Pre-treatment waveform for irreversible electroporation

Abstract

An electroporation ablation system for treating a target tissue in a patient. 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 a catheter electrode at the distal end of the shaft and spatially arranged to generate an electric field in the target tissue in response to an electric pulse. The electroporation generator is operably coupled to the catheter electrode and configured to deliver an electric pulse in a sequence of irreversible electroporation pulses to the one or more catheter electrodes, the sequence of irreversible electroporation pulses including a pre-treatment pulse sequence and an electroporation pulse sequence. Wherein the pre-treatment pulse sequence includes pre-treatment electric pulses configured to cause electrolysis in the vicinity of the target tissue and to cause skeletal muscle stimulation tetanus in the patient.

Description

Technical Field

[0001] This application claims priority to provisional application number 63 / 085452, filed on September 30, 2020, which is incorporated herein by reference in its entirety. Technical Field

[0003] This disclosure relates to medical devices, systems, and methods for ablating patient tissue. More specifically, this disclosure relates to medical devices, systems, and methods for ablating tissue via electroporation. Background Technology

[0004] Ablation procedures are used to treat many different conditions in patients. Ablation can be used to treat arrhythmias, benign tumors, cancerous tumors, and can be used to control bleeding during surgery. Typically, ablation is performed using thermal ablation techniques, including radiofrequency (RF) ablation and cryoablation. In RF ablation, a probe is inserted into the patient's body, and radiofrequency waves are transmitted through the probe to the surrounding tissue. The radiofrequency waves generate heat, which destroys the surrounding tissue and burns blood vessels. In cryoablation, a hollow needle or cryoprobe is inserted into the patient's body, and a cold, heat-conducting fluid circulates through the probe to freeze and kill the surrounding tissue. Both RF ablation and cryoablation techniques indiscriminately kill tissue through cell necrosis, which may damage or kill other healthy tissues, such as esophageal tissue, phrenic nerve cells, and coronary artery tissue.

[0005] Another ablation technique uses electroporation. In electroporation, or electropermeabilization, an electric field is applied to the cells to increase the permeability of the cell membrane. Electroporation can be reversible or irreversible, depending on the strength of the electric field. If electroporation is reversible, the increased cell membrane permeability can be used to introduce chemicals, drugs, and / or deoxyribonucleic acid (DNA) into the cells before they heal and recover. If electroporation is irreversible, the affected cells are killed through apoptosis.

[0006] Irreversible electroporation (IRE) can be used as a non-thermal ablation technique. In IRE, a series of short, high-voltage pulses are used to generate a sufficiently strong electric field to kill cells through apoptosis. In the ablation of cardiac tissue, IRE may be a safe and effective alternative to the indiscriminate killing of cells by thermal ablation techniques such as RF ablation and cryoablation. IRE can be used to kill targeted tissues, such as myocardial tissue, by using the intensity and duration of an electric field that kills the targeted tissue without permanently damaging other cells or tissues, such as non-targeted myocardial tissue, erythrocytes, vascular smooth muscle tissue, endothelial tissue, and nerve cells.

[0007] In some IRE procedures, the electroporation pulses cause skeletal muscle stimulation (SMS) and are involved in adverse side effects. One approach to reduce SMS is to refine the IRE pulses, thereby optimizing the pulses to avoid SMS. This typically results in a smaller ablation field and smaller lesions. A method is needed to deliver effective IRE energy while avoiding SMS. Summary of the Invention

[0008] In Example 1, an electroporation ablation system for treating targeted tissue in a patient is provided. 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 a catheter electrode located at the distal end of the shaft and spatially arranged to generate an electric field in the target tissue in response to an electrical pulse. The electroporation generator is operatively coupled to the catheter electrode and configured to deliver electrical pulses from an irreversible electroporation pulse sequence to one or more catheter electrodes, the irreversible electroporation pulse sequence including a pretreatment pulse sequence and an electroporation pulse sequence. The pretreatment pulse sequence includes pretreatment electrical pulses configured to induce electrolysis near the target tissue and cause tetany of skeletal muscle stimulation in the patient.

[0009] In Example 2, the electroporation ablation system of Example 1 includes a surface patch electrode attached to a patient and configured to generate an electric field within the patient in response to an electrical pulse.

[0010] In Example 3, the electroporation ablation system of Example 2, wherein the pretreatment pulse sequence includes a monopolar electrical pulse originating from a surface patch electrode and fed in through one or more conduit electrodes.

[0011] In Example 4, the electroporation ablation system of Example 2, wherein the pretreatment pulse sequence includes a monopolar electrical pulse that originates from one or more catheter electrodes and is channeled through a surface patch electrode.

[0012] In Example 5, the electroporation ablation system of any one of Examples 1-4, wherein the pretreatment pulse sequence includes bipolar electrical pulses originating from at least one of one or more catheter electrodes and converging through at least another of one or more catheter electrodes.

[0013] In Example 6, the electroporation ablation system of any one of Examples 1-5, wherein the pretreatment pulse sequence includes pretreatment pulses delivered at a selected frequency.

[0014] In Example 7, the electroporation ablation system of any one of Examples 1-6, wherein the pretreatment pulse sequence includes pretreatment pulses in which the voltage rises from a lower voltage ramp to a higher voltage over time.

[0015] In Example 8, the electroporation ablation system of any one of Examples 1-7, wherein the pretreatment pulse sequence includes a pretreatment pulse comprising an exponentially decaying back waveform that induces electrolysis near the target tissue.

[0016] In Example 9, the electroporation ablation system of any one of Examples 1-8, wherein the pretreatment pulse sequence comprises a single-phase pretreatment pulse.

