the subject matter of this disclosure. Such a method and other related methods for ablating a patient's target tissue by irreversible electroporation are disclosed herein.

[0085] This method includes delivering an IRE (irreversible electroporation) pulse sequence, which includes the steps of delivering a preconditioning pulse sequence 402 and delivering an electroporation pulse sequence 404. In embodiments, the electroporation pulse sequence is delivered during or within the preconditioning pulse sequence. In other embodiments, the electroporation pulse sequence is delivered after the preconditioning pulse sequence has stopped. In exemplary embodiments, the IRE pulse sequence, including the preconditioning pulse sequence and the electroporation pulse sequence, is delivered to the patient within one or more of the following timeframes: the patient's cardiac refractory time, less than 330 milliseconds, and 100 to 250 milliseconds.

[0086] The step of delivering the 402 preconditioning pulse sequence includes delivering the preconditioning pulse sequence between a surface patch electrode and one or more catheter electrodes on a catheter to induce electrolysis near target tissue and tetany skeletal muscle stimulation in the patient. In embodiments, the preconditioning pulse sequence includes a plurality of unipolar electrical pulses sourced from the surface patch electrode and sunk by one or more catheter electrodes. In other embodiments, the preconditioning pulse sequence includes a plurality of unipolar electrical pulses sourced from one or more catheter electrodes and sunk by the surface patch electrode. Also in embodiments, the preconditioning pulse sequence includes a plurality of preconditioning pulses that are single-phase.

[0087] A preconditioning pulse sequence includes multiple preconditioning pulses delivered at a selected frequency, with the voltage increasing over time from lower to higher voltages. In embodiments, the preconditioning pulse sequence includes multiple preconditioning pulses delivered at approximately 1 kilohertz. In embodiments, the preconditioning pulse sequence also includes multiple preconditioning pulses with voltages increasing from 0 volts to 5-100 volts. Increasing the pulse voltage over time from lower to higher voltages contributes to inducing tetany skeletal muscle contractions in the patient. The preconditioning pulse sequence also includes multiple preconditioning pulses with exponentially decaying trailing waveforms that induce or contribute to electrolysis near the target tissue.

[0088] The step of delivering the electropermeabilization pulse sequence 404 includes delivering the electropermeabilization pulse sequence to catheter electrodes on a catheter to induce irreversible electropermeabilization ablation of target tissue. In embodiments, the electropermeabilization pulse sequence includes a plurality of bipolar electrical pulses delivered to one or more pairs of catheter electrodes on the catheter electrode. In other embodiments, the electropermeabilization pulse sequence includes a plurality of unipolar electrical pulses delivered between a surface patch electrode and one or more catheter electrodes on a catheter.

[0089] In embodiments, the method further includes monitoring an accelerometer 117 on the patient, which is configured to detect tetany by sensing the contraction of the patient's skeletal muscles, such as the contraction of the patient's pectoral muscles. In a closed-loop system, the signal from the accelerometer 117 is received by an electroporation generator 130, which processes the signal to determine whether the patient's skeletal muscular system is contracting and whether tetany has been achieved. In embodiments, the electroporation generator 130 is configured to provide an electroporation pulse sequence only after tetany has been achieved in the patient, which may be during or after a preconditioning pulse sequence.

[0090] In the embodiment, the method also includes monitoring the local impedance of the target tissue and the surrounding tissue to calculate pre-ablation and post-ablation values ​​for evaluating the effectiveness of the lesion.

[0091] Various modifications and additions can be made to the exemplary embodiments described without departing from the scope of this disclosure. For example, while the embodiments described above refer to specific features, the scope of this disclosure also includes embodiments having different combinations of features, and embodiments that do not include all of the described features. Accordingly, the scope of this disclosure is intended to encompass all such alternative forms, modifications, and variations that fall within the claims, along with all their equivalents.

Claims

1. A device for use in ablation of a patient's target tissue by irreversible electroporation, An electroporation generator, configured to deliver an irreversible electroporation pulse sequence to one or more catheter electrodes operably coupled to the electroporation generator, comprises an electroporation generator, The irreversible electroporation pulse sequence includes a preconditioning pulse sequence and an electroporation pulse sequence. The preconditioning pulse sequence comprises a plurality of preconditioning electrical pulses configured to induce electrolysis near the target tissue and provide sufficient skeletal muscle stimulation to induce tetany in the patient. The apparatus comprises a plurality of preconditioning electrical pulses, the preconditioning pulse sequence including a subsequent waveform in which the voltage increases from a lower voltage to a higher voltage and then decays.

2. The apparatus according to claim 1, wherein the preconditioning pulse sequence includes a plurality of unipolar electrical pulses delivered between one or more catheter electrodes and surface patch electrodes attached to the patient's body.

3. The apparatus according to claim 1 or 2, wherein the preconditioning pulse sequence includes a plurality of bipolar electrical pulses sourced from at least one of the one or more catheter electrodes and sunk by at least one of the one or more catheter electrodes.

4. The apparatus according to any one of claims 1 to 3, wherein the preconditioning pulse sequence includes a plurality of preconditioning electrical pulses delivered at a selected frequency.

5. The apparatus according to claim 4, wherein the selected frequency is in the range of 200 Hz to 1 kHz.

6. The apparatus according to claim 4, wherein the selected frequency is 1000 Hz.

7. The apparatus according to any one of claims 1 to 6, wherein the preconditioning pulse sequence includes a plurality of single-phase preconditioning electrical pulses.

8. The apparatus according to any one of claims 1 to 7, wherein the irreversible electropermeation pulse sequence, including the preconditioning pulse sequence and the electropermeation pulse sequence, is delivered to the patient within one or more time frames of the patient's cardiac refractory time, less than 330 milliseconds, and 100 to 250 milliseconds.

9. The apparatus according to any one of claims 1 to 8, wherein the electroporation pulse sequence is delivered within the preconditioning pulse sequence.

10. The apparatus according to any one of claims 1 to 9, wherein the electroperforation pulse sequence includes a plurality of bipolar electrical pulses delivered to one or more pairs of catheter electrodes of the catheter electrode.

11. The apparatus according to any one of claims 1 to 10, wherein the electroporation generator is configured to receive a signal from an accelerometer attached to the patient's body, and further configured to process the signal to determine whether tetany has been achieved in response to the delivery of the preconditioning pulse sequence.

12. The apparatus according to claim 11, wherein the electroporation generator is configured to deliver the electroporation pulse sequence only after tetany has been achieved in the patient.

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