Systems, devices, and methods for delivering pulsed electric field ablation energy to endocardial tissue

Abstract

Systems, devices, and methods for delivering pulsed electric field ablation energy to endocardial tissue are disclosed, wherein the system includes a pulsed waveform signal generator for medical ablation therapy and an endocardial ablation device including at least one electrode for delivering ablation pulses to tissue. The signal generator can deliver voltage pulses to the ablation device in the form of a pulsed waveform. The system can include a cardiac stimulator for generating a pacing signal and for delivering a pulsed waveform in sequence in synchronization with the pacing signal.

Description

[0001] This application is a divisional application of Chinese patent application No. 201780005770.7, filed on January 4, 2017, entitled "System, Apparatus and Method for Delivering Pulsed Electric Field Ablation Energy to Endocardial Tissue".

[0002] Cross-reference to related applications

[0003] This application claims priority to U.S. Provisional Application Serial No. 62 / 274,943, filed January 5, 2016, entitled “SYSTEMS, APPARATUSES AND DEVICESFOR DELIVERY OF PULSED ELECTRIC FIELD ABLATIVE ENERGY TO ENDOCARDIAL TISSUE”, the disclosure of which is incorporated herein by reference in its entirety. Background Technology

[0004] Over the past two decades, the generation of pulsed electric fields for tissue therapy has moved from the laboratory to clinical applications, while the effects of brief pulses of high voltage and large electric fields on tissues have been studied for the past four decades or more. Applying a brief high DC voltage to tissue can generate a localized high electric field, typically in the range of several hundred volts per centimeter, which disrupts the cell membrane by creating pores. While the precise mechanism of this electrically driven stomatalization, or electroporation, is still under investigation, it is believed that applying a relatively brief and large electric field creates instability in the lipid bilayer of the cell membrane, leading to the distribution of localized gaps or pores within the cell membrane. This electroporation can be irreversible if the applied electric field at the membrane exceeds a threshold, causing the pores to remain open and allowing biomolecular materials to cross the membrane for exchange, resulting in necrosis and / or apoptosis (cell death). Subsequently, the surrounding tissue can heal naturally.

[0005] While pulsed DC voltage can drive electroporation when the conditions are right, there remains an unmet need for thin, flexible, and non-invasive devices that can efficiently and selectively deliver high-DC voltage electroporation ablation therapy to the relevant endocardial tissue while minimizing damage to healthy tissue. Summary of the Invention

[0006] This document describes systems, apparatus, and methods for ablating tissue via irreversible electroporation. Typically, a system for delivering a pulsed waveform to tissue may include a signal generator configured to generate the pulsed waveform and an ablation device coupled to the signal generator and configured to receive the pulsed waveform. The ablation device may include a set of ridges. The ablation device may be configured to deliver the pulsed waveform to tissue via one or more of the set of ridges during use. Each ridge may include a set of independently addressable electrodes formed on the surface of the ridge. Each electrode in the set of electrodes may have an associated insulated electrical lead. The insulated electrical lead may be disposed within the body of the ridge.

[0007] In some embodiments, the insulated leads may be configured to maintain a voltage potential of at least about 700 V without dielectric breakdown of the corresponding insulation. The system may also include a cardiac stimulator configured to generate a pacing signal for cardiac stimulation during use. The cardiac stimulator may be communicatively coupled to the signal generator and further configured to transmit an indication of the pacing signal to the signal generator. The signal generator may be further configured to generate the pulse waveform synchronously with the indication of the pacing signal. The signal generator may be further configured to generate the pulse waveform with a time offset relative to the indication of the pacing signal. The ablation device may also include a distal cap configured to tether the set of ridges to form the distal end of the ablation device. The ablation device may also include ridge wires configured to electrically couple electrodes between a pair of ridges in the set of ridges. The pair of ridges may be adjacent to each other. The ridge wire may be the first ridge wire in a set of ridge wires. Each ridge wire in the set of ridge wires may couple electrodes between different pairs of ridges in the set of ridges. The set of ridge wires can form a continuous loop between the electrodes coupled to them. The set of ridge wires can be a first set of ridge wires coupling electrodes on the set of ridges. The ablation device may also include a second set of ridge wires coupling electrodes on the set of ridges. The second set of ridge wires can couple electrodes on the set of ridges that are different from those of the first set of ridge wires. The first set of ridge wires can form a first continuous loop between the electrodes coupled to it, and the second set of ridge wires can form a second continuous loop between the electrodes coupled to it. The first continuous loop can be electrically isolated from the second continuous loop. The first ridge wire in the set of ridge wires can couple an electrode between the first and second ridges in the set of ridges. The second ridge wire in the set of ridge wires can couple an electrode between the first and third ridges in the set of ridges. The first ridge wire in the set of ridge wires can couple an electrode between the first and second ridges in the set of ridges. The second ridge wire in the set of ridge wires can couple an electrode between the third and fourth ridges in the set of ridges.

[0008] In some embodiments, the electrodes may be electrically connected together (to place them at the same potential) at a proximal portion of the device's shaft or within the device's handle. In these embodiments, the electrical connection between the electrodes may be similar to the variations described herein. For example, a ring of electrodes at the same potential may be formed, or adjacent electrodes on adjacent ridges may be at the same potential, or generally, the first set of electrodes on a ridge may be maintained at the same potential as the second set of electrodes on the ridge through a suitable electrical connection between electrode leads at a proximal portion of the device's shaft or within the device's handle.

[0009] In some embodiments, the set of ridges may include 3 to 20 ridges. The set of electrodes may include 2 to 64 electrodes. Each electrode in the set of electrodes may have approximately 0.5 mm in diameter. 2 Approximately 20 mm 2 The surface area. Each ridge in the set of ridges may have approximately 0.2 mm. 2 approximately 15 mm 2 The cross-sectional area. The set of ridges can form a delivery assembly at the distal portion of the ablation device. The delivery assembly can be configured to switch between a first configuration and a second configuration, in the first configuration, the set of ridges being radially outward from the longitudinal axis of the ablation device, and in the second configuration, the set of ridges being arranged substantially parallel to the longitudinal axis of the ablation device. The delivery assembly may have approximately 1 mm. 2 approximately 25mm 2 The system may also include a shank coupled to the set of ridges. The shank may be configured to influence the transition of the set of ridges between the first configuration and the second configuration. The set of ridges may include a first ridge and a second ridge adjacent to the first ridge. The electrode of the first ridge may be positioned closer to the distal end of the ablation device than the electrode of the second ridge. The set of ridges may be present in the distal portion of the ablation device. Electrical leads of at least two electrodes in the set of electrodes may be electrically coupled in or near the proximal portion of the ablation device.

[0010] In some embodiments, the set of ridges may form an expansion structure during use. The cross-sectional area at the first plane of the expansion structure may differ from the cross-sectional area at the second plane of the expansion structure. At least one electrode of the set of electrodes, or at least a portion thereof, may be disposed in the distal end plane of the expansion structure. The set of ridges may converge at a point within the expansion structure at their distal ends.

[0011] In some embodiments, the pulse waveform may include a first level of a hierarchical structure comprising pulses. Each pulse may have a pulse duration and a first time interval separating consecutive pulses. The second level of the hierarchical structure comprises a plurality of pulses as a second pulse group and a second time interval separating consecutive second pulse groups. The second time interval may be at least three times the duration of the first time interval. The third level of the hierarchical structure comprises a plurality of second pulse groups as a third pulse group and a third time interval separating consecutive third pulse groups. The third time interval may be at least thirty times the duration of the second-level time interval.

[0012] Methods for treating atrial fibrillation via irreversible electroporation are also described herein. Generally, these methods include the following steps: generating a pulsed waveform and delivering it to the pulmonary vein orifice of a patient's heart via one or more ridges of a set of ridges in an ablation device. Each ridge may include a set of independently addressable electrodes formed on the surface of the ridge. Each electrode in the set of electrodes may have an associated insulated electrical lead. The insulated electrical lead may be disposed within the body of the ridge.

[0013] In some embodiments, the ablation device may be disposed in the endocardial space of the left atrium of the heart and in contact with the pulmonary vein orifice. Each insulated lead may be configured to maintain a voltage potential of at least about 700 V without dielectric breakdown of its corresponding insulator. A pacing signal for cardiac stimulation of the heart may be generated. The pacing signal may be applied to the heart, and a pulse waveform may be generated synchronously with the pacing signal. The pulse waveform may include a time offset relative to the pacing signal, and such offset is understood to be covered by the term "synchronization" as used herein. A group of electrodes on the set of ridges may include a group of electrodes for each of the set of ridges. The method may further include the steps of configuring a first electrode in the group of electrodes as an anode, configuring a second electrode in the group of electrodes as a cathode, and delivering the pulse waveform to the first and second electrodes.

[0014] In some embodiments, the method may further include the steps of: configuring a first set of electrodes on a first ridge of the set of ridges as an anode, configuring a second set of electrodes on a second ridge of the set of ridges as a cathode, and delivering a pulse waveform to the first set of electrodes and the second set of electrodes. The ablation device may further include a first set of ridge wires and a second set of ridge wires. Each ridge wire may be configured to electrically couple electrodes between a pair of ridges in the set of ridges. The second set of ridge wires may couple electrodes on the set of ridges that are different from those on the first set of ridge wires. The first set of ridge wires may form a first continuous loop between the electrodes to which it is coupled, and the second set of ridge wires may form a second continuous loop between the electrodes to which it is coupled. The first continuous loop may be electrically isolated from the second continuous loop. The method may further include the steps of: configuring an electrode coupled to the first continuous loop as an anode, configuring an electrode coupled to the second continuous loop as a cathode, and delivering a pulse waveform to the electrodes coupled to the first continuous loop and the electrodes coupled to the second continuous loop.

[0015] In some embodiments, the ridge wires, or the first set of ridge wires and the second set of ridge wires, may be replaced by an electrical connection between suitable leads at the proximal portion of the device's shaft or within the device handle (to bring them to the same potential). In these embodiments, the electrical connection between the electrodes may be similar to the variations described above. For example, a loop of electrodes at the same potential may be formed, or adjacent electrodes on adjacent ridges may be at the same potential, or generally, the first set of electrodes on the ridge may be maintained at the same potential as the second set of electrodes on the ridge through a suitable electrical connection between electrode leads at the proximal portion of the device's shaft or within the device handle.

[0016] In some embodiments, the ablation device may further include a first ridge wire coupling an electrode between a first ridge and a second ridge in the set of ridges. A second ridge wire may couple an electrode between a first ridge and a third ridge in the set of ridges. The method may further include the steps of configuring the electrode coupled by the first ridge wire and the second ridge wire as an anode or cathode, and delivering a pulse waveform to the electrode coupled by the first ridge wire and the second ridge wire. The ablation device may further include a first ridge wire coupling an electrode between a first ridge and a second ridge in the set of ridges. A second ridge wire may couple an electrode between a third ridge and a fourth ridge in the set of ridges. The method may further include the steps of configuring the electrode coupled by the first ridge wire as an anode, configuring the electrode connected by the second ridge wire as a cathode, and delivering a pulse waveform to the anode and the cathode. In some embodiments, the ridge wire, or the first ridge wire and the second ridge wire, may be replaced by an electrical connection between suitable leads (so that they are at the same potential) at a proximal portion of the device shaft or within the device handle. In these embodiments, the electrical connection between the electrodes may be similar to the variations described above, and the method may further include the steps of: configuring a first set of electrically coupled electrodes as an anode, configuring a second set of electrically coupled electrodes as a cathode, and delivering a pulse waveform to the anode and cathode.

[0017] The set of ridges may form a delivery assembly at the distal portion of the ablation device. The delivery assembly may be configured to transition between first configurations, in which the set of ridges bends radially outward from the longitudinal axis of the ablation device. The method may further include the steps of: positioning the delivery assembly in the first configuration in contact with the pulmonary vein orifice, and transitioning the delivery assembly to a second configuration prior to the delivery pulse waveform. The set of ridges may be present in the distal portion of the ablation device. Electrical leads of at least two electrodes in the set of electrodes may be electrically coupled at or near the proximal portion of the ablation device.

[0018] In some embodiments, the pulse waveform may include a first level of a hierarchical structure comprising a first group of pulses. Each pulse may have a pulse duration and a first time interval separating consecutive pulses. A second level of the hierarchical structure may include a plurality of first groups of pulses as a second pulse group. A second time interval may separate consecutive first groups of pulses. The second time interval may be at least three times the duration of the first time interval. A third level of the hierarchical structure may include a plurality of second groups of pulses as a third pulse group. A third time interval may separate consecutive second groups of pulses. The third time interval may be at least thirty times the duration of the second-level time interval.

[0019] In some embodiments, the system for ablating tissue described herein may include a signal generator configured to generate a pulsed waveform. The system also includes an ablation device coupled to the signal generator and configured to deliver the pulsed waveform to the tissue. The ablation device may include a set of ridges, and the ablation device may be configured to deliver the pulsed waveform to the tissue via one or more of the set of ridges during use. Each ridge may include a set of independently addressable electrodes formed on a surface of the ridge. Each electrode in the set of electrodes may have an associated insulated electrical lead. The insulated electrical lead may be disposed within the body of the ridge.

[0020] In some embodiments, a system may include a signal generator configured to generate a pulse waveform and an ablation device coupled to the signal generator. The ablation device may include a set of electrodes and is configured to receive the pulse waveform. The ablation device may be configured to deliver the pulse waveform to tissue via the set of electrodes during use. Each electrode in the set of electrodes may have an associated insulated lead. Each insulated lead may be configured to maintain a voltage potential of at least about 700 V without dielectric breakdown of its corresponding insulator. In some embodiments, the system may also include a cardiac stimulator configured to generate a pacing signal for cardiac stimulation during use. The cardiac stimulator may be communicatively coupled to the signal generator and further configured to transmit an indication of the pacing signal to the signal generator. The signal generator may be further configured to generate the pulse waveform synchronously with the indication of the pacing signal.