[0017] In Example 10, the electroporation ablation system of any one of Examples 1-9, wherein an irreversible electroporation pulse sequence, including a pretreatment pulse sequence and an electroporation pulse sequence, is delivered to the patient within one or more refractory periods of the patient's heart (less than 330 milliseconds) and a window of 100-250 milliseconds.

[0018] In Example 11, the electroporation ablation system of any one of Examples 1-10, wherein the electroporation pulse sequence is delivered within a pulse sequence during the pretreatment refractory period.

[0019] In Example 12, the electroporation ablation system of any one of Examples 1-11, wherein the electroporation pulse sequence comprises bipolar electrical pulses delivered to one or more catheter electrode pairs.

[0020] In Example 13, the electroporation ablation system of any one of Examples 1-12 includes an accelerometer configured to monitor skeletal muscle stimulation in a patient, and wherein the electroporation ablation system is a closed-loop system such that an electroporation generator is configured to deliver a pretreatment pulse sequence, detect the patient's rigidity, and then deliver an electroporation pulse sequence, and wherein local impedance is measured to calculate pre-ablation and post-ablation values ​​to assess the efficacy of the treatment.

[0021] In Example 14, an electroporation ablation system for treating targeted tissue in a patient is provided. 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 a catheter electrode located at the distal end of the shaft and spatially arranged to generate an electric field in the target tissue in response to an electrical pulse. The electroporation generator is operatively 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 from an irreversible electroporation pulse sequence comprising a pretreatment pulse sequence and an electroporation pulse sequence to the plurality of electrodes, wherein the electroporation generator delivers the electroporation pulse sequence during the pretreatment pulse sequence.

[0022] In Example 15, the electroporation ablation system of Example 14, wherein the pretreatment pulse sequence includes electrical pulses configured to induce electrolysis near the target tissue and to induce tetany of skeletal muscles in the patient.

[0023] In Example 16, an electroporation ablation system for treating targeted tissue in a patient is provided. 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 a catheter electrode located at the distal end of the shaft and spatially arranged to generate an electric field in the target tissue in response to an electrical pulse. The electroporation generator is operatively coupled to the catheter electrode and configured to deliver electrical pulses from an irreversible electroporation pulse sequence comprising a pretreatment pulse sequence and an electroporation pulse sequence to one or more catheter electrodes, wherein the pretreatment pulse sequence includes pretreatment electrical pulses configured to induce electrolysis near the target tissue and cause tetany of skeletal muscle stimulation in the patient.

[0024] In Example 17, the electroporation ablation system of Example 16 includes a surface patch electrode attached to a patient and configured to generate an electric field in the patient’s body in response to an electrical pulse.

[0025] In Example 18, the electroporation ablation system of Example 16, wherein the pretreatment pulse sequence includes a monopolar electrical pulse originating from a surface patch electrode and fed in through one or more conduit electrodes.

[0026] In Example 19, the electroporation ablation system of Example 16, wherein the pretreatment pulse sequence includes a monopolar electrical pulse originating from one or more catheter electrodes and fed in through a surface patch electrode.

[0027] In Example 20, the electroporation ablation system of Example 16, wherein the pretreatment pulse sequence includes bipolar electrical pulses originating from at least one of one or more catheter electrodes and converging through at least another of one or more catheter electrodes.

[0028] In Example 21, the electroporation ablation system of Example 16, wherein the pretreatment pulse sequence includes pretreatment pulses delivered at a selected frequency.

[0029] In Example 22, the electroporation ablation system of Example 16, wherein the pretreatment pulse sequence includes pretreatment pulses in which the voltage rises from a lower voltage ramp to a higher voltage over time.

[0030] In Example 23, the electroporation ablation system of Example 16, wherein the pretreatment pulse sequence includes a pretreatment pulse comprising an exponentially decaying back waveform that induces electrolysis near the target tissue.

[0031] In Example 24, the electroporation ablation system of Example 16 is used, wherein the pretreatment pulse sequence comprises a single-phase pretreatment pulse.

[0032] In Example 25, the electroporation ablation system of Example 16, wherein an irreversible electroporation pulse sequence, including a pretreatment pulse sequence and an electroporation pulse sequence, is delivered to the patient within one or more refractory periods of the patient's heart (less than 330 milliseconds) and within a window of 100-250 milliseconds.

[0033] In Example 26, the electroporation ablation system of Example 16 is used, wherein the electroporation pulse sequence is delivered within a pretreatment pulse sequence.

[0034] In Example 27, the electroporation ablation system of Example 16, wherein the electroporation pulse sequence includes bipolar electrical pulses delivered to one or more catheter electrode pairs.

[0035] In Example 28, the electroporation ablation system of Example 16 includes an accelerometer configured to monitor skeletal muscle stimulation in a patient, and wherein the electroporation ablation system is a closed-loop system such that an electroporation generator is configured to deliver a pretreatment pulse sequence, detect the patient's rigidity, and then deliver an electroporation pulse sequence, and wherein local impedance is measured to calculate pre-ablation and post-ablation values ​​to assess the efficacy of the treatment for the lesion.

[0036] In Example 29, an electroporation ablation system for treating targeted tissue in a patient is provided. 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 a catheter electrode located at the distal end of the shaft and spatially arranged to generate an electric field in the target tissue in response to an electrical pulse. The electroporation generator is operatively 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 from an irreversible electroporation pulse sequence comprising a pretreatment pulse sequence and an electroporation pulse sequence to the plurality of electrodes, wherein the electroporation generator delivers the electroporation pulse sequence during the pretreatment pulse sequence.

[0037] In Example 30, the electroporation ablation system of Example 29, wherein the pretreatment pulse sequence includes a pretreatment electrical pulse configured to induce electrolysis near the target tissue and cause skeletal muscle stimulation tetany in the patient.

[0038] In Example 31, the electroporation ablation system of Example 29, wherein the electroporation pulse sequence includes bipolar electrical pulses delivered to selected catheter electrode pairs.