[0021] In some embodiments, the signal generator may be further configured to generate a pulse waveform with a time offset relative to an indication of a pacing signal. In other embodiments, the system may also include a guidewire having a nonlinear distal portion. An ablation device may be configured to be placed on the guidewire during use. In some other embodiments, the ablation device may include a nonlinear distal portion having one or more electrodes from the set of electrodes disposed thereon. The pulse waveform may include a first stage of a graded structure of pulse waveforms comprising pulses. Each pulse may have a pulse duration and a first time interval separating consecutive pulses. A second stage of the graded structure of pulse waveforms may include multiple pulses as a second pulse group. A second time interval may separate consecutive second pulse groups. The second time interval may be at least three times the duration of the first time interval. A third stage of the graded structure of pulse waveforms may include multiple second pulse groups as a third pulse group. A third time interval may separate consecutive third pulse groups. The third time interval may be at least thirty times the duration of the second stage time interval.

[0022] In some embodiments, a system for delivering a pulse waveform to tissue may include a signal generator configured to generate the pulse waveform and a guidewire coupled to the signal generator and configured to receive the pulse waveform. The guidewire may include a proximal portion and a nonlinear distal portion. The nonlinear distal portion may be configured to deliver the pulse waveform to tissue during use. The proximal portion may have an associated insulator configured to maintain a voltage potential of at least about 700 V without dielectric breakdown. In some embodiments, the system may also include a cardiac stimulator configured to generate a pacing signal for cardiac stimulation during use. The cardiac stimulator may be communicatively coupled to the signal generator and further configured to transmit an indication of the pacing signal to the signal generator. The signal generator may be further configured to generate the pulse waveform synchronously with the indication of the pacing signal. A first level of the hierarchical structure of the pulse waveform may include a set of pulses. Each pulse may have a pulse duration and a first time interval separating consecutive pulses. A second level of the hierarchical structure of the pulse waveform may include a plurality of first pulse groups as a second pulse group. A second time interval may separate consecutive first pulse groups. The second time interval can be at least three times the duration of the first time interval. The third level of the hierarchical structure of the pulse waveform may include multiple second pulse groups as a third pulse group. The third time interval can separate consecutive second pulse groups. The third time interval can be at least thirty times the duration of the second-level time interval.

[0023] In some embodiments, a system for delivering a pulsed waveform to tissue may include a signal generator configured to generate the pulsed waveform and an ablation device coupled to the signal generator. The ablation device may include a set of electrical leads and be configured to receive the pulsed waveform. Each lead in the set of electrical leads may have an associated insulator. Each lead in the set of electrical leads may be configured to form a loop at a distal portion of the ablation device, such that the ablation device includes a set of loops. Each loop in the set of loops may have a non-insulated portion serving as an electrode, such that the ablation device includes a set of electrodes at a distal portion of the ablation device. The ablation device may be configured to deliver the pulsed waveform to tissue via the set of electrodes during use. The system may also include a cardiac stimulator configured to generate a pacing signal for cardiac stimulation during use. The cardiac stimulator may be communicatively coupled to the signal generator and further configured to transmit an indication of the pacing signal to the signal generator. The signal generator may be further configured to generate the pulsed waveform synchronously with the indication of the pacing signal.

[0024] In some embodiments, the set of rings at the distal portion of the ablation device may be configured to deliver a pulse waveform to the tissue. In other embodiments, each of the set of leads may be configured to maintain a voltage potential of at least about 700 V without dielectric breakdown of its corresponding insulator. In still other embodiments, the ablation device is further configured to deliver a pulse waveform to the tissue during use by configuring a first electrode of the set of electrodes as an anode and a second electrode of the set of electrodes as a cathode. A first level of the hierarchical structure of the pulse waveform may include a first pulse group. Each pulse has a pulse duration and a first time interval separating consecutive pulses. A second level of the hierarchical structure of the pulse waveform may include a plurality of first pulse groups as second pulse groups. A second time interval may separate consecutive first pulse groups. The second time interval may be at least three times the duration of the first time interval. A third level of the hierarchical structure of the pulse waveform may include a plurality of second pulse groups as third pulse groups. A third time interval may separate consecutive second pulse groups. The third time interval may be at least thirty times the duration of the second level time interval.

[0025] In some embodiments, a system for delivering a pulsed waveform to tissue may include a signal generator configured to generate the pulsed waveform and an ablation device coupled to the signal generator and configured to receive the pulsed waveform. The ablation device may include a set of ridges. The ablation device may be configured to deliver the pulsed waveform to tissue via one or more of the set of ridges during use. Each ridge may include a set of independently addressable electrodes formed on the surface of each of the one or more ridges. Each electrode in the set of electrodes may have an associated insulated electrical lead. The insulated electrical lead may be disposed in the body of each of the one or more ridges. The set of ridges may include a first ridge and a second ridge adjacent to the first ridge. The electrode of the first ridge may be positioned closer to the distal end of the ablation device than the electrode of the second ridge. Attached Figure Description

[0026] Figure 1 This is a block diagram of the electroporation system according to the implementation plan.

[0027] Figure 2 This is a perspective view of the ablation catheter according to the implementation plan.

[0028] Figure 3 This is a perspective view of an ablation catheter based on other implementation schemes.

[0029] Figure 4 This is a perspective view of an ablation catheter based on other implementation schemes.

[0030] Figure 5 This is a detailed perspective view of the distal portion of the ablation catheter according to other implementation schemes.

[0031] Figure 6 This is a side view of the ablation catheter according to other implementation schemes.

[0032] Figure 7 This is a side view of the ablation catheter according to other implementation schemes.

[0033] Figures 8A-8B These are, respectively, a side view and a front sectional view of the ablation catheter according to other implementation schemes.

[0034] Figures 9A-9E This is a side view of the ablation catheter according to other implementation schemes.

[0035] Figure 10 This is a perspective view of a balloon ablation catheter positioned in the left atrial ventricle of the heart, according to other implementation schemes.

[0036] Figure 11 This is a cross-sectional view of a balloon ablation catheter positioned in the left atrium of the heart, according to other implementation schemes.

[0037] Figure 12A-12B This is a schematic diagram of the return electrode of the ablation system according to the implementation plan.

[0038] Figure 13 A method for tissue ablation according to an implementation scheme is shown.

[0039] Figure 14 Methods for tissue ablation according to other implementation schemes are shown.

[0040] Figure 15 It is located in the left atrium of the heart. Figure 2 An illustration of the ablation catheter depicted.

[0041] Figure 16 It is located in the left atrium of the heart. Figure 3 An illustration of the ablation catheter depicted.

[0042] Figure 17 These are two chambers located in the left atrium of the heart. Figure 4 An illustration of the ablation catheter depicted.

[0043] Figure 18 It is located in the left atrium of the heart. Figure 5 An illustration of the ablation catheter depicted.

[0044] Figures 19A-19B These are schematic perspective and sectional views of a set of electrodes disposed in the pulmonary vein ostium according to other embodiments.

[0045] Figures 20A-20BThese are schematic perspective and cross-sectional views of the electric field generated by electrodes placed in the pulmonary vein orifice, according to other embodiments.

[0046] Figure 21 This is an example waveform illustrating a voltage pulse sequence with a pulse width defined for each pulse, according to the implementation scheme.

[0047] Figure 22 The schematic diagram illustrates a pulse hierarchy structure according to an embodiment, showing the pulse width, the interval between pulses, and the pulse grouping.

[0048] Figure 23 A schematic diagram of a nested hierarchical structure of a single-phase pulse, showing different levels of nested hierarchical structure according to the implementation scheme, is provided.

[0049] Figure 24 This is a schematic diagram of a nested hierarchical structure of biphase pulses with different levels of nested hierarchical structure, according to the implementation plan.

[0050] Figure 25 The diagram schematically illustrates the electrocardiogram and cardiac pacing signals, as well as the atrial and ventricular refractory periods, according to the implementation scheme, and indicates the time series of time windows used for irreversible electroporation ablation. Detailed Implementation

[0051] This document describes systems, apparatus, and methods for selectively and rapidly applying pulsed electric fields to ablate tissue via irreversible electroporation. Typically, the systems, apparatus, and methods described herein can generate a large electric field size at a desired, relevant region and reduce peak electric field values ​​elsewhere to minimize unwanted tissue damage and arcing. Irreversible electroporation systems as described herein may include a signal generator and a processor configured to apply one or more voltage pulse waveforms to a selected set of electrodes of an ablation apparatus to deliver energy to the relevant region (e.g., ablation energy for a group of tissues at the pulmonary vein ostium). The pulse waveforms disclosed herein can aid in the treatment of various cardiac arrhythmias (e.g., atrial fibrillation). To deliver the pulse waveforms generated by the signal generator, one or more electrodes of the ablation apparatus may have insulated leads configured to maintain a voltage potential of at least about 700 V without dielectric breakdown of their corresponding insulators. The electrodes may be independently addressable, allowing each electrode to be controlled (e.g., energy delivery) independently of any other electrode in the apparatus. In this way, the electrodes can collaboratively deliver different energy waveforms at different timings for electroporation of the tissue.

[0052] As used herein, “electroporation” refers to applying an electric field to a cell membrane to alter its permeability to the extracellular environment. As used herein, “reversible electroporation” refers to applying an electric field to a cell membrane to temporarily alter its permeability to the extracellular environment. For example, cells undergoing reversible electroporation may exhibit temporary and / or intermittent formation of one or more stomata in their cell membranes, which close upon removal of the electric field. As used herein, “irreversible electroporation” refers to applying an electric field to a cell membrane to permanently alter its permeability to the extracellular environment. For example, cells undergoing irreversible electroporation may exhibit the formation of one or more stomata in their cell membranes, which remain intact upon removal of the electric field.

[0053] The pulse waveforms for electroporation energy delivery disclosed herein can enhance the safety, efficiency, and effectiveness of energy delivery to tissue by reducing the electric field threshold associated with irreversible electroporation, thereby producing more effective ablation lesions with a reduced total delivered energy. In some embodiments, the voltage pulse waveforms disclosed herein may be hierarchical and have a nested structure. For example, the pulse waveforms may include hierarchical groupings of pulses with associated time scales. In some embodiments, the methods, systems, and apparatuses disclosed herein may include one or more of the methods, systems, and apparatuses described in International Application Serial No. PCT / US2016 / 057664, filed October 19, 2016, entitled “SYSTEMS, APPARATUSES AND METHODS FOR DELIVERY OF ABLATIVE ENERGY TO TISSUE,” the contents of which are incorporated herein by reference in their entirety.

[0054] In some embodiments, the system may further include a cardiac stimulator for synchronizing the generation of the pulse waveform with the pacing heartbeat. The cardiac stimulator can electrically pace the heart and ensure that pacing capture establishes the periodicity and predictability of the cardiac cycle. A time window within the refractory period of the periodic cardiac cycle can be selected for the delivery of the voltage pulse waveform. Therefore, the voltage pulse waveform can be delivered during the refractory period of the cardiac cycle to avoid interruption of the heart's sinus rhythm. In some embodiments, the ablation device may include one or more catheters, guidewires, balloons, and electrodes. The ablation device can be adapted to different configurations (e.g., compact and expanded) to position the device within the endocardial space. In some embodiments, the system may optionally include one or more return electrodes.

[0055] Typically, to ablate tissue, one or more catheters are advanced minimally invasively through the vascular system to the target location. In cardiac applications, electrodes delivering voltage pulse waveforms can be positioned on an epicardial or endocardial device. The methods described herein may include introducing the device into the endocardial space of the left atrium of the heart and positioning the device in contact with the pulmonary vein orifice. Pulsed waveforms can be generated and delivered to one or more electrodes of the device to ablate tissue. In some embodiments, the pulse waveforms may be generated in sync with the heart's pacing signals to avoid interruption of the heart's sinus rhythm. In some embodiments, the electrodes may be configured as an anode-cathode subset. The pulse waveforms may include graded waveforms to facilitate tissue ablation and reduce damage to healthy tissue.

[0056] I. System

[0057] Overview

[0058] This document discloses systems and apparatuses configured to ablate tissue by selectively and rapidly applying voltage pulse waveforms to facilitate tissue ablation, thereby resulting in irreversible electroporation. Typically, the systems for tissue ablation described herein may include a signal generator and an ablation device having one or more electrodes for selectively and rapidly applying a DC voltage to drive electroporation. As described herein, the systems and apparatuses may be deployed at the epicardium and / or endocardium to treat atrial fibrillation. Voltage may be applied to a selected subset of electrodes, with independent subset selection for the selection of anodic and cathodic electrodes. Pulse waveforms may be generated by the signal generator in synchronization with a pacing signal used for cardiac stimulation.

[0059] Typically, the systems and devices described herein include one or more catheters configured to ablate tissue in the left atrial ventricle of the heart. Figure 1 An ablation system (100) configured to deliver voltage pulse waveforms is shown. The system (100) may include a device (120) comprising a signal generator (122), a processor (124), a memory (126), and a cardiac stimulator (128). The device (120) may be coupled to an ablation device (110) and optionally to a pacemaker (130) and / or an optional return electrode (140) (e.g., a return pad, shown in dashed lines here).

[0060] A signal generator (122) may be configured to generate a pulsed waveform for irreversible electroporation of tissue (e.g., the pulmonary vein orifice). For example, the signal generator (122) may be a voltage pulsed waveform generator and deliver the pulsed waveform to the ablation device (110). A return electrode (140) may be coupled to the patient (e.g., positioned on the patient's back) to allow current to flow from the ablation device (110) through the patient and then to the return electrode (140) to provide a safe current return path from the patient (not shown). A processor (124) may combine data received from a memory (126), a cardiac stimulator (128), and a pacemaker (130) to determine parameters (e.g., amplitude, width, duty cycle, etc.) of the pulsed waveform generated by the signal generator (122). The memory (126) may further store instructions that cause the signal generator (122) to execute modules, processes, and / or functions associated with the system (100), such as pulsed waveform generation and / or cardiac pacing synchronization. For example, the memory (126) can be configured to store pulse waveform and / or cardiac pacing data, respectively, used for pulse waveform generation and / or cardiac pacing.

[0061] In some embodiments, the ablation device (110) may include a catheter configured to receive and / or deliver pulsed waveforms, described in more detail below. For example, the ablation device (110) may be introduced into the endocardial space of the left atrium and positioned to align one or more electrodes (112) with one or more pulmonary vein orifices, and then deliver pulsed waveforms to ablate tissue. The ablation device (110) may include one or more electrodes (112), which in some embodiments may be a set of independently addressable electrodes. Each electrode may include an insulated lead configured to maintain a voltage potential of at least about 700 V without dielectric breakdown of its corresponding insulation. In some embodiments, the insulation on each of the leads may maintain a potential difference of about 200 V to about 1,500 V across its thickness without dielectric breakdown. For example, the electrode (112) can be divided into one or more anode-cathode subsets, such as a subset including one anode and one cathode, a subset including two anodes and two cathodes, a subset including two anodes and one cathode, a subset including one anode and two cathodes, a subset including three anodes and one cathode, a subset including three anodes and two cathodes, etc.

[0062] A pacing device (130) may be suitably coupled to a patient (not shown) and configured to receive a cardiac pacing signal for cardiac stimulation generated by a cardiac stimulator (128) of the device (120). An indication of the pacing signal may be transmitted from the cardiac stimulator (128) to a signal generator (122). Based on the pacing signal, an indication of a voltage pulse waveform that may be generated by the signal generator (122) may be selected, calculated, and / or otherwise identified by a processor (124). In some embodiments, the signal generator (122) is configured to generate the pulse waveform synchronously with the indication of the pacing signal (e.g., within a common response window). For example, in some embodiments, the common response window may begin substantially immediately after a ventricular pacing signal (or after a very small delay) and then last for a duration of approximately 130 ms or less. In such embodiments, the entire pulse waveform may be delivered within said duration.

[0063] The processor (124) can be any suitable processing device configured to run and / or execute a set of instructions or code. The processor can be, for example, a general-purpose processor, a field-programmable gate array (FPGA), an application-specific integrated circuit (ASIC), a digital signal processor (DSP), etc. The processor can be configured to run and / or execute application processes and / or other modules, processes, and / or functions associated with the system and / or a network (not shown) associated with it. A variety of component types can be used to provide the underlying device technology, such as metal-oxide-semiconductor field-effect transistor (MOSFET) technology like complementary metal-oxide-semiconductor (CMOS), bipolar technology like emitter-coupled logic (ECL), polymer technologies (e.g., silicon conjugated polymers and metal conjugated polymer-metal structures), hybrid analog and digital, etc.

[0064] The memory (126) may include a database (not shown) and may be, for example, random access memory (RAM), a memory buffer, a hard disk drive, an erasable programmable read-only memory (EPROM), an electrically erasable read-only memory (EEPROM), a read-only memory (ROM), a flash memory, etc. The memory (126) may store instructions that cause the processor (124) to execute modules, processes, and / or functions associated with the system (100), such as pulse waveform generation and / or cardiac pacing.

[0065] The system (100) can communicate with other devices (not shown) via, for example, one or more networks, each of which can be any type of network. A wireless network can refer to any type of digital network not connected by any kind of cable. However, a wireless network can connect to a wired network to interact with the Internet, other carrier voice and data networks, business networks, and personal networks. Wired networks typically transmit over copper twisted-pair, coaxial, or fiber optic cables. Many different types of wired networks exist, including Wide Area Networks (WANs), Metropolitan Area Networks (MANs), Local Area Networks (LANs), Campus Networks (CANs), Global Area Networks (GANs) like the Internet, and Virtual Private Networks (VPNs). In the following text, a network refers to any combination of wireless, wired, public, and private data networks, typically interconnected via the Internet to provide a unified networking and information access solution.

[0066] ablation device

[0067] The system described herein may include one or more multi-electrode ablation devices configured to ablate tissue in the left atrial ventricle of the heart for the treatment of atrial fibrillation. Figure 2 This is a perspective view of an ablation device (200) including a catheter (210) and a guidewire (220) (e.g., structurally and / or functionally similar to an ablation device (110)), the guidewire (220) being slidable within the lumen of the catheter (210). The guidewire (220) may include a non-linear distal portion (222), and the catheter (210) may be configured to be positioned on the guidewire (220) during use. The distal portion (222) of the guidewire (220) may be shaped to facilitate placement of the catheter (210) within the lumen of the patient. For example, the shape of the distal portion (222) of the guidewire (220) may be configured for placement in and / or near the ostium of a pulmonary vein, as per [reference needed]. Figure 15 To describe in more detail. The distal portion (222) of the guidewire (220) may include and / or be shaped to reduce damage to tissue (e.g., prevent and / or reduce the likelihood of tissue puncture). For example, the distal portion (222) of the guidewire (220) may include shapes such as circular, annular (e.g., circular, ring-shaped). Figure 2The guidewire (220) may be a non-linear shape, such as an ellipse or any other geometry. In some embodiments, the guidewire (220) may be configured to be resilient, such that the guidewire with a non-linear shape conforms to the lumen of the catheter (210) when placed in the catheter (210) and reshapes / otherwise restores its non-linear shape when withdrawn from the catheter (210). In other embodiments, the catheter (210) may be similarly configured to be resilient, such as to aid in advancing the catheter (210) through a sheath (not shown). The shaped distal portion (222) of the guidewire (220) may be angled relative to the other portions of the guidewire (220) and the catheter (210). The dimensions of the catheter (210) and the guidewire (220) may be set for advancement into the endocardial space (e.g., the left atrium). The diameter of the shaped distal portion (222) of the guidewire (220) may be approximately the same as the diameter of the lumen in which the catheter (230) will be placed.

[0068] The catheter (210) can be slidably advanced on the guidewire (220) for placement on the guidewire (220) during use. A distal portion (222) of the guidewire (220) positioned within the lumen (e.g., near the pulmonary vein orifice) can act as a stop for the advancement of the distal portion of the catheter (210). The distal portion of the catheter (210) may include a set of electrodes (212) (e.g., structurally and / or functionally similar to electrode (112)) configured to contact an inner radial surface of the lumen (e.g., the pulmonary vein orifice). For example, the electrodes (212) may include generally circularly arranged electrodes configured to contact the pulmonary vein orifice. Figure 2 As shown, one or more electrodes (212) may comprise a series of metal strips or loops disposed along the catheter axis and electrically connected together. For example, the ablation device (200) may comprise a single electrode having multiple strips, one or more electrodes each having its own strip, and combinations thereof. In some embodiments, the electrodes (212) may be shaped to conform to the distal portion (222) of the guidewire (220). The catheter axis may include flexible portions between the electrodes to enhance flexibility. In other embodiments, one or more electrodes (212) may include helical windings to enhance flexibility.

[0069] Each electrode of the ablation device discussed herein can be connected to an insulated electrical lead (not shown) leading to a stalk (not shown) coupled to a proximal portion of a catheter. The insulation on each lead can maintain a potential difference of at least 700 V across its thickness without dielectric breakdown. In other embodiments, the insulation on each lead can maintain a potential difference of about 200 V to about 2000 V (inclusive of all values ​​and subranges therein) across its thickness without dielectric breakdown. This allows the electrodes to efficiently deliver electrical energy and ablate tissue through irreversible electroporation. The electrodes can, for example, receive pulse waveforms generated by a signal generator (122), as described above regarding... Figure 1 As discussed. In other embodiments, the guidewire (220) may be detached from the ablation device (200) (e.g., the ablation device (200) includes a catheter (210) but not the guidewire (220). For example, the guidewire (220) may be advanced into the endocardial space by itself, and thereafter the catheter (210) may be advanced into the endocardial space over the guidewire (220).

[0070] Figure 3 This is a perspective view of another embodiment of an ablation device (300) including a catheter (310) (e.g., structurally and / or functionally similar to an ablation device (110)), wherein a set of electrodes (314) is disposed along a distal portion (312) of the catheter (310). The distal portion (312) of the catheter (310) may be non-linear and formed in a generally circular shape. The set of electrodes (314) may be disposed along the non-linear distal portion (312) of the catheter (310) and may be formed in a generally circular arrangement. During use, the electrodes (314) may be positioned at the pulmonary vein orifice to deliver pulsed waveforms to ablate tissue, as per [reference needed]. Figure 16 A more detailed description follows. The shaped distal portion (312) of the catheter (310) may be angled relative to other portions of the catheter (310). For example, the distal portion (312) of the catheter (310) may be substantially perpendicular to adjacent portions of the catheter (310). In some embodiments, a handle (not shown) may be coupled to the proximal portion of the catheter (310) and may include a bending mechanism (e.g., one or more drawstrings (not shown)) configured to modify the shape of the distal portion (312) of the catheter (310). For example, operation of the drawstrings of the handle may increase or decrease the circumference of the circular shape of the distal portion (312) of the catheter (310). The diameter of the distal portion (312) of the catheter (310) may be modified to allow an electrode (314) to be positioned near and / or in contact with the pulmonary vein orifice (e.g., in contact with the inner radial surface of the pulmonary vein). The electrode (314) may include a series of metal strips or loops and may be independently addressable.

[0071] In some embodiments, a pulse waveform may be applied between electrodes (314) configured as an anode and cathode group. For example, adjacent or substantially diametrically opposed electrode pairs may be activated together as an anode-cathode group. It should be understood that any pulse waveform disclosed herein may be applied gradually or sequentially to a series of anode-cathode electrodes.

[0072] Figure 4 This is a perspective view of another embodiment of an ablation device (400) including a catheter (410) and a guidewire (420) (e.g., structurally and / or functionally similar to an ablation device (110)), the guidewire (420) having a shaped, non-linear distal portion (422). The guidewire (420) is slidable within the lumen of the catheter (410). The guidewire (420) can be advanced through the lumen of the catheter (410), and the distal portion (422) of the guidewire (420) can be generally circular. The shape and / or diameter of the distal portion (422) of the guidewire (420) can be as described above regarding... Figure 3 The described bending mechanism is used for modification. The catheter (410) can be flexible so as to be deflectable. In some embodiments, the catheter (410) and / or guidewire (420) can be configured to be elastic, such that they conform to the lumen in which they are positioned and take on a second shape when pushed out of the lumen. By modifying the size of the guidewire (420) and manipulating the deflection of the catheter (410), the distal portion (422) of the guidewire (420) can be positioned at a target tissue site, such as the pulmonary vein orifice. Except where the guidewire (420) extends from the catheter (410), the distal end (412) of the catheter (410) can be sealed so that the catheter (410) can electrically insulate the portion of the guidewire (420) within the lumen of the catheter (410). For example, in some embodiments, the distal end (412) of the catheter (410) may include a seal with an opening that allows the guidewire (420) to pass through when force is applied to form a compression hold between the seal and the guidewire (420) (which may be impermeable to fluid).

[0073] In some embodiments, the exposed distal portion (422) of the guidewire (420) may be coupled to an electrode and configured to receive pulse waveforms from a signal generator and deliver the pulse waveforms to tissue during use. For example, the proximal end of the guidewire (420) may be coupled to a suitable lead and connected to... Figure 1 The signal generator (122). The size of the distal portion (422) of the guidewire (420) can be set such that it can be positioned at the pulmonary vein orifice. For example, the diameter of the shaped distal portion (422) of the guidewire (420) can be approximately the same as the diameter of the pulmonary vein orifice. The shaped distal portion (422) of the guidewire (420) can be angled relative to the other portions of the guidewire (420) and the catheter (410).

[0074] The guidewire (420) may comprise stainless steel, nitinol, platinum, or other suitable biocompatible materials. In some embodiments, the distal portion (422) of the guidewire (420) may comprise a platinum coil physically and electrically attached to the guidewire (420). The platinum coil may be an electrode configured to deliver a voltage pulse waveform. Platinum is radiation-impermeable, and its use increases flexibility to aid in the advancement and positioning of the ablation device (400) within the endocardial space.

[0075] Figure 5 This is a detailed perspective view of the flower-shaped distal portion of an ablation device (500) including a set of electrodes (520, 522, 524, 526) (e.g., structurally and / or functionally similar to an ablation device (110)), each of which extends from a pair of insulated lead segments (510, 512, 514, 516). Each pair of adjacent insulated lead segments coupled to non-insulated electrodes (e.g., lead segments (510, 512) and electrode (526)) forms a loop. Figure 5 A set of four rings is shown. The set of rings at the distal portion of the ablation device (500) can be configured to deliver a pulsed waveform to the tissue. The ablation device (500) may include a set of insulated lead segments (510, 512, 514, 516) branching at the distal end of the device (500) to connect to corresponding exposed electrodes (520, 522, 524, 526), ​​as shown. Figure 5 As shown. Electrodes (520, 522, 524, 526) may include exposed portions of electrical conductors. In some embodiments, one or more of the electrodes (520, 522, 524, 526) may include platinum coils. One or more segments (510, 512, 514, 516) may be coupled to a bending mechanism (e.g., a support, a drawwire, etc.) controlled by a shank (not shown) to control the size and / or shape of a distal portion of the device (500).