[0039] In Example 32, a method for ablation of a target tissue in a patient via irreversible electroporation is provided. The method includes delivering an irreversible electroporation pulse sequence, including delivering a pretreatment pulse sequence between multiple electrodes comprising a surface patch electrode and one or more catheter electrodes on a catheter to induce electrolysis near the target tissue and to induce skeletal muscle tetany in the patient, and delivering the electroporation pulse sequence to the multiple electrodes to induce irreversible electroporation ablation of the target tissue.

[0040] In Example 33, according to the method of Example 32, the delivery of the pretreatment pulse sequence includes delivering electrical pulses whose voltage increases from a lower voltage ramp to a higher voltage over time, and wherein one or more electrical pulses include an exponentially decaying back waveform.

[0041] In Example 34, the method is according to Example 32, wherein an electroporation pulse sequence is delivered during a pretreatment pulse sequence.

[0042] In Example 35, the method according to Example 32 includes monitoring an accelerometer on a patient in a closed-loop system, delivering a pretreatment pulse sequence to induce tetany in the patient, detecting tetany in the patient via the accelerometer, and delivering an electroporation pulse sequence after inducing tetany.

[0043] While several embodiments have been disclosed, other embodiments of this disclosure will become apparent to those skilled in the art from the following detailed description, which illustrates and describes illustrative embodiments of this disclosure. Therefore, the drawings and detailed description are to be regarded as illustrative in nature and not restrictive. Attached Figure Description

[0044] Figure 1 This is a diagram illustrating an exemplary clinical setup for treating a patient and treating the patient's heart using an electrophysiological system, according to embodiments of the subject matter of this disclosure.

[0045] Figure 2A This is a diagram illustrating the interaction between the distal end of a shaft included in a catheter and between electrode pairs according to an embodiment of the subject matter of this disclosure.

[0046] Figure 2B This is a diagram illustrating the axial electric field generated by the interaction between electrode pairs according to an embodiment of the subject matter of this disclosure.

[0047] Figure 2C This is a diagram illustrating the circumferential electric field generated by the interaction between electrode pairs in a conduit according to an embodiment of the subject matter of this disclosure.

[0048] Figure 3This is a diagram illustrating an IRE pulse sequence including a pretreatment pulse sequence and an electroporation pulse sequence according to an embodiment of the subject matter of this disclosure.

[0049] Figure 4 This is a flowchart illustrating a method for ablating targeted tissue in a patient via irreversible electroporation, according to an embodiment of the subject matter of this disclosure.

[0050] While this disclosure is applicable to various modifications and alternatives, specific embodiments have been shown by way of example in the accompanying drawings and are described in detail below. However, it is not intended to limit this disclosure to the specific embodiments described. Rather, this disclosure is intended to cover all modifications, equivalents, and alternatives that fall within the scope of this disclosure as defined by the appended claims. Detailed Implementation

[0051] The following detailed description is exemplary in nature and is not intended to limit the scope, applicability, or configuration of the invention in any way. Rather, the following description provides some practical illustrations for implementing exemplary embodiments of the invention. Examples of structure, material, and / or size are provided for selected elements. Those skilled in the art will recognize that many of the mentioned examples have various suitable alternatives.

[0052] Figure 1 This is a diagram illustrating an exemplary clinical setup 10 for treating a patient 20 and the heart 30 of the patient 20 using an electrophysiological system 50, according to embodiments of the subject matter of this disclosure. The electrophysiological system 50 includes an electroporation system 60 and an electroanatomical mapping (EAM) system 70, which includes a positioning field generator 80, a mapping and navigation controller 90, and a display 92. Furthermore, the clinical setup 10 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 electrophysiological system 50. As will be understood by those skilled in the art, the clinical setup 10 may have… Figure 1 Other components and component arrangements not shown.

[0053] The electroporation system 60 includes an electroporation catheter 105, an insertion sheath 110, a surface patch electrode 115, and an electroporation generator 130. Furthermore, in embodiments, the electroporation system 60 includes an accelerometer 117, which may be a separate sensor or part of the surface patch electrode 115. Additionally, the electroporation system 60 includes various connecting elements (e.g., cables, umbilical cables, etc.) that operate 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 the connecting elements is not essential to this disclosure, and those skilled in the art will recognize that the various components described herein can be interconnected in various ways.

[0054] In one embodiment, the electroporation system 60 is configured to deliver electric field energy to targeted tissue within the patient's heart 30 to induce tissue cell apoptosis, rendering the tissue unable to conduct electrical signals. The electroporation generator 130 is configured to control functional aspects of the electroporation system 60. In one embodiment, the electroporation generator 130 is operable as a pulse generator to generate and provide a pulse sequence to the electroporation catheter 105 and the surface patch electrode 115, as described in more detail herein. In another embodiment, the electroporation generator 130 is operable to receive sensing signals from an accelerometer 117 and, based on the received sensing signals, act as a pulse generator to generate and provide a pulse sequence to the electroporation catheter 105 and the surface patch electrode 115, as described in more detail herein.

[0055] In one embodiment, the electroporation generator 130 includes one or more controllers, microprocessors, and / or computers that execute off-memory code to control and / or perform functional aspects of the electroporation catheter system 60. In another embodiment, the memory may be part of one or more controllers, microprocessors, and / or computers, and / or a portion of a memory capacity accessible via a network such as the World Wide Web.

[0056] In one embodiment, the delivery sheath 110 is operable to provide a delivery catheter through which the electroporation catheter 105 can be deployed to a specific target site within the patient's heart 30. However, it should be understood that the delivery sheath 110 is shown and described herein to provide context for the entire electrophysiological system 50, but this is not essential to the novelty of the various embodiments described herein.