[0076] Electrodes (520, 522, 524, 526) can be flexible and form a compact first configuration for advancement into the endocardial space, such as adjacent to the pulmonary vein orifice. Once positioned at the desired location, electrodes (520, 522, 524, 526) can transform into an expanded second configuration upon being pushed out of a lumen, such as a sheath, to form a flower-like distal portion, as... Figure 5As shown. In other embodiments, the insulated lead segments (510, 512, 514, 516) and electrodes (520, 522, 524, 526) may be biased to expand outward (e.g., spring open) into a second configuration when pushed out of the cavity (e.g., sheath) of the carrier device (500). The electrodes (520, 522, 524, 526) may be independently addressable and each has an insulated lead configured to maintain a voltage potential of at least about 700 V without dielectric breakdown of their corresponding insulation. In other embodiments, the insulation on each of the leads may maintain a potential difference of about 200 V to about 2000 V across its thickness without dielectric breakdown.

[0077] In some embodiments, the ablation device (5000) may be configured to deliver a pulsed waveform to tissue via the set of electrodes (520, 522, 524, 526) during use. In some embodiments, the pulsed waveform may be applied between electrodes (520, 522, 524, 526) configured as an anode and cathode pair. For example, electrode pairs that are generally diametrically opposed (e.g., electrodes (520, 524) and (522, 526)) may be activated together as an anode-cathode pair. In other embodiments, adjacent electrodes may be configured as an anode-cathode pair. As an example, the first electrode (520) in the set of electrodes may be configured as an anode and the second electrode (522) may be configured as a cathode.

[0078] Figure 6-9E An embodiment of an ablation device (e.g., structurally and / or functionally similar to ablation device (110)) that can be configured to deliver voltage pulse waveforms using a set of electrodes to ablate tissue and electrically isolate pulmonary veins is shown. In some of these embodiments, the ablation device can be converted from a first configuration to a second configuration such that the electrodes of the ablation device extend outward to contact the lumen of the tissue (e.g., the pulmonary vein orifice).

[0079] Figure 6 This is a side view of one embodiment of an ablation device (600), which includes a catheter shaft (610) located at a proximal end of the device (600), a distal cap (612) of the device (600), and a set of ridges (614) coupled thereto. The distal cap (612) may include a non-damaging shape to reduce damage to tissue. The proximal ends of the set of ridges (614) may be coupled to the distal ends of the set of ridges (614), while the distal ends of the set of ridges (614) may be tethered to the distal cap (612) of the device (600). The ablation device (600) may be configured to deliver pulsed waveforms to tissue via one or more of the set of ridges (614) during use.

[0080] Each ridge (614) of the ablation device (600) may include one or more independently addressable electrodes (616) formed on the surface of the ridge (614). Each electrode (616) may include insulated leads configured to maintain a voltage potential of at least about 700 V without dielectric breakdown of its corresponding insulator. In other embodiments, the insulator on each of the leads may maintain a potential difference of about 200 V to about 2000 V across its thickness without dielectric breakdown. Each ridge (614) may include insulated leads of each electrode (616) formed in the body of the ridge (614) (e.g., within the cavity of the ridge (614)). Figure 6 A set of ridges (614) is shown, wherein each ridge (614) includes a pair of electrodes (616) having substantially the same size, shape, and spacing as the electrodes (616) of the adjacent ridges (614). In other embodiments, the size, shape, and spacing of the electrodes (616) may be different.

[0081] For each of the ablation devices described herein, and especially Figure 6 The ablation device described in -9 may include a set of ridges, each of which may include a flexible curvature. The minimum radius of curvature of the ridge may be in the range of about 1 cm or greater. For example, the set of ridges may form a delivery assembly at the distal portion of the ablation device and be configured to transition between a first configuration and a second configuration, in which the set of ridges bends radially outward from the longitudinal axis of the ablation device, and in the second configuration, the set of ridges is arranged generally parallel to the longitudinal axis of the ablation device. In this way, the ridges can more easily conform to the geometry of the endocardial space. Generally, the “cage-like body” of the ridge may have an asymmetrical shape along its axial length, such that one end of the cage-like body (e.g., the distal end) is more spherical than the other end (e.g., the proximal end). The delivery assembly may be configured in the first configuration to contact the pulmonary vein orifice and transition to the second configuration before delivering a pulse waveform. In some of these embodiments, a shank may be coupled to the set of ridges and configured to influence the transition of the set of ridges between the first and second configurations. In some embodiments, the electrical leads of at least two of the electrodes in the set of electrodes may be electrically coupled at or near the proximal portion of the ablation device (such as within the handle).

[0082] In one embodiment, each of the electrodes (616) on a ridge (614) may be configured as an anode, while each of the electrodes (616) on an adjacent ridge (614) may be configured as a cathode. In another embodiment, the electrodes (616) on a ridge may alternate between anode and cathode, wherein the electrodes on adjacent ridges have opposite configurations (e.g., cathode and anode). The ablation device (600) may include any number of ridges, such as 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20 or more ridges, including all values ​​and subranges therein. In some embodiments, the ablation device (600) may include 3 to 20 ridges. For example, the ablation device (600) may include 6 to 12 ridges.

[0083] Figure 7 This is a side view of another embodiment of an ablation device (700), which includes a catheter shaft (710) located at a proximal end of the device (700), a distal cap (712) of the device (700), and a set of ridges (714) coupled thereto. The distal cap (712) may include a non-damaging shape. The proximal ends of the set of ridges (714) may be coupled to the distal ends of the catheter shaft (710), while the distal ends of the set of ridges (714) may be tethered to the distal cap (712) of the device (700). Each ridge (714) of the ablation device (700) may include one or more independently addressable electrodes (716) formed on the surface of the ridge (714). Each electrode (716) may include insulated leads configured to maintain a voltage potential of at least about 700 V without dielectric breakdown of its corresponding insulation. In other embodiments, the insulation on each of the electrical leads can maintain a potential difference of about 200V to about 1500V across its thickness without dielectric breakdown. Each ridge (714) may include an insulated electrical lead formed in the body of the ridge (714) for each electrode (716) (e.g., within the cavity of the ridge (714)). A set of ridge wires (718, 719) may be conductive and electrically coupled to adjacent electrodes (716) of an electrode (716) such as a pair of ridges (718, 719) on different ridges (714). For example, the ridge wires (718, 719) may extend in a transverse direction relative to the longitudinal axis of the ablation device (700).

[0084] Figure 7A set of ridges (714) is shown, wherein each ridge (714) includes a pair of electrodes (716) having substantially the same size, shape, and spacing as the electrodes (716) of the adjacent ridges (714). In other embodiments, the size, shape, and spacing of the electrodes (716) may differ. For example, the size and / or shape of the electrodes (716) electrically coupled to the first ridge filament (718) may differ from the size and / or shape of the electrodes (716) electrically coupled to the second ridge filament (719).

[0085] In some embodiments, the first ridge wire (718) may include a first set of ridge wires (720, 721, 722, 723), wherein each ridge wire in the set of ridge wires (720, 721, 722, 723) may couple electrodes (716) between different pairs of ridges in the set of ridges (714). In some of these embodiments, the set of ridge wires (720, 721, 722, 723) may form a continuous loop between the electrodes (716) therewith. Similarly, the second ridge wire (719) may include a second set of ridge wires (724, 725, 726), wherein each ridge wire in the set of ridge wires (724, 725, 726) may couple electrodes (716) on the set of ridges (714). The second set of ridges (724, 725, 726) may couple electrodes (716) on the first set of ridges (714) that are different from those on the first set of ridges (720, 721, 722, 723). In some of these embodiments, the first set of ridges (720, 721, 722, 723) may form a first continuous loop between the electrodes (716) to which they are coupled, while the second set of ridges (724, 725, 726) may form a second continuous loop between the electrodes (716) to which they are coupled. The first continuous loop may be electrically isolated from the second continuous loop. In some of these embodiments, the electrode (716) coupled to the first continuous loop may be configured as an anode, while the electrode (716) coupled to the second continuous loop may be configured as a cathode. A pulse waveform may be delivered to the electrodes (716) of the first and second continuous loops. In some embodiments, ridges such as 721, 722, 723 may be replaced by similar electrical connections in a proximal portion of the device (e.g., in the device handle). For example, electrodes 716 can be electrically connected together in the handle of the device.

[0086] In another embodiment, the first ridge filament (721) of the set of ridge filaments (720, 721, 722, 723) may couple an electrode (716) between the first ridge (711) and the second ridge (713) of the set of ridge filaments (714), while the second ridge filament (720) of the set of ridge filaments (720, 721, 722, 723) may couple an electrode (716) between the first ridge (711) and the third ridge (715) of the set of ridge filaments (714). The electrode (716) coupled by the first ridge filament (721) and the second ridge filament (720) may be configured as an anode and a cathode (or vice versa). In another embodiment, the first ridge wire (721) of the set of ridge wires (720, 721, 722, 723) may couple an electrode (716) between the first ridge (711) and the second ridge (713) of the set of ridges (714), while the second ridge wire (723) of the set of ridge wires (720, 721, 722, 723) may couple an electrode (716) between the third ridge (715) and the fourth ridge (717) of the set of ridges (714). A pulse waveform may be delivered to the electrode (716) coupled by the first ridge wire (721) and the second ridge wire (723). In some embodiments, instead of ridge wires, the electrical leads of at least two electrodes in the set of electrodes are electrically coupled at or near the proximal portion of the ablation device (such as within the stalk).

[0087] In other embodiments, one or more of the ridge wires (718, 719) may form a continuous loop between the electrically coupled electrodes (716). For example, a first set of ridge wires (718) may form a first continuous loop between the electrodes (716) coupled thereto, while a second set of ridge wires (719) may form a second continuous loop between the electrodes (716) coupled thereto. In this case, the first continuous loop may be electrically isolated from the second continuous loop. In one embodiment, each of the electrodes (716) coupled to the first set of ridge wires (718) may be configured as an anode, while each of the electrodes (716) coupled to the second set of ridge wires (719) may be configured as a cathode. Each set of electrically coupled electrodes (716) may be independently addressable. In some embodiments, instead of ridge wires, the electrical leads of at least two electrodes in the set of electrodes are electrically coupled at or near the proximal portion of the ablation device (such as within the stalk).

[0088] In some implementation schemes, such as the following regarding Figures 8A-8BAs discussed in further detail, the ridge wires can be electrically coupled to a set of electrodes (e.g., 2, 3, 4, 5, etc.) without forming a continuous loop. For example, two ridge wires can be used to form a discontinuous loop. In other embodiments, the size, shape, and spacing of the electrodes (716) can vary. The ablation device (700) can include any number of ridges, for example, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, or more ridges. In some embodiments, the ablation device (700) can include 3 to 20 ridges. For example, in one embodiment, the ablation device (700) can include 6 to 9 ridges.

[0089] Figures 8A-8B These are the side and front sectional views of the ablation catheter (800). Figure 8A This is a side view of one embodiment of an ablation device (800), which includes a catheter shaft (810) located at a proximal end of the device (800), a distal cap (812) of the device (800), and a set of ridges (814) coupled thereto. The distal cap (812) may include a non-damaging shape. The proximal ends of the set of ridges (814) may be coupled to the distal ends of the catheter shaft (810), while the distal ends of the set of ridges (814) may be tethered to the distal cap (812) of the device (800). Each ridge (814) of the ablation device (800) may include one or more independently addressable electrodes (816, 818) formed on the surface of the ridge (814). Each electrode (816, 818) may include insulated leads configured to maintain a voltage potential of at least about 700 V without dielectric breakdown of its corresponding insulation. In other embodiments, the insulation on each of the electrical leads may maintain a potential difference of about 200 V to about 2000 V (inclusive of all values ​​and subranges therebetween) across its thickness without dielectric breakdown. Each ridge (814) may include an insulated electrical lead for each electrode (816, 818) formed in the body of the ridge (814) (e.g., within a cavity of the ridge (814)). One or more ridge wires (817, 819) may be conductive and electrically coupled to adjacent electrodes (816, 818) on different ridges (814). For example, the ridge wires (817, 819) may extend in a transverse direction relative to the longitudinal axis of the ablation device (800).

[0090] Figure 8B yes Figure 8AA front sectional view taken along line 8B-8B. Each ridge (817, 819, 821, 823) is electrically coupled to a pair of adjacent electrodes (816, 818, 820, 822) on different ridges. In some embodiments, each coupled electrode pair may be electrically isolated from each other. In some embodiments, the coupled electrode pairs may be configured to have a common polarity. Adjacent electrode pairs may be configured to have opposite polarities (e.g., the first electrode pair is configured as an anode, while the adjacent second electrode pair is configured as a cathode). For example, the electrode (816) coupled to the first set of ridges (817) may be configured as an anode, while each electrode (818) coupled to the second set of ridges (819) may be configured as a cathode. In some embodiments, each electrode formed on the ridge (814) may have a common polarity (e.g., configured as an anode or cathode). Each coupled electrode pair may be independently addressable. In some embodiments, the ablation device (800) may include an even number of ridges. The ablation device (800) may include any number of ridges, such as 4, 6, 8, 10 or more ridges. In some embodiments, the ablation device may include 4 to 10 ridges. For example, in one embodiment, the ablation device may include 6 to 8 ridges. As previously indicated, in some embodiments, ridges such as 817, 819 may be replaced by similar electrical connections in the proximal portion of the device (e.g., in the device handle). For example, electrodes 816 may be electrically connected together in the device handle such that these electrodes are at the same potential during ablation.