[0057] The EAM system 70 is operable to track the position of various functional components of the electroporation system 60 and generate high-fidelity three-dimensional anatomical and electroanatomical maps of the chambers of interest. In an embodiment, the EAM system 70 may be a RHYTHMIA system sold by Boston Scientific Corporation. TM HDx mapping system. Furthermore, in embodiments, the mapping and navigation controller 90 of the EAM system 70 includes one or more controllers, microprocessors, and / or computers that execute off-memory code to control and / or perform functional aspects of the EAM system 70, wherein in embodiments, the memory may 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.

[0058] As understood by those skilled in the art, Figure 1The description of the electrophysiological system 50 shown 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 junction boxes, workstations, etc., may and are likely to be included in the electrophysiological system 50.

[0059] The EAM system 70 generates a positioning field via a field generator 80 to define a positioning volume around the heart 30, and one or more position sensors or sensing elements on one or more tracked devices (e.g., electroporation catheter 105) generate an output that can be processed by a mapping and navigation controller 90 to track the position of the sensors and thus the corresponding devices within the tracking volume. In the illustrated embodiment, magnetic tracking is used to achieve device tracking, wherein the field generator 80 is a magnetic field generator that generates a magnetic field that defines the positioning volume, and the position sensors on the tracked devices are magnetic field sensors.

[0060] In other embodiments, impedance tracking methods can be employed to track the position of various devices. In such embodiments, the positioning field is an electric field generated, for example, by an external field generator (e.g., surface electrodes), by an in vivo or intracardiac device (e.g., an intracardiac catheter), or both. In these embodiments, position sensing elements can form electrodes on the tracked device that generate outputs received and processed by the mapping and navigation controller 90 to track the positions of various position sensing electrodes within the positioning volume.

[0061] In this embodiment, the EAM system 70 is equipped with magnetic and impedance tracking capabilities. In such embodiments, in some cases, impedance tracking accuracy can be enhanced by first creating a map of the electric field sensed by an electric field generator within the chamber of interest using a probe equipped with a magnetic position sensor, as described above with the RHYTHMIA HDx. TM The mapping system is possible. An example probe is the Intellapate Orion, sold by Boston Scientific. TM Mapping catheter.

[0062] Regardless of the tracking method used, the EAM system 70 utilizes the location information of various tracked devices, as well as electrocardiographic activity acquired via, for example, an electroporation catheter 105 or another catheter or probe equipped with sensing electrodes, to generate and display on the display 92 a detailed three-dimensional geometric anatomy or representation of the heart chambers, and an electroanatomical map of the electrocardiographic activity of interest superimposed on the geometric anatomy. Furthermore, the EAM system 70 can generate graphical representations of various tracked devices within the geometric anatomy and / or electroanatomical maps.

[0063] Although the EAM system 70 is shown in combination with the electroporation system 60 to provide a comprehensive description of the exemplary clinical setup 10, the EAM system 70 is not essential to the operation and function of the electroporation system 60. That is, in the embodiments, the electroporation system 60 can be used independently of the EAM system 70 or any similar electroanatomical mapping system.

[0064] In the illustrated embodiment, the electroporation catheter 105 includes a handle 105a, a shaft 105b, and an electroporation electrode arrangement 150, which will be further described below. The handle 105a is configured to be operated by a user to position the electroporation electrode arrangement 150 at a desired anatomical location. The shaft 105b has a distal end 105c and generally defines the longitudinal axis of the electroporation catheter 105. As shown, the electroporation electrode arrangement 150 is located at or near the distal end 105c of the shaft 105b. In this embodiment, the electroporation electrode arrangement 150 is electrically coupled to an electroporation generator 130 to receive a sequence or burst of electrical pulses to selectively generate an electric field for ablation of targeted tissue via irreversible electroporation.

[0065] In one embodiment, the surface patch electrode 115 includes a conductive electrode that can be attached to the body of the patient 20, for example, to 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 sequences or bursts of electrical pulses from the electroporation generator 130, thereby acting as an electrical energy source and selectively generating an electric field for use in the irreversible ablation of targeted tissue via electroporation. In one 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 arrangement 150. In one embodiment, the surface patch electrode 115 acts as an electrical energy source, and the electroporation catheter 105, including the electroporation electrode arrangement 150, acts as a return or sink for the source electrical energy.

[0066] The electroporation system 60 is operable to generate an IRE pulse sequence comprising a pretreatment (pre-treatment) pulse sequence and an electroporation pulse sequence. The IRE pulse sequence is configured to ablate the target tissue. In one embodiment, the pretreatment pulse sequence is a series of electrical pulses with an amplitude ramp that tetanizes skeletal muscle tissue and provides electrolysis near the target tissue. In another embodiment, the electroporation pulse sequence is a series of electroporation pulses configured to cause irreversible damage to the target tissue.

[0067] In one embodiment, the electroporation system 60 includes an accelerometer 117, which may be attached to the body of the patient 20, for example, to the patient's chest, and electrically coupled to an electroporation generator 130. The accelerometer 117 is configured to sense contraction of the patient's skeletal muscle system to detect tetany. The electroporation generator 130 receives signals from the accelerometer 117 and processes these signals to determine whether the patient's skeletal muscle system is contracting and whether tetany has occurred. In one embodiment, the electroporation generator 130 is configured to provide an electroporation pulse sequence only after tetany has occurred in the patient.

[0068] In this embodiment, the electroporation system 60 acts as a closed system, the surface accelerometer 117 monitors chest vibrations, and the electroporation generator 130 modulates pulses until tetany is achieved, after which the electroporation generator 130 delivers electroporation pulses. Furthermore, in this embodiment, local impedance of the target tissue and surrounding tissue can be measured during this time to calculate pre- and post-ablation values ​​for evaluating the effectiveness of the treatment.

[0069] Figure 2A-2C Features of an electroporation catheter 105 are shown, the electroporation catheter including an electroporation electrode arrangement 150 according to an exemplary embodiment. Figure 2A In the illustrated embodiment, the electroporation electrode arrangement 150 includes a plurality of electrodes 201a, 201b, 201c, 201d, 201e, and 201f arranged in a three-dimensional electrode array, such that each of the electrodes 201a, 201b, 201c, 201d, 201e, and 201f is spaced apart from each other axially (i.e., in the direction of the longitudinal axis LA), circumferentially about the longitudinal axis LA, and / or radially relative to the longitudinal axis LA. In some embodiments, each of the electrodes 201a, 201b, 201c, 201d, 201e, and 201f is individual and can be transmitted via the electroporation generator 130 ( Figure 1 Selective addressing is used to define multiple anode-cathode electrode pairs, each of which is capable of receiving a sequence of electrical pulses from the electroporation generator 130 and thus generating an electric field that can selectively target tissues through electroporation, including targeting tissues through IRE ablation. Figure 2A The diagram schematically illustrates the interaction (e.g., the current forming an electric field) between electrode pairs formed between electrodes 201 (e.g., 201a, 201b, 201c, 201d, 201e, and 201f) included in the electroporation conduit 105. In this figure, the interaction is shown as paired arrows (e.g., ad, be, and df) indicating the currents between the electrodes 201. The electrode pairs (e.g., 201a and 201d, 201b and 201e, and 201d and 201f) are shown, and their respective currents (e.g., ad, be, and df) are labeled.

[0070] Figure 2B This is a diagram illustrating the electric field 210 generated by the interaction between electrode pairs in the electroporation catheter 105. In this diagram, the axially oriented electric field 210 is shown positioned at the opening 221 between the left atrium 223 and the left inferior pulmonary vein 225. In an embodiment, the axially oriented electric field 210 is generated by delivering electrical pulses to axially spaced anodes and cathodes.

[0071] Figure 2C This diagram also illustrates the electric field 210 generated by the interaction between electrode pairs in the electroporation conduit 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”).

[0072] Figure 2A-2C Multiple electric fields 210 are shown to be generated simultaneously and / or sequentially, and in both axial and circumferential orientations. For example, in an embodiment, electric fields 210 in both axial and circumferential orientations can be generated non-simultaneously in a predefined order by selectively controlling the timing of the electrical pulses delivered to each electrode 201. Furthermore, it should be understood that the intermittent generation of electric fields 210 caused by the staggered interactions between multiple sets of electrode pairs and the electric field orientations other than axial and circumferential are not beyond the scope of this disclosure.

[0073] like Figure 2A As shown, the electroporation electrode arrangement 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 arranged to generate a first electric field generally oriented circumferentially relative to the longitudinal axis when a first pulse sequence is delivered thereto. The second anode-cathode pair may be arranged to generate a second electric field generally oriented in the same direction as the longitudinal axis when a second pulse sequence is delivered thereto. The third anode-cathode pair may be arranged to generate a third electric field 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.

[0074] In an embodiment, the electroporation electrode arrangement 150 may be configured to structurally arrange electrodes 201a, 201b, 201c, 201d, 201e, and 201f in a first region at a distal end and a second region at a more proximal end. Thus, electrode pairs may be formed on various electrodes 201 within the electroporation electrode arrangement 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 a corresponding electrode pair. Therefore, electrode pairs may include axially spaced electrodes, laterally spaced electrodes, or circumferentially spaced electrodes. Furthermore, in an embodiment, a given electrode (e.g., 201d) may be used as a common electrode in at least two electrode pairs to generate an electric field 210.

[0075] Figure 2B A schematic diagram of an exemplary electric field 210 that can be generated by an electroporation electrode arrangement 150 is shown. The electroporation electrode arrangement 150 can be configured to generate a multidirectional electric field 210 when at least one pulse sequence is delivered thereto. The multidirectional electric field 210 can include at least two of the following directions relative to the longitudinal axis: generally axial, circumferential, and transverse. As used herein, transverse can refer to any non-parallel angle relative to the longitudinal axis. As described elsewhere herein, the electroporation electrode arrangement 150 can be configured to be operatively coupled to an electroporation generator configured to generate at least one pulse sequence. The electroporation electrode arrangement 150 can be configured to receive at least one pulse sequence from the electroporation generator. Thus, the electroporation electrode arrangement 150 and the electroporation generator can be operatively in communication with each other. In this disclosure, such communication can be used to generate an electric field 210 that is at least substantially gapless.

[0076] Undesirable gaps in the electric field 210 generated by the electroporation electrode arrangement 150 can be limited or at least substantially eliminated. For example, such gaps can lead to lesion gaps, thus requiring multiple catheter repositionings. Overlapping electric fields 210 can at least substantially limit the number of such gaps. In embodiments, at least some of the electric fields 210 generated in the first pulse sequence set can at least partially overlap each other. For example, adjacent electric fields 210 in the combined electric field 211 (e.g., axial, transverse, and / or circumferential) can intersect each other, such that the combined electric field 211 is limited to be gap-free. Overlap can occur at or near the periphery of adjacent electric fields 210, or can occur over the main or majority of one or more adjacent electric fields 210. In this disclosure, adjacent means adjacent electrode 201 or electrode 201 that is otherwise close to each other. The electroporation generator can be configured to generate pulse sequences for generating overlapping electric fields.