[0091] Figure 9A This is a side view of another embodiment of the ablation device (900), which includes a catheter shaft (910) located at a proximal end of the device (900), a distal cap (912) of the device (900), and a set of ridges (914) coupled thereto. The distal cap (912) may include a non-damaging shape. The proximal ends of the set of ridges (914) may be coupled to the distal ends of the catheter shaft (910), while the distal ends of the set of ridges (914) may be tethered to the distal cap (912) of the device (900). Each ridge (914) of the ablation device (900) may include one or more independently addressable electrodes (916, 918) formed on the surface of the ridge (914). Each electrode (916, 918) may include insulated leads configured to maintain a voltage potential of at least about 700 V without dielectric breakdown of its corresponding insulation. In other embodiments, the insulation on each of the leads can maintain a potential difference of about 200V to about 2000V across its thickness without dielectric breakdown. Each ridge (914) may include an insulated lead for each electrode (916, 918) formed in the body of the ridge (914) (e.g., within a cavity of the ridge (914)). Figure 9AA set of ridges (914) is shown, wherein each ridge (914) includes electrodes (916, 918) spaced apart from the electrodes (916, 918) of adjacent ridges (914). For example, the set of ridges (914) includes a first ridge (920) and a second ridge (922) adjacent to the first ridge (920), wherein the electrode (916) of the first ridge (920) is positioned closer to the distal end (912) of the ablation device (900) than the electrode (918) of the second ridge (922). In other embodiments, the size and shape of the electrodes (916, 918) may also be different.

[0092] In some embodiments, adjacent distal electrodes (916) and proximal electrodes (918) may form an anode-cathode pair. For example, the distal electrode (916) may be configured as the anode, and the proximal electrode (918) may be configured as the cathode. In some embodiments, the ablation device (900) may include 6 to 12 ridges. Figure 9A In this ablation device (900), an electrode (916, 918) is formed on the surface of each ridge (914), such that each ridge (914) includes an insulated electrical lead. Therefore, the diameter of the inner cavity of the ridge (914) can be reduced, allowing the ridge (914) to be thicker and more mechanically robust. This further reduces dielectric breakdown of the insulation, thereby improving the reliability and lifespan of each ridge (914) and the ablation device (900). The ablation device (900) may include any number of ridges, for example, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, or more ridges. In some embodiments, the ablation device (900) may include 3 to 20 ridges. For example, in one embodiment, the ablation device (900) may include 6 to 10 ridges. Furthermore, in some embodiments, the shape of the spherical expansion structure (930) of the expanded set of ridges (914) can be asymmetrical, for example, its distal portion is more spherical or rounded than its proximal portion (e.g., see Figure 9B-9E This spherical distal portion helps to position the device at the pulmonary vein orifice.

[0093] refer to Figure 9B-9E It should be understood that, unless otherwise specified, it has the same meaning as Figure 9A The reference numerals in the figures are similar to those of the reference numerals for the parts (e.g., Figure 9A Electrode (916) and Figure 9B The electrodes (916') in the middle may be similar in structure and / or function. Figure 9BThe diagram shows the ridges (914', 920', 922') that form the expansion structure (930') during use, such as during deployment. The first plane (924A'), sometimes also referred to as the proximal plane, of the expansion structure (930') has a different cross-sectional area (930') than the cross-sectional area at the second plane (924B') of the expansion structure (930'). In some embodiments, such as... Figure 9B As shown, the cross-sectional area at the second plane (924B') of the expanded structure (930') is larger than the cross-sectional area at the first plane (924A'). (As per...) Figure 9B The terms "first plane" and "second plane" as used may refer to planes orthogonal to the longitudinal axis of the catheter shaft (910'), each formed at a distance of approximately 1 cm, approximately 2 cm, and approximately 3 cm or more (inclusive) from the distal end of the catheter shaft (910') and the proximal end of the distal operculum (912'), respectively. Similar to... Figure 9A The electrode (916') of the first ridge (920') is positioned closer to the distal cap (912') of the ablation device (900') than the electrode (918') of the second ridge (922').

[0094] Figure 9C The diagram shows the ridges (914", 920", 922") that form the expansion structure (930") during use, such as during deployment. The first plane (924A") of the expansion structure (930"), sometimes also referred to as the proximal plane, has a different cross-sectional area than the cross-sectional area at the second plane (924B) of the expansion structure (930). In some embodiments, such as... Figure 9C As shown, the cross-sectional area at the second plane (924B”) of the expanded structure (930”) is larger than the cross-sectional area at the first plane (924A”). (As per...) Figure 9C The terms “first plane” and “second plane” as used may refer to planes orthogonal to the longitudinal axis of the catheter shaft (910”), each formed at a distance of approximately 1 cm, approximately 2 cm, and approximately 3 cm or more (inclusive) from the distal end of the catheter shaft (910”) and the proximal end of the distal cap (912”), respectively. Figures 9A-9B Unlike other methods, multiple electrodes can be present on each spine, and some electrodes can be equidistant from the distal cap (912”). In this way, relatively distal electrodes such as 932” and 934” can be placed side by side at the pulmonary vein ostium or proximal / centrally during ablation delivery to generate perioral lesions around the pulmonary vein.

[0095] Figure 9D This illustrates the formation of an expansion structure during use, such as during deployment. ) spine Spine At its distal end, it converges to the expansion structure points within .like Figure 9D As shown, in this configuration, the spine... At least some electrodes on Can be located in the expansion structure distal end plane In China. For example, regarding... Figure 9D The term "distal end plane" as used can refer to the plane relative to the catheter axis. The longitudinal axis is orthogonal to the expansion structure The plane of the far boundary. In this way, the expansion structure can be... Pressing against, for example, the posterior wall of the left atrium, so as to directly generate damage thereon by activating an appropriate electrode in the distal end plane using any suitable polarity combination. For example, the electrode and It can be configured to have opposite polarities.

[0096] Figure 9E The diagram shows ridges (944, 940, 942) that form an expansion structure (950) during use, such as during deployment. The ridges (944, 940, 942) converge at their distal ends into a distal cap within the expansion structure (950). At the proximal end. For example... Figure 9E As shown, in this configuration, at least some electrodes (952, 954) on the ridge wires (944, 940) may be located in the distal end plane (946) of the expanded structure (950). (As per...) Figure 9E The term "distal end plane" as used can refer to the plane relative to the catheter axis. The longitudinal axis is orthogonal to the plane passing through the distal boundary of the expansion structure (950). In this way, the expansion structure (950) can be pressed against the posterior wall of the left atrium to directly generate damage thereon by activating any suitable electrode in the distal end plane (946) using any appropriate polarity combination. For example, electrodes 952 and 954 can be configured to have opposite polarities. Relative to Figure 9D Expansion structure in , Figure 9E The expanded structure (950) has a more orthogonal (e.g., flattened) shape, which can be pressed against, for example, the posterior wall of the left atrium for tissue ablation. In other words, the expanded structure distal end plane The cross-sectional area at the point is smaller than the cross-sectional area at the distal end plane (946) of the expansion structure (950).

[0097] For each of the ablation devices described herein, each ridge may comprise a polymer and define an inner lumen to form a hollow tube. One or more electrodes of the ablation devices described herein may comprise a diameter of about 0.2 mm to about 2.0 mm and a length of about 0.2 mm to about 5.0 mm. In some embodiments, the electrodes may comprise a diameter of about 1 mm and a length of about 1 mm. Because the electrodes can be independently addressable, the electrodes can be energized in any sequence using any pulse waveform sufficient to ablate tissue through irreversible electroporation. For example, different sets of electrodes may deliver different sets of pulses (e.g., graded pulse waveforms), as discussed further below. It should be understood that the size, shape, and spacing of electrodes on and between ridges can be configured to deliver adjacent / transmural energy to electrically isolate one or more pulmonary veins. In some embodiments, alternating electrodes (e.g., all distal electrodes) may be at the same potential, and so may all other electrodes (e.g., all proximal electrodes). Thus, ablation can be rapidly delivered when all electrodes are activated simultaneously. Various such electrode pairing options exist and can be implemented based on their convenience.

[0098] balloon

[0099] In some implementations, the ablation device may include one or more balloons for delivering energy to ablate tissue via irreversible electroporation. Figure 10An embodiment of a balloon ablation device (1010) (e.g., structurally and / or functionally similar to an ablation device (110)) disposed in the left atrial ventricle (1000) of the heart is depicted. The ablation device (1010) may include a first balloon (1012) and a second balloon (1014), the balloons being configured to be disposed in the orifice (1002) of a pulmonary vein (1004). The first balloon (1012) in an expanded (e.g., inflated) configuration may have a larger diameter than the second balloon (1014) in an expanded configuration. This allows the second balloon (1014) to be advanced and further disposed in the pulmonary vein (1014), while the first balloon (1012) may be disposed at and / or near the orifice (1002) of the pulmonary vein (1004). The inflated second balloon is used to stabilize the positioning of the first balloon at the orifice of the pulmonary vein. In some embodiments, the first balloon (1012) and the second balloon (1014) may be filled with any suitable conductive fluid, such as saline solution. The first balloon (1012) and the second balloon (1014) may be electrically isolated from each other. For example, each balloon (1012, 1014) may include an associated insulated electrical lead, each lead having sufficient insulation to maintain a potential difference of at least 700 V across its thickness without dielectric breakdown. In other embodiments, the insulation on each of the leads may maintain a potential difference of about 200 V to about 2500 V (inclusive of all values ​​and subranges therein) across its thickness without dielectric breakdown. For example, the lead of the second balloon (1014) may be insulated as it extends through the first balloon (1012).

[0100] In some embodiments, the first balloon (1012) and the second balloon (1014) may form an anode-cathode pair. For example, the first balloon (1012) may be configured as the cathode and the second balloon (1014) as the anode, or vice versa, wherein electrical energy may be capacitively coupled across the balloon or saline-filled electrodes. The device (1010) may receive a pulsed waveform to be delivered to the tissue (1002). For example, one or more biphasic and monophasic signals may be applied such that the tissue may be ablated at a desired location in the pulmonary vein (1004) between the first balloon (1012) and the second balloon (1014). The first balloon (1012) and the second balloon (1014) may substantially confine the electric field between the first balloon (1012) and the second balloon (1014) to reduce the electric field and damage to tissues remote from the opening (1002) of the pulmonary vein (1004). In some implementations, one or more of the balloons (1012, 1014) may include wire mesh.

[0101] Figure 11This is a cross-sectional view of another embodiment of a balloon ablation device (1110) disposed in the left atrial ventricle (1100) and the right atrial ventricle (1104) (e.g., structurally and / or functionally similar to the ablation device (110)). The ablation device (1110) may include a balloon (1112) configured to be advanced into and disposed in the right atrial ventricle (1104). For example, the balloon (1112) may be configured to contact the diaphragm (1106) of the heart. The balloon (1112) may be filled with saline. The device (1110) may also include an electrode (1120) that can be advanced from the right atrial ventricle (1104) through the balloon (1112) and the diaphragm (1106) and into the left atrial ventricle (1100). For example, the electrode (1120) may extend from the balloon (1112) and pierce the septum (1106) and be advanced into the left atrial ventricle (1100). Once the electrode (1120) is advanced into the left atrial ventricle (1100), the distal portion of the electrode (1120) may be modified to form a predetermined shape. For example, the distal portion of the electrode (1120) may include a non-linear shape such as circular, elliptical, or any other geometry. Figure 11 In this embodiment, the distal portion of the electrode (1120) forms a ring that can surround a single opening or two or more openings of the pulmonary vein (1102) in the left atrial ventricle (1100). In other embodiments, the distal portion of the electrode (1120) may have a diameter approximately the same as the opening of the pulmonary vein (1102).

[0102] The balloon (1112) and the electrode (1120) may be electrically isolated from each other. For example, the balloon (1112) and the electrode (1120) may each include corresponding insulated electrical leads (1114, 1122), each lead (1114, 1122) having sufficient electrical insulation to maintain a potential difference of at least 700 V across its thickness without dielectric breakdown. In other embodiments, the insulation on each of the leads may maintain a potential difference of about 200 V to about 2,000 V (inclusive of all values ​​and sub-ranges therein) across its thickness without dielectric breakdown. The lead (1122) of the electrode (1120) may be insulated by the balloon (1112). In some embodiments, the balloon (1112) and the electrode (1120) may form an anode-cathode pair. For example, the balloon (1112) may be configured as the cathode, and the electrode (1120) may be configured as the anode. The device (1110) can receive a pulse waveform to be delivered to the orifice of a pulmonary vein (1102). For example, one or more of a biphasic and monophasic signal can be applied to ablate tissue. While the applied current is capacitively coupled to the balloon (1112) to turn on the circuit, the pulse waveform can create a strong electric field around the electrode (1120). In some embodiments, the electrode (1120) may comprise fine-gauge wires, and the balloon (1112) may comprise a wire mesh.

[0103] In another embodiment, the electrode (1120) may be advanced through the pulmonary vein (1102) and positioned in one or more of the pulmonary vein ostia without being advanced through the balloon (1112) and / or diaphragm (1106). The balloon (1112) and the electrode (1120) may be configured as a cathode-anode pair and receive pulse waveforms in the same manner as discussed above.

[0104] Return electrode

[0105] Some implementations of the ablation system described herein may also include a return electrode coupled to the patient or a set of distributed return electrodes to reduce the risk of unintentional damage to healthy tissue. Figure 12A-12B This is a schematic diagram of a set of return electrodes (1230) (e.g., return pads) of an ablation system placed on a patient (1200). Figure 12A-12B The image shows a set of four openings of the pulmonary vein (1210) in the left atrium. Electrodes (1220) of the ablation device may be positioned around one or more openings of the pulmonary vein (1210). In some embodiments, a set of return electrodes (1230) may be positioned on the back of the patient (1200) to allow current to flow from the electrodes (1220) through the patient (1200) and then to the return electrodes (1230).