[0077] The configuration of the electroporation electrode arrangement 150 in various embodiments can take any form, whether now known or later developed, suitable for three-dimensional electrode structures. In exemplary embodiments, the electroporation electrode arrangement 150 may be in the form of a splined basket-like conduit, with individual electrodes 201a, 201b, 201c, 201d, 201e, and 201f positioned on a plurality of splines in any manner known in the art. In embodiments, the electroporation electrode arrangement 150 may be formed on an inflatable balloon, for example, where electrodes are formed on flexible circuit branches or individual traces are disposed on the surface of the balloon. In other embodiments, the electroporation electrode arrangement 150 may be in the form of an inflatable mesh. In short, the specific structure used to form the electroporation electrode arrangement 150 is not critical to the embodiments of this disclosure.

[0078] Figure 3 This diagram illustrates an ablation energy application sequence 300 according to an exemplary embodiment, also referred to herein as IRE pulse sequence 300, which includes a pretreatment pulse sequence 302 and an electroporation pulse sequence 304. The pretreatment pulse sequence 302 is a series of pulses 306 whose amplitude ramps up from a lower voltage to a higher voltage. The electroporation pulse sequence 304 is a series of high-energy electroporation pulses 308 having large positive and / or negative voltage values.

[0079] The electroporation system 60 is configured to deliver a pretreatment pulse sequence 302, which delivers a series of pulses 306 or a sequence of pulses 306 for achieving direct current and for generating electrolysis. Figure 3 In the diagram, for clarity, only the three pulses 306 of the pretreatment pulse sequence 302 are shown; however, in an embodiment, the sequence of pulses 306 includes all pulses of the pretreatment pulse sequence 302. The electroporation system 60 is also 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 an embodiment, all pulses of the IRE pulse sequence 300 are delivered within the refractory period of the heart, for example, within 250-330 milliseconds.

[0080] The sequence of pulses 306 is a series of monophasic pulses whose amplitude ramps up over time from a lower voltage to a higher voltage. This ramping up of voltage results in relatively slow recruitment of skeletal muscle, ultimately leading to a tetanic skeletal muscle contraction preceding the higher voltage electroporation pulse 308 in the electroporation pulse sequence 304. Each pulse 306, or at least some pulses 306, also possesses features that promote electrolysis, such as including a monophasic exponentially decaying waveform 310 (or a drooping waveform) on the back of pulse 306. Figure 3In the diagram, for clarity, only the three exponentially decaying waveforms 310 in the pretreatment pulse sequence 302 are shown; however, in embodiments, all pulses in the pretreatment pulse sequence 302 include exponentially decaying waveforms 310. In embodiments, pulse 306 may not be entirely monophase, but may include at least some asymmetric phases balanced with the positive and negative component charges. In some embodiments, the duration of pulse 306 is between 1 millisecond (ms) and 60 ms, and in some embodiments, the waveform tilt / droop / exponential decay is in the range of 20% to 80% of the leading edge.

[0081] Pulse 306 can have many different characteristics. In an embodiment, pulse 306 in the pretreatment pulse sequence 302 is provided at a selected frequency, such as 1 kHz. In some embodiments, this frequency is in the range of 200-1000 Hz. In an embodiment, the voltage of pulse 306 ramps up from 0 volts to between 5 volts and 100 volts, and in some embodiments, the amplitude reaches between 100 volts and 1000 volts. Furthermore, in an embodiment, the ramp rate can be increased from 1% to 30% of the previous pulse. In some embodiments, the pretreatment pulse sequence 302 is applied with a sequence duration of 100-250 milliseconds.

[0082] The pretreatment pulse sequence 302 pre-treats the body with electroporation in at least two ways. First, the pretreatment pulse sequence 302 acts as a series of tetanic skeletal muscle pulses 306 that induce tetany, i.e., contraction of the patient's skeletal muscles, before receiving a higher voltage electroporation pulse sequence 304. Over time, the amplitude of the pulses 306 increases from a lower voltage ramp to a higher voltage, causing or contributing to the induction of tetany. This SMS prepares the patient for the higher voltage electroporation pulses 308 in the electroporation pulse sequence 304, which could otherwise be a shock or a painful experience for the patient. Second, the pretreatment pulse sequence 302 acts as a series of electrolysis-inducing pulses 306 that induce electrolysis near the target tissue. This results in a cytotoxic environment near the target tissue, allowing smaller electroporation pulses to be used to permeate the target tissue and cause cell death, thus producing greater damage with smaller electroporation pulses.

[0083] This synergistic electrolysis is induced by applying relatively long low-voltage pulses to the target region, such as pretreatment pulse sequence 302. Specifically, the exponentially decaying waveform 310 (or drooping waveform) on the backside of pulse 306 of pretreatment pulse sequence 302 induces electrolysis near the electrode. In a further explanation, synergistic electrolysis occurs when new chemical substances are generated at the electrode interface due to electron transfer between ions in the electrode and solution. Driven by the electrochemical potential, these new chemical substances diffuse from the electrode into the tissue. In physiological solutions, the electrolytic reaction produces pH changes, resulting in an acidic region near the anode and an alkaline region near the cathode. The cytotoxic environment created by the localized pH changes, the presence of some new chemical substances formed during solution electrolysis, and the permeability of electroporation lead to cell death.

[0084] In an exemplary embodiment, a pretreatment pulse sequence 302 is delivered as a series of monopolar electrical pulses 306. A surface patch electrode 115 attached to the chest of the patient 20 receives and provides electrical energy from the electroporation generator 130, wherein the surface patch electrode 115 acts as the source electrode of the electrical pulses. One or more electrodes on the electroporation catheter 105 converge the electrical energy provided by the surface patch electrode 115, wherein one or more electrodes on the electroporation catheter 105 act as the confluence of the electrical pulses. This causes the patient's skeletal muscles to contract, reaching tetany, and generating synergistic electrolysis near the target tissue, wherein the electrodes of the electroporation catheter 105 are located near the target tissue.

[0085] In other embodiments, one or more electrodes on the electroporation catheter 105 receive pulses 306 from the electroporation generator 130 and provide electrical energy, such that one or more electrodes on the electroporation catheter 105 act as source electrodes for the electrical pulses 306. A surface patch electrode 115 attached to the chest of the patient 20 receives the electrical energy provided by one or more electrodes on the electroporation catheter 105, such that the surface patch electrode 115 acts as a confluence point for the electrical pulses.

[0086] After delivering at least some pretreatment pulse sequences 302, the electroporation system 60 is configured to deliver an 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, the electroporation pulses 308 of the electroporation pulse sequence 304 are biphasic, including, for example, positive and negative pulses. In one embodiment, the electroporation pulses 308 may be positive 1000 volts and negative 1000 volts. In other embodiments, the electroporation pulses 308 may be monophasic, including, for example, all positive pulses or all negative pulses.

[0087] By applying at least some of the pulses 206 of the pretreatment pulse sequence 302 prior to the application of the electroporation pulse 308, electrolysis near or at the target tissue makes it possible to use an electroporation pulse 308 with an amplitude that is typically or otherwise required when using the electroporation pulse alone (500 V / cm to 2500 V / cm), for example from 250 volts / cm (V / cm) to 1000 V / cm.

[0088] 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 pretreatment pulse sequence 302. In other embodiments, 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 pretreatment pulse sequence 302 have been delivered.

[0089] The electroporation pulse 308 of the electroporation pulse sequence 304 can be a monopolar pulse or a bipolar pulse. In an embodiment, the electrode pairs (or electrode groups) on the electroporation catheter 105 are selected to deliver bipolar pulses between the selected electrode pairs. Each electrode in the electrode pair can act as a source electrode, and each electrode in the electrode pair can act as a sink to deliver electroablation energy to the target tissue.

[0090] In other embodiments, to provide a monopolar pulse, one or more electrodes on the electroporation catheter 105 receive electroporation pulses 308 from the electroporation generator 130 of the electroporation pulse sequence 304 and provide electrical energy, such that one or more electrodes on the electroporation catheter 105 act as source electrodes for the electrical pulse. A surface patch electrode 115 attached to the chest of the patient 20 receives the electrical energy provided by one or more electrodes on the electroporation catheter 105, such that the surface patch electrode 115 acts as a confluence point for the electrical pulse.

[0091] In one embodiment, the electroporation system 60 includes an accelerometer 117 configured to sense contraction of the patient's skeletal muscles, such as the patient's pectoral muscles, to detect tetany. An electroporation generator 130 receives signals from the accelerometer 117 and processes these signals to determine whether the patient's skeletal muscle system is contracting and whether tetany has occurred. In another embodiment, the electroporation generator 130 is configured to provide the electroporation pulse sequence 304 only after tetany has occurred in the patient. The electroporation generator 130 may provide the electroporation pulse sequence 304 during or after the pretreatment pulse sequence 302.

[0092] Therefore, the electroporation system 60 acts as a closed system, with the surface accelerometer 117 monitoring chest vibrations and the electroporation generator 130 modulating pulses 306 until tetany is achieved, followed by the delivery of electroporation pulses 308. Furthermore, in this embodiment, local impedance of the target tissue and surrounding tissue can be measured during this time to calculate pre- and post-ablation values ​​for evaluating the effectiveness of the treatment.

[0093] By applying at least some of the pulses 306 in the pretreatment pulse sequence 302 prior to the delivery of the electroporation pulse 308 of the electroporation 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 prior to the delivery of the electroporation pulse 308 of the electroporation pulse sequence 304. This results in the ability to produce the same magnitude of damage using lower energy and / or fewer electroporation pulses 308 as could be produced using higher energy or more electroporation pulses 308 without the pretreatment pulse sequence 302.

[0094] Figure 4 This is a flowchart illustrating a method for ablating targeted tissue in a patient's body via irreversible electroporation, according to embodiments of the subject matter of this disclosure. This document discloses this method and other related methods for ablating targeted tissue in a patient's body via irreversible electroporation.

[0095] The method includes delivering an IRE (irreversible electroporation) pulse sequence, comprising delivering a pretreatment pulse sequence at 402 and an electroporation pulse sequence at 404. In embodiments, the electroporation pulse sequence is delivered during or within the pretreatment pulse sequence. In other embodiments, the electroporation pulse sequence is delivered after the pretreatment pulse sequence has ceased. In an exemplary embodiment, the IRE pulse sequence, including the pretreatment pulse sequence and the electroporation pulse sequence, is delivered to the patient within one or more refractory periods of the patient's heart (less than 330 milliseconds) and within a window of 100-250 milliseconds.

[0096] Delivering a pretreatment pulse sequence at 402 includes delivering the pretreatment pulse sequence between a surface patch electrode and one or more catheter electrodes on the catheter to induce electrolysis near the target tissue and cause skeletal muscle stimulation tetany in the patient. In an embodiment, the pretreatment pulse sequence includes monopolar electrical pulses originating from the surface patch electrode and converging through one or more catheter electrodes. In other embodiments, the pretreatment pulse sequence includes monopolar electrical pulses originating from one or more catheter electrodes and converging through the surface patch electrode. Furthermore, in an embodiment, the pretreatment pulse sequence includes monophasic pretreatment pulses.

[0097] The pretreatment pulse sequence includes pretreatment pulses delivered at a selected frequency, with the voltage ramping up from a lower voltage to a higher voltage over time. In one embodiment, the pretreatment pulse sequence includes pretreatment pulses delivered at approximately 1 kHz. Furthermore, in another embodiment, the pretreatment pulse sequence includes pretreatment pulses with the voltage ramping up from 0 volts to between 5 volts and 100 volts. Ramping the voltage of the pulses from a lower voltage to a higher voltage over time helps to induce tetany in the skeletal muscles of the patient. Additionally, the pretreatment pulse sequence includes pretreatment pulses comprising an exponentially decaying backwave that induces or contributes to electrolysis near the targeted tissue.

[0098] Delivering an electroporation pulse sequence at 404 includes delivering the electroporation pulse sequence to a catheter electrode on the catheter to induce irreversible electroporation ablation of the target tissue. In one embodiment, the electroporation pulse sequence includes bipolar electrical pulses delivered to one or more catheter electrode pairs. In other embodiments, the electroporation pulse sequence includes unipolar electrical pulses delivered between a surface patch electrode and one or more catheter electrodes on the catheter.

[0099] In one embodiment, the method further includes monitoring an accelerometer 117 on the patient, the accelerometer 117 being configured to sense contraction of the patient's skeletal muscles, such as the contraction of the patient's pectoral muscles, to detect tetany. In a closed-loop system, signals from the accelerometer 117 are received by an electroporation generator 130, which processes these signals to determine whether the patient's skeletal muscular system is contracting and whether tetany has occurred. In one embodiment, the electroporation generator 130 is configured to provide an electroporation pulse sequence only after tetany has occurred in the patient, which can be during or after a pretreatment pulse sequence.

[0100] Furthermore, in an embodiment, the method includes monitoring the local impedance of the target tissue and the tissue surrounding the target tissue to calculate pre- and post-ablation values ​​for evaluating the efficacy of the treatment on the lesion.

[0101] Various modifications and additions may be made to the exemplary embodiments discussed without departing from the scope of this disclosure. For example, although the above embodiments relate to specific features, the scope of this disclosure also includes embodiments with different combinations of features and embodiments that do not include all of the stated features. Therefore, the scope of this disclosure is intended to include all such alternatives, modifications, and variations falling within the scope of the claims, as well as all equivalents thereof.

Claims

1. An electroporation ablation system for treating targeted tissues in a patient, the electroporation ablation system comprising: Ablation catheter, comprising: handle; A shaft with a distal end; and A catheter electrode, located at the distal end of the axis and spatially arranged to generate an electric field in the target tissue in response to an electrical pulse; and An electroporation generator, operatively coupled to the catheter electrode and configured to deliver electrical pulses from an irreversible electroporation pulse sequence, comprising a pretreatment pulse sequence and an electroporation pulse sequence, to one or more catheter electrodes. The pretreatment pulse sequence includes a pretreatment electrical pulse configured to induce electrolysis near the target tissue and cause tetany of skeletal muscle in the patient.

2. The electroporation ablation system of claim 1, comprising a surface patch electrode attached to the patient and configured to generate an electric field in the patient in response to the electrical pulse.

3. The electroporation ablation system according to claim 2, wherein, The pretreatment pulse sequence includes monopolar pulses, which originate from the surface patch electrode and converge through one or more conduit electrodes.

4. The electroporation ablation system according to claim 2, wherein, The pretreatment pulse sequence includes monopolar electrical pulses, which originate from the one or more catheter electrodes and converge through the surface patch electrodes.

5. The electroporation ablation system according to any one of claims 1-4, wherein, The pretreatment pulse sequence includes bipolar electrical pulses originating from at least one of the one or more catheter electrodes and entering through at least another of the one or more catheter electrodes.

6. The electroporation ablation system according to any one of claims 1-4, wherein, The pretreatment pulse sequence includes pretreatment pulses delivered at a selected frequency.

7. The electroporation ablation system according to any one of claims 1-4, wherein, The pretreatment pulse sequence includes pretreatment pulses in which the voltage rises from a lower voltage ramp to a higher voltage over time.

8. The electroporation ablation system according to any one of claims 1-4, wherein, The pretreatment pulse sequence includes pretreatment pulses, which include exponentially decaying back waveforms that induce electrolysis near the target tissue.

9. The electroporation ablation system according to any one of claims 1-4, wherein, The pretreatment pulse sequence includes single-phase pretreatment pulses.

10. The electroporation ablation system according to any one of claims 1-4, wherein, The irreversible electroporation pulse sequence, including the pretreatment pulse sequence and the electroporation pulse sequence, is delivered to the patient within one or more refractory periods of less than 330 milliseconds and within a window of 100-250 milliseconds of the patient's heart.

11. The electroporation ablation system according to any one of claims 1-4, wherein, The electroporation pulse sequence is delivered within the pretreatment pulse sequence.

12. The electroporation ablation system according to any one of claims 1-4, wherein, The electroporation pulse sequence includes bipolar electrical pulses delivered to one or more catheter electrode pairs of the catheter electrodes.

13. The electroporation ablation system according to any one of claims 1-4, comprising an accelerometer configured to monitor skeletal muscle stimulation of the patient, and wherein, The electroporation ablation system is a closed-loop system, such that the electroporation generator is configured to deliver the pretreatment pulse sequence, detect tetany in the patient, and then deliver the electroporation pulse sequence, wherein local impedance is measured to calculate pre-ablation and post-ablation values ​​for evaluating the efficacy of the treatment.

14. An electroporation ablation system for treating targeted tissues in a patient, the electroporation ablation system comprising: Ablation catheter, comprising: handle; A shaft with a distal end; and A catheter electrode, located at the distal end of the axis and spatially arranged to generate an electric field in the target tissue in response to an electrical pulse; and An electroporation generator operatively coupled to a plurality of electrodes including one or more surface patch electrodes and one or more catheter electrodes, and configured to deliver electrical pulses from an irreversible electroporation pulse sequence comprising a pretreatment pulse sequence and an electroporation pulse sequence to the plurality of electrodes, wherein the electroporation generator delivers the electroporation pulse sequence during the pretreatment pulse sequence. The pretreatment pulse sequence includes electrical pulses configured to induce electrolysis near the target tissue and to induce tetany in the skeletal muscles of the patient.

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