[0106] For example, one or more return electrodes may be placed on the skin of a patient (1200). In one embodiment, eight return electrodes (1230) may be positioned on the patient's back to surround the pulmonary vein orifice (1210). A conductive gel may be applied between the return electrodes (1230) and the skin to improve contact. It should be understood that any ablation device described herein may be used with one or more return electrodes (1230). Figure 12A-12B In the middle, the electrode (1220) is arranged around the four ports (1210).

[0107] Figure 12B An energized electrode (1220) is shown that forms an electric field (1240) around the mouth (1210) of the pulmonary vein. A return electrode (1230) can then receive pulsed single-phase and / or biphase waveforms delivered by the electrode (1220). In some embodiments, the number of return electrodes (1230) may be inversely proportional to the surface area of ​​the return electrodes (1230).

[0108] For each of the ablation devices discussed herein, the electrodes (e.g., ablation electrodes, return electrodes) may comprise biocompatible metals such as titanium, palladium, silver, platinum, or platinum alloys. For example, the electrodes may preferably comprise platinum or platinum alloys. Each electrode may comprise an electrical lead with sufficient electrical insulation to maintain a potential difference of at least 700 V across its thickness without dielectric breakdown. In other embodiments, the insulation on each of the electrical leads may maintain a potential difference of about 200 V to about 2500 V (inclusive of all values ​​and sub-ranges therein) across its thickness without dielectric breakdown. The insulated electrical lead may extend from its location where it can be connected to a suitable electrical connector to the proximal stem portion of the catheter. The catheter shaft may be made of a flexible polymer material such as Teflon, nylon, Pebax, etc.

[0109] II. Methods

[0110] A method for ablating tissue in a cardiac chamber using the system and apparatus described herein is also described. The cardiac chamber may be the left atrial chamber and include its associated pulmonary veins. Typically, the method described herein involves introducing and positioning the apparatus in contact with one or more pulmonary vein orifices. A pulse waveform may be delivered by one or more electrodes of the apparatus to ablate the tissue. In some embodiments, a cardiac pacing signal may synchronize the delivered pulse waveform with the cardiac cycle. Alternatively or additionally, the pulse waveform may include multiple stages of a graded structure to reduce the total energy delivery. Thus, the performed tissue ablation can be delivered synchronously with the pacing heartbeat and with less energy delivery to reduce damage to healthy tissue. It should be understood that any ablation apparatus described herein may be used to ablate tissue using the methods discussed below, as appropriate.

[0111] Figure 13This is a method (1300) for one embodiment of a tissue ablation procedure. In some embodiments, a voltage pulse waveform as described herein may be applied during the refractory period of the cardiac cycle to avoid interruption of the sinus rhythm. The method (1300) includes introducing a device (e.g., an ablation device, such as any one of ablation device (110) and / or ablation devices (200, 300, 400, 500, 600, 700, 800, 900, 1010, 1110)) into the endocardial space of the left atrium at step (1302). The device may be advanced to be positioned in contact with the pulmonary vein orifice (1304). For example, the electrodes of the ablation device may be formed in a generally circular arrangement of electrodes positioned to contact the inner radial surface at the pulmonary vein orifice. In some embodiments, a pacing signal for cardiac stimulation of the heart may be generated (1306). The pacing signal may then be applied to the heart (1308). For example, the heart can be electrically paced using a cardiac stimulator to ensure that pacing capture establishes the periodicity and predictability of the cardiac cycle. One or more of atrial and ventricular pacing can be applied. An indication of the pacing signal can be transmitted to a signal generator (1310). A time window within the refractory period of the cardiac cycle can then be defined, within which one or more voltage pulse waveforms can be delivered. In some embodiments, the refractory time window may follow the pacing signal. For example, a common refractory time window may lie between the atrial refractory time window and the ventricular refractory time window.

[0112] A pulse waveform can be generated synchronously with the pacing signal (1312). For example, a voltage pulse waveform can be applied within a common refractory time window. In some embodiments, the pulse waveform can be generated with a time offset relative to the indication of the pacing signal. For example, the start of the refractory time window can be offset from the pacing signal offset time. A voltage pulse waveform can be applied for a series of heartbeats within the corresponding common refractory time window. The generated pulse waveform can be delivered to tissue (1314). In some embodiments, the pulse waveform can be delivered to the pulmonary vein orifice of the patient's heart via one or more ridges of a set of ridges of the ablation device. In other embodiments, the voltage pulse waveform, as described herein, can be selectively delivered to a subset of electrodes, such as an anode-cathode subset for ablation and isolation of the pulmonary veins. For example, a first electrode in a set of electrodes can be configured as an anode, while a second electrode in the set of electrodes can be configured as a cathode. These steps can be repeated for a desired number of pulmonary vein orifices that have been ablated (e.g., 1, 2, 3, or 4 orifices).

[0113] In some implementations, graded voltage pulse waveforms with nested structures and time interval gradations as described herein can be used for irreversible electroporation, thereby providing control and selectivity in different tissue types. Figure 14This is a flowchart (1400) of another embodiment of the tissue ablation process. The method (1400) includes introducing a device (e.g., an ablation device, such as ablation device (110) and / or ablation devices (200, 300, 400, 500, 600, 700, 800, 900, 1010, 1110) into the endocardial space of the left atrium (1402). The device may be advanced to be positioned in the pulmonary vein orifice (1404). In embodiments where the device may include first and second configurations (e.g., compact and expanded), the device may be introduced in the first configuration and transformed into the second configuration to contact tissue at or near the pulmonary vein orifice (1406). The device may include electrodes and may be configured as an anode-cathode subset (1408), as discussed in detail above. For example, a subset of the electrodes of the device may be selected as the anode, and another subset of the electrodes of the device may be selected as the cathode, applying a voltage pulse waveform between the anode and cathode.

[0114] A pulse waveform can be generated by a signal generator (e.g., signal generator 122), and the pulse waveform may include multiple levels (1410) in a hierarchical structure. Various hierarchical waveforms can be generated using the signal generator disclosed herein. For example, the pulse waveform may include a first level of a hierarchical structure of pulse waveforms comprising a first group of first pulses. Each pulse has a pulse duration and a first time interval separating consecutive pulses. A second level of the hierarchical structure of pulse waveforms may include multiple first groups of pulses as a second group of pulses. A second time interval may separate consecutive first groups of pulses. The second time interval may be at least three times the duration of the first time interval. A third level of the hierarchical structure of pulse waveforms may include multiple second groups of pulses as a third group of pulses. A third time interval may separate consecutive second groups of pulses. The third time interval may be at least thirty times the duration of the second level time interval.

[0115] It should be understood that while the examples in this paper identify individual monophasic and biphasic waveforms, it should also be understood that combined waveforms, where some parts of the waveform hierarchy are monophasic and others are biphasic, can also be generated. Voltage pulse waveforms with a hierarchical structure (optionally with time delays) can be applied to different anode-cathode subsets. As discussed above, one or more waveforms applied to the anode-cathode subsets can be applied during the refractory period of the cardiac cycle. The pulse waveforms can be delivered to tissue (1412). It should be understood that... Figure 13 and 14 The steps described herein can be combined and modified as needed.

[0116] Figure 15-18 Describing the use of the ablation device described herein (e.g., Figure 2-5 An implementation scheme for ablation of tissue in the left atrial ventricle of the heart as described above. Figure 15 Is it using the corresponding Figure 2 A cross-sectional view of an embodiment of a method for ablation of tissue located in the left atrial ventricle of the heart using the ablation device (1500) depicted in the ablation device (210). The left atrial ventricle (1502) is depicted as having four pulmonary veins (1504), and the ablation device (1500) can be used to sequentially ablate tissue to electrically isolate one or more pulmonary veins (1504). Figure 15 As shown, the ablation device (1500) can be introduced into the endocardial space, such as the left atrial ventricle (1502), using a septal-crossing method (e.g., extending from the right atrial ventricle through the septum and into the left atrial ventricle (1502)). The ablation device (1500) may include a catheter (1510) and a guidewire (1520) that can slide within the lumen of the catheter (1510). The distal portion of the catheter (1510) may include a set of electrodes (1512). The distal portion (1522) of the guidewire (1520) may be advanced into the left atrial ventricle (1502) to be positioned near the orifice of the pulmonary vein (1504). The catheter (1510) may then be advanced over the guidewire (1520) to position the electrodes (1512) near the orifice of the pulmonary vein (1504). Once the electrode (1512) contacts the orifice of the pulmonary vein (1504), the electrode (1512) can be configured as an anode-cathode subset. A voltage pulse waveform generated by a signal generator (not shown) can be delivered to the tissue in sync with the pacing heartbeat using the electrode (1512), and / or include a waveform gradation structure. After ablation of tissue in one of the pulmonary veins (1504) is completed, the catheter (1510) and guidewire (1520) can be repositioned at another pulmonary vein (1504) to ablate tissue in one or more of the remaining pulmonary veins (1504).

[0117] Figure 16 Is it using the corresponding Figure 3 A cross-sectional view of an embodiment of a method for ablation of tissue disposed within the left atrial chamber of the heart using the ablation device (1600) depicted in the ablation apparatus (310). The left atrial chamber (1602) is depicted as having four pulmonary veins (1604), and the ablation device (1600) can be used to sequentially ablate tissue to electrically isolate one or more pulmonary veins (1604). Figure 16As shown, the ablation device (1600) can be introduced into an endocardial space such as the left atrial ventricle (1602) using a transseptal approach. The ablation device (1600) may include a sheath (1610) and a catheter (1620) that can slide within the lumen of the sheath (1610). The distal portion (1622) of the catheter (1620) may include a set of electrodes. The distal portion (1622) of the catheter (1620) may be advanced into the left atrial ventricle (1602) to position the electrodes near the orifice of a pulmonary vein (1604). Once the electrodes are in contact with the orifice of the pulmonary vein (1604), the electrodes may be configured as an anode-cathode subset. A voltage pulse waveform generated by a signal generator (not shown) may be delivered to the tissue in sync with the pacing heartbeat using the electrodes, and / or may include a waveform gradation structure. After the tissue ablation in the pulmonary vein (1604) is completed, the catheter (1620) can be repositioned at another pulmonary vein (1604) to ablate tissue in one or more of the remaining pulmonary veins (1604).

[0118] Figure 17 Is it using the corresponding Figure 4 The diagram shows a cross-sectional view of an embodiment of a method for ablating tissue located in the left atrial ventricle of the heart using an ablation device (410). The left atrial ventricle (1702) is depicted as having four pulmonary veins (1704), and the ablation device (1700) can be used to ablate tissue to electrically isolate one or more pulmonary veins (1704). Figure 17As shown, the ablation device (1700) can be introduced into an endocardial space, such as the left atrial ventricle (1702), using a septal transect method. The ablation device (1700) may include a sheath (1710) and a plurality of catheters (1720, 1721) that can slide within the lumen of the sheath (1710). Each of the catheters (1720, 1721) may include a corresponding guidewire (1722, 1723) that can slide within the catheter (1720, 1721). The distal portion of the guidewire (1722, 1723) may include an electrode configured to deliver a voltage pulse waveform. Each of the catheters (1720, 1721) and the corresponding guidewire (1722, 1723) may be advanced into the left atrial ventricle (1702) to be positioned near a corresponding orifice of the pulmonary vein (1704). Once the guidewire electrodes (1722, 1723) are in contact with the orifices of the pulmonary veins (1704), the electrodes can be configured as an anode-cathode subset. For example, the first guidewire (1722) can be configured as the anode, and the second guidewire (1723) can be configured as the cathode. In this configuration, a voltage pulse waveform generated by a signal generator (not shown) can be delivered for ablation and simultaneous isolation of the pair of pulmonary veins (1704). Alternatively or concurrently, the voltage pulse waveform can be delivered to the tissue in sync with a pacing heartbeat using the electrodes, and / or include a waveform gradation structure. After ablation of the tissue in both pulmonary veins (1704) is completed, the catheters (1720, 1721) can be repositioned to ablate the tissue at the two remaining pulmonary veins (1704). In some embodiments, the sheath (1710) may include three or four catheters to be placed in the pulmonary veins (1704).

[0119] Figure 18 Is it using the corresponding Figure 5 A cross-sectional view of an embodiment of a method for ablation of tissue disposed within the left atrial chamber of the heart using the ablation device (1800) depicted in the ablation apparatus (500). The left atrial chamber (1802) is depicted as having four pulmonary veins (1804), and the ablation device (1800) can be used to sequentially ablate tissue to electrically isolate one or more pulmonary veins (1804). Figure 18 As shown, the ablation device can be introduced into an endocardial space such as the left atrial ventricle (1802) using a transseptal approach. The ablation device may include a sheath (1820) and a catheter (1810) that can slide within the lumen of the sheath (1820). The distal portion (1812) of the catheter (1810) may be flower-shaped, as described above. Figure 5 Detailed discussion. The distal portion (1812) of the catheter (1810) can be advanced into the left atrial ventricle (1802) in a compact first configuration and positioned near the orifice of the pulmonary vein (1804). Then, the distal portion 1812 of the catheter (1810) can be transformed into an expanded second configuration to form a flower-shaped distal portion, as... Figure 18 As shown, the distal portion (1812) of the catheter (1810) is positioned near the orifice of the pulmonary vein (1804). Once the electrode contacts the orifice of the pulmonary vein (1804), the electrode can be configured as an anode-cathode subset. A voltage pulse waveform generated by a signal generator (not shown) can be delivered to the tissue in sync with a pacing heartbeat using the electrode, and / or include a waveform gradation structure. After ablation of the tissue in the pulmonary vein (1804) is completed, the catheter (1810) can be repositioned at another pulmonary vein (1804) to ablate tissue in one or more of the remaining pulmonary veins (1804).

[0120] It should be understood that any method described herein (e.g., Figure 13-18 It may also include returning the electrode (e.g., Figure 12A-12B One or more return electrodes (1230) depicted in the figure are coupled to the back of the patient and configured to safely remove current from the patient during the application of a voltage pulse waveform.

[0121] Figure 19A-20B An embodiment is described, in which an electrode is positioned in contact with the perioral region of a pulmonary vein and the electric field generated therefrom. Figure 19A This is a schematic diagram (1900) of an embodiment of a set of electrodes (1910) disposed in the mouth of the pulmonary vein (1904). The left atrial ventricle (1902) may include a blood pool (1906), and the pulmonary vein (1904) may include a blood pool (1908). The left atrial ventricle (1902) and the pulmonary vein (1904) may each have a wall thickness of up to about 4 mm.

[0122] Figure 19B This is another schematic diagram (1900) of the set of electrodes (1910) arranged radially along the inner surface of the pulmonary vein (1904). The pulmonary vein (1904) may include an arterial wall (1905) containing a blood pool (1908). Adjacent electrodes (1910) may be separated by a predetermined distance (1911). In some embodiments, the pulmonary vein (1904) may have an inner diameter of about 16 mm. Figures 19A-19B In this embodiment, the electrodes (1910) may have a length of about 10 mm and be spaced about 4 mm apart from each other. It should be understood that the electrodes (1910) in other embodiments may be any electrodes disclosed herein. For example, the electrodes (1910) may include... Figure 5 The electrode and / or the distal part of the flower-like structure Figure 3 The electrodes are depicted in a generally circular arrangement.

[0123] Figures 20A-20B Schematic diagram (2000) of an implementation scheme of an electric field (2020) generated by a set of electrodes (2010) placed in the mouth of the pulmonary vein (2002). Figure 20AThis is a perspective view of the pulmonary veins (2002) and the outer wall of the left atrium (2004), while Figure 20B This is a cross-sectional view. The shadow electric field (2020) shows the location where the electric field (2020) exceeds a threshold when adjacent electrodes (2010) deliver energy (e.g., voltage pulse waveforms) to ablate tissue. For example, the electric field (2020) represents a potential difference of 1500 V applied between adjacent electrodes (2010). At said applied voltage, the magnitude of the electric field (2020) is at least higher than the threshold of 500 V / cm within the shadow volume electric field (2020) and may be sufficient to generate irreversible ablation in cardiac tissue. As described in detail above, the pulmonary vein (2002) orifice can be ablated to electrically isolate the pulmonary vein (2002) from the left atrial ventricle (2004) by sequencing the pulse waveforms on the adjacent electrode (2010) pairs.

[0124] pulse waveform

[0125] This document discloses methods, systems, and apparatus for selectively and rapidly applying pulsed electric fields / waveforms to achieve tissue ablation with irreversible electroporation. The pulsed waveforms disclosed herein can be used in any of the systems (100), apparatuses (e.g., 200, 300, 400, 500, 600, 700, 800, 900, 1010, 1110, 1230, 1500, 1600, 1700, 1800, 1910, 2010), and methods (e.g., 1300, 1400) described herein. Some embodiments involve pulsed high-voltage waveforms and sequential delivery schemes for delivering energy to tissue via an electrode array. In some embodiments, peak electric field values ​​can be reduced and / or minimized while maintaining a sufficiently large electric field size in the area where tissue ablation is desired. This also reduces the likelihood of excessive tissue damage or arcing and increases localized high temperatures. In some embodiments, a system for irreversible electroporation includes a signal generator and a processor configured to apply pulsed voltage waveforms to selected electrodes or subsets of electrodes of an ablation device. In some embodiments, the processor is configured to control inputs, thereby enabling the sequential triggering of anode-cathode subsets of selected pairs of electrodes based on a predetermined sequence, and in one embodiment, sequential delivery may be triggered by a cardiac stimulator and / or pacing device. In some embodiments, the ablation pulse waveform is applied during the refractory period of the cardiac cycle to avoid interruption of the heart's sinus rhythm. An exemplary method for enforcing this approach is to electrically pace the heart with a cardiac stimulator and ensure that pacing capture establishes the periodicity and predictability of the cardiac cycle, and then define a time window within the refractory period of the periodic cycle to deliver the ablation waveform within that time window.

[0126] In some embodiments, the pulse voltage waveforms disclosed herein are hierarchically graded and have a nested structure. In some embodiments, the pulse waveforms comprise graded groups of pulses with multiple associated time scales. Furthermore, the associated time scales and pulse widths, as well as the number of pulses and graded groups, can be selected to satisfy one or more of a set of Diophantine inequalities relating to cardiac pacing frequency.

[0127] The pulsed waveforms for energy delivery in electroporation, as disclosed herein, can improve the safety, efficiency, and effectiveness of energy delivery by reducing the electric field threshold associated with irreversible electroporation, thereby producing more effective ablation damage with a reduced total delivered energy. This, in turn, expands the clinical applications of electroporation, including the treatment of various cardiac arrhythmias.

[0128] Figure 21 The diagram shows a pulsed voltage waveform in the form of a rectangular double-pulse sequence, where each pulse (such as pulse (2100)) is associated with a pulse width or duration. The pulse width / duration can be approximately 0.5 microseconds, approximately 1 microsecond, approximately 5 microseconds, approximately 10 microseconds, approximately 25 microseconds, approximately 50 microseconds, approximately 100 microseconds, approximately 125 microseconds, approximately 140 microseconds, approximately 150 microseconds, and all values ​​and subranges thereof. Figure 21 The pulse waveform shows a set of single-phase pulses, where all pulses have the same polarity. Figure 21 All values ​​are positive (e.g., measured from a zero baseline). In some implementations, such as for irreversible electroporation applications, the height of each pulse (2100) or the voltage amplitude of the pulse (2100) can range from approximately 400 volts, approximately 1,000 volts, approximately 5,000 volts, approximately 10,000 volts, to approximately 15,000 volts, including all values ​​and subranges therein. Figure 21 As shown, the pulse (2100) is separated from the adjacent pulse by a time interval (2102), sometimes also referred to as the first time interval. In order to generate irreversible electroporation, the first time interval can be about 10 microseconds, about 50 microseconds, about 100 microseconds, about 200 microseconds, about 500 microseconds, about 800 microseconds, about 1 millisecond, including all values ​​and subranges in between.

[0129] Figure 22 This section introduces pulse waveforms with a hierarchical structure featuring nested pulses. Figure 22A series of single-phase pulses are shown, such as pulses (2200) having a pulse width / pulse duration w, with consecutive pulses separated by a time interval (2202) of duration t1 (sometimes also called a first time interval), and m1 consecutive pulses arranged to form a pulse group (2210) (sometimes also called a first pulse group). Furthermore, the waveform has m2 such pulse groups separated by a time interval (2212) of duration t2 (sometimes also called a second time interval). Figure 22 The set of m² such pulse groups, labeled (2220), constitutes the next level of the hierarchical structure, which may be referred to as a group and / or a third pulse group. The pulse width and time interval t1 between pulses can range from several microseconds to hundreds of microseconds, including all values ​​and subranges in between. In some embodiments, the time interval t2 can be at least three times larger than the time interval t1. In some embodiments, the ratio t2 / t1 can range from about 3 to about 300, including all values ​​and subranges in between.

[0130] Figure 23 The structure of the nested pulse hierarchy waveform is further illustrated. In this figure, a series of m1 pulses (individual pulses not shown) form a pulse group (2300) (e.g., the first pulse group). A series of m2 such groups, separated from the next group by an inter-group time interval (2310) of duration t2 (e.g., the second time interval), form a group 132 (e.g., the second pulse group). A series of m3 such groups, separated from the next group by a time interval (2312) of duration t3 (e.g., the third time interval), form the next level in the hierarchy, namely the supergroup (e.g., the third pulse group) labeled (2320) in the figure. In some embodiments, the time interval t3 may be at least thirty times larger than the time interval t2. In some embodiments, the time interval t3 may be at least fifty times larger than the time interval t2. In some embodiments, the ratio t3 / t2 may be in the range of about 30 to about 800, including all values ​​and subranges therebetween. The amplitude of a single voltage pulse in a pulse hierarchy structure can be any value in the range of 500 volts to 7,000 volts or higher, including all values ​​and subranges in between.

[0131] Figure 24Examples of biphase waveform sequences with a hierarchical structure are provided. In the example shown in the figure, a biphase pulse such as (2400) has a positive voltage portion and a negative voltage portion to complete one cycle of the pulse. There is a time delay (2402) (e.g., a first time interval) between adjacent cycles of duration t1, and n1 such cycles form a pulse group (2410) (e.g., a first pulse group). A series of n2 such groups, separated from the next group by an inter-group time interval (2412) of duration t2 (e.g., a second time interval), form a group (2420) (e.g., a second pulse group). The figure also shows a second group (2430) with a time delay (2432) of duration t3 (e.g., a third time interval) between them. More advanced hierarchical structures can also be formed, just like single-phase pulses. The amplitude of each pulse or the voltage amplitude of a biphase pulse can be any value in the range of 500 volts to 7,000 volts or higher, including all values ​​and subranges in between. The pulse width / pulse duration can range from nanoseconds or even sub-nanoseconds to tens of microseconds, while the delay t1 can range from zero to several microseconds. The inter-group time interval t2 can be at least ten times larger than the pulse width. In some embodiments, the time interval t3 can be at least about twenty times larger than the time interval t2. In some embodiments, the time interval t3 can be at least fifty times larger than the time interval t2.

[0132] The embodiments disclosed herein include waveforms structured as hierarchical waveforms, wherein the hierarchical waveforms include waveform elements / pulses at various levels of the hierarchical structure. Such as Figure 22 A single pulse in (2200) comprises the first stage of a hierarchical structure and has an associated pulse duration and a first time interval between consecutive pulses. Pulse groups or elements of the first-stage structure form the second stage of the hierarchical structure, such as... Figure 22 The pulse group / second pulse group (2210) in the middle. Among other parameters, those associated with the waveform are parameters such as the total duration of the second pulse group (not shown) describing the second-level structure / second pulse group, the total number of first-level elements / first pulse groups, and the second time interval between consecutive first-level elements. In some embodiments, the total duration of the second pulse group can be between about 20 microseconds and about 10 milliseconds, including all values ​​and subranges therebetween. The group, second pulse group, or elements of the second-level structure form the third level of the hierarchical structure, such as Figure 22The grouping / third pulse group (2220) in the diagram. Among other parameters, there are the total duration of the third pulse group (not shown), which describes the third-level structure / third pulse group, the total number of second-level elements / second pulse groups, and the third time interval between consecutive second-level elements. In some embodiments, the total duration of the third pulse group can be between about 60 microseconds and about 200 milliseconds, including all values ​​and subranges therebetween. The generally iterative or nested structure of the waveform can continue to more levels, such as a ten-level structure or more.

[0133] In some implementations, hierarchical waveforms with nested structures and time intervals, as described herein, can be used for irreversible electroporation ablation energy delivery, thus providing a good degree of control and selectivity for applications involving different tissue types. A suitable pulse generator can be used to generate various hierarchical waveforms. It should be understood that while individual single-phase and bi-phase waveforms are identified in the examples herein for clarity, it should be noted that combined waveforms in which some parts of the waveform hierarchy are single-phase while others are bi-phase can also be generated / implemented.

[0134] In some embodiments, the ablation pulse waveform described herein is applied during the refractory period of the cardiac cycle to avoid interruption of the heart's sinus rhythm. In some embodiments, a treatment method includes electrically pacing the heart with a cardiac stimulator to ensure that pacing capture establishes the periodicity and predictability of the cardiac cycle, and then defining a time window within the refractory period of the cardiac cycle in which one or more pulse ablation waveforms may be delivered. Figure 25 Examples of atrial and ventricular pacing application are shown (e.g., pacing leads or catheters located in the right atrium and right ventricle, respectively). Time is represented on the horizontal axis. Figure 25 This shows a series of ventricular pacing signals such as (2500) and (2510) and a series of atrial pacing signals (2520, 2530), as well as a series of ECG waveforms (2540, 2542) driven by the pacing signals. Figure 25 The thick arrows indicate the atrial refractory time window (2522) and ventricular refractory time window (2502) that respectively follow the atrial pacing signal (2522) and the ventricular pacing signal (2500). Figure 25 As shown, the duration is T r The common refractory time window (2550) can be defined as falling within both the atrial refractory time window (2522) and the ventricular refractory time window (2502). In some embodiments, an electroporation ablation waveform can be applied within the common refractory time window (2550). The start of the refractory time window (2522) is offset from the pacing signal (2500) by a time offset (2504), such as... Figure 25As shown. In some implementations, the time offset (2504) may be less than about 25 milliseconds. At the next heartbeat, a similarly defined common-response time window (2552) is the next time window available for applying the ablation waveform. In this way, the ablation waveform can be applied over a series of heartbeats, each heartbeat remaining within the common-response time window. In one implementation, each pulse group as defined above in the pulse waveform hierarchy can be applied over the heartbeats, such that for a given set of electrodes, a series of groups are applied over a series of heartbeats.

[0135] As used herein, the terms “about” and / or “approximately”, when used in conjunction with numerical values ​​and / or ranges, generally refer to those values ​​and / or ranges that are close to the listed values ​​and / or ranges. In some cases, the terms “about” and “approximately” may mean within ±10% of the stated value. For example, in some cases, “about 100 [units]” may mean within 100 ± 10% (e.g., 90 to 110). The terms “about” and “approximately” are used interchangeably.

[0136] Some embodiments described herein relate to computer storage products having a non-transitory computer-readable medium (also referred to as a non-transitory processor-readable medium) having instructions or computer code thereon for performing operations of various computer implementations. A computer-readable medium (or processor-readable medium) is non-transitory in the sense that it does not itself include transient propagation signals (e.g., propagating electromagnetic waves carrying information over a transmission medium such as space or cable). The medium and computer code (also referred to as code or algorithm) can be those codes or algorithms designed and constructed for a specific purpose or objective. Examples of non-transitory computer-readable media include, but are not limited to: magnetic storage media such as hard disks, floppy disks, and magnetic tapes; optical storage media such as compact discs / digital video discs (CD / DVD), compact disc read-only memory (CD-ROM), and holographic devices; magneto-optical storage media such as optical discs; carrier signal processing modules; and hardware devices specifically configured to store and execute program code, such as application-specific integrated circuits (ASICs), programmable logic devices (PLDs), read-only memory (ROM), and random access memory (RAM) devices. Other embodiments described herein relate to computer program products that may include, for example, instructions and / or computer code disclosed herein.

[0137] The systems, apparatuses, and / or methods described herein may be implemented by software (executing on hardware), hardware, or a combination thereof. Hardware modules may include, for example, general-purpose processors (or microprocessors or microcontrollers), field-programmable gate arrays (FPGAs), and / or application-specific integrated circuits (ASICs). Software modules (executing on hardware) may be expressed in a variety of software languages ​​(e.g., computer code), including C, C++, Java®, Ruby, Visual Basic®, and / or other object-oriented, procedural, or other programming languages ​​and development tools. Examples of computer code include, but are not limited to, microcode or microinstructions, such as machine instructions generated by a compiler, code for generating web services, and files containing higher-level instructions executed by a computer using an interpreter. Additional examples of computer code include, but are not limited to, control signals, encryption code, and compression code.

[0138] The specific examples and descriptions in this document are exemplary in nature, and those skilled in the art can develop implementation schemes based on the materials taught herein without departing from the scope of the invention as defined only by the appended claims.

Claims

1. A system comprising: A signal generator configured to generate pulse waveforms; as well as An ablation device coupled to the signal generator and configured to receive the pulse waveform, the ablation device including a set of ridges, the ablation device being configured to deliver the pulse waveform to tissue via one or more of the set of ridges during use, each ridge including: A set of independently addressable electrodes, the set of electrodes being formed on the surface of each of the one or more ridges, each of the set of electrodes having an associated insulated electrical lead disposed in the body of each of the one or more ridges.

2. The system of claim 1, wherein the insulated electrical leads are configured to maintain a voltage potential of at least about 700 V without dielectric breakdown of the corresponding insulation.

3. The system of claim 1, further comprising a cardiac stimulator configured to generate a pacing signal for cardiac stimulation during use, the cardiac stimulator being communicatively coupled to the signal generator and further configured to transmit an indication of the pacing signal to the signal generator. The signal generator is further configured to generate the pulse waveform in synchronization with the indication of the pacing signal.

4. The system of claim 3, wherein the signal generator is further configured to generate the pulse waveform with a time offset relative to the indication of the pacing signal.

5. The system of claim 1, wherein the ablation device further comprises a distal cap configured to fasten the set of ridges to form a distal end of the ablation device.

6. The system of claim 1, wherein the ablation device further comprises a spine wire configured for electrically coupling the electrode between a pair of spines in the set of spines.

7. The system of claim 6, wherein the pair of ridges are adjacent to each other.

8. The system of claim 6, wherein the spine is the first spine in a set of spines, and each spine in the set of spines is coupled to an electrode between different pairs of spines in the set of spines.

9. The system of claim 8, wherein the set of ridge wires forms a continuous loop between the electrodes coupled thereto.

10. The system of claim 8, wherein the set of ridges is a first set of ridges coupling the electrodes on the set of ridges, and the ablation device further includes a second set of ridges coupling the electrodes on the set of ridges, the second set of ridges coupling electrodes on the set of ridges that are different from the first set of ridges.

11. The system of claim 10, wherein the first set of ridge wires forms a first continuous loop between the electrodes coupled thereto, and the second set of ridge wires forms a second continuous loop between the electrodes coupled thereto, the first continuous loop being electrically isolated from the second continuous loop.

12. The system of claim 8, wherein the first ridge filament of the set of ridge filaments is coupled to an electrode between the first ridge and the second ridge of the set of ridge filaments, and the second ridge filament of the set of ridge filaments is coupled to an electrode between the first ridge and the third ridge of the set of ridge filaments.

13. The system of claim 8, wherein the first ridge filament of the set of ridge filaments is coupled to an electrode between the first ridge and the second ridge of the set of ridge filaments, and the second ridge filament of the set of ridge filaments is coupled to an electrode between the third ridge and the fourth ridge of the set of ridge filaments.

14. The system according to claim 1, wherein the set of ridges comprises 3 to 20 ridges.

15. The system according to claim 1, wherein the set of electrodes comprises 2 to 64 electrodes.

16. The system of claim 1, wherein each electrode in the set of electrodes has approximately 0.5 mm. 2 Approximately 20 mm 2 Surface area.

17. The system of claim 1, wherein each ridge in the set of ridges has approximately 0.2 mm. 2 approximately 15 mm 2 The cross-sectional area.

18. The system of claim 1, wherein the set of ridges forms a delivery assembly at a distal portion of the ablation device, the delivery assembly being configured to transition between a first configuration and a second configuration, wherein in the first configuration the set of ridges bends radially outward from the longitudinal axis of the ablation device, and in the second configuration the set of ridges is arranged substantially parallel to the longitudinal axis of the ablation device.

19. The system of claim 18, wherein the delivery component has approximately 1 mm 2 approximately 25 mm 2 The maximum cross-sectional area.

20. The system of claim 18, further comprising a shank coupled to the set of ridges, the shank being configured to influence the transition of the set of ridges between the first configuration and the second configuration.

21. The system according to any one of claims 1-20, 22, 47 and 50-53, wherein the pulse waveform comprises: The first level of the hierarchical structure of the pulse waveform includes a first pulse group, each pulse having a pulse duration, and a first time interval separating consecutive pulses; The second level of the hierarchical structure of the pulse waveform includes a plurality of first pulse groups as second pulse groups, with a second time interval separating consecutive first pulse groups, the second time interval being at least three times the duration of the first time interval; and The third level of the hierarchical structure of the pulse waveform includes a plurality of second pulse groups as a third pulse group, and a third time interval separates the consecutive second pulse groups, the third time interval being at least thirty times the duration of the second level time interval.

22. The system of claim 1, wherein the set of ridges includes a first ridge and a second ridge adjacent to the first ridge, wherein the electrode of the first ridge is configured to be closer to the distal end of the ablation device than the electrode of the second ridge.

23. A method for treating atrial fibrillation by irreversible electroporation, comprising: Generate pulse waveforms; as well as The pulse waveform is delivered to the pulmonary vein orifice of the patient's heart via one or more of a set of ridges in the ablation device, each ridge comprising: A set of independently addressable electrodes is formed on the surface of the ridge, each electrode having an associated insulated electrical lead disposed in the body of the ridge.

24. The method of claim 23, further comprising placing the ablation device in the endocardial space of the left atrium of the heart and in contact with the pulmonary vein orifice.

25. The method of claim 23, wherein each insulated lead is configured to maintain a voltage potential of at least about 700V without dielectric breakdown of its corresponding insulation.

26. The method of claim 23, further comprising: Generate a pacing signal for cardiac stimulation of the heart; as well as The pacing signal is applied to the heart. The pulse waveform is generated synchronously with the pacing signal.

27. The method of claim 23, wherein the pulse waveform includes a time offset relative to the pacing signal.

28. The method of claim 23, wherein the set of ridges comprises a group of electrodes, the group of electrodes comprising the group of electrodes for each ridge in the set of ridges, the method further comprising: The first electrode in the group of electrodes is configured as the anode; The second electrode in the group of electrodes is configured as the cathode; as well as The pulse waveform is delivered to the first electrode and the second electrode.

29. The method of claim 23, further comprising: The first set of electrodes of the first ridge in the set of ridges is configured as the anode; The second set of electrodes of the second ridge in the set of ridges is configured as a cathode; as well as The pulse waveform is delivered to the first set of electrodes and the second set of electrodes.

30. The method according to claim 23, The ablation device includes a first set of ridge wires and a second set of ridge wires, each ridge wire being configured to electrically couple an electrode between a pair of ridges in the first set of ridge wires, and the second set of ridge wires coupling electrodes on the first set of ridge wires that are different from those on the first set of ridge wires. The first set of ridge wires forms a first continuous loop between the electrodes coupled thereto, and the second set of ridge wires forms a second continuous loop between the electrodes coupled thereto, wherein the first continuous loop and the second continuous loop are electrically isolated. The method further includes: The electrode coupled to the first continuous ring is configured as the anode; The electrode coupled to the second continuous ring is configured as a cathode; as well as The pulse waveform is delivered to the electrode coupled to the first continuous loop and the electrode coupled to the second continuous loop.

31. The method according to claim 23, The ablation device includes: A first ridge wire, the first ridge wire coupling the electrode between the first ridge and the second ridge in the set of ridges; as well as The second ridge wire couples the electrode between the first and third ridges in the set of ridges. The method further includes: The electrode coupled by the first ridge wire and the second ridge wire is configured as an anode or a cathode; as well as The pulse waveform is delivered to the electrode coupled by the first ridge filament and the second ridge filament.

32. The method according to claim 23, The ablation device includes: A first ridge wire, the first ridge wire coupling the electrode between the first ridge and the second ridge in the set of ridges; as well as The second ridge wire couples the electrode between the third and fourth ridges of the set of ridges. The method further includes: The electrode coupled by the first ridge wire is configured as the anode; The electrode coupled by the second ridge filament is configured as a cathode; and The pulse waveform is delivered to the electrode coupled by the first ridge filament and the second ridge filament.

33. The method of claim 23, wherein the set of ridges forms a delivery assembly at a distal portion of the ablation device, the delivery assembly being configured to transition between first configurations, in which the set of ridges bends radially outward from the longitudinal axis of the ablation device, the method further comprising: The delivery component in the first configuration is positioned to contact the pulmonary vein orifice; as well as The delivery component is converted to a second configuration before the pulse waveform is delivered.

34. The method according to any one of claims 23-33 and 48, wherein the pulse waveform comprises: The first level of the hierarchical structure of the pulse waveform includes a first pulse group, each pulse having a pulse duration, and a first time interval separating consecutive pulses; The second level of the hierarchical structure of the pulse waveform includes a plurality of first pulse groups as second pulse groups, with a second time interval separating consecutive first pulse groups, the second time interval being at least three times the duration of the first time interval; and The third level of the hierarchical structure of the pulse waveform includes a plurality of second pulse groups as a third pulse group, and a third time interval separates the consecutive second pulse groups, the third time interval being at least thirty times the duration of the second level time interval.

35. A system comprising: A signal generator configured to generate pulse waveforms; An ablation device coupled to the signal generator and configured to receive the pulse waveform, the ablation device including a set of electrodes configured to deliver the pulse waveform to tissue via the set of electrodes during use, each of the set of electrodes having an associated insulated lead, each insulated lead being configured to maintain a voltage potential of at least about 700 V without dielectric breakdown of its corresponding insulator; as well as A cardiac stimulator configured to generate a pacing signal for cardiac stimulation during use, the cardiac stimulator being communicatively coupled to the signal generator and further configured to transmit an indication of the pacing signal to the signal generator; The signal generator is further configured to generate the pulse waveform in synchronization with the indication of the pacing signal.

36. The system of claim 35, wherein the signal generator is further configured to generate the pulse waveform with a time offset relative to the indication of the pacing signal.

37. The system of claim 35, further comprising a guidewire including a non-linear distal portion, the ablation device being configured to be disposed on the guidewire during use.

38. The system of claim 35, wherein the ablation device includes a nonlinear distal portion having one or more electrodes from the set of electrodes disposed thereon.

39. The system according to any one of claims 35-38, wherein the pulse waveform comprises: The first level of the hierarchical structure of the pulse waveform includes a first pulse group, each pulse having a pulse duration, and a first time interval separating consecutive pulses; The second level of the hierarchical structure of the pulse waveform includes a plurality of first pulse groups as second pulse groups, with a second time interval separating consecutive first pulse groups, the second time interval being at least three times the duration of the first time interval; and The third level of the hierarchical structure of the pulse waveform includes a plurality of second pulse groups as a third pulse group, and a third time interval separates the consecutive second pulse groups, the third time interval being at least thirty times the duration of the second level time interval.

40. A system comprising: A signal generator configured to generate pulse waveforms; A guidewire coupled to the signal generator and configured to receive the pulse waveform, the guidewire including a proximal portion and a nonlinear distal portion, the nonlinear distal portion being configured to deliver the pulse waveform to tissue during use, the proximal portion having an associated insulator configured to maintain a voltage potential of at least about 700 V without dielectric breakdown; as well as A cardiac stimulator configured to generate a pacing signal for cardiac stimulation during use, the cardiac stimulator being communicatively coupled to the signal generator and further configured to transmit an indication of the pacing signal to the signal generator; The signal generator is further configured to generate the pulse waveform in synchronization with the indication of the pacing signal.

41. The system according to claim 40, wherein the pulse waveform comprises: The first level of the hierarchical structure of the pulse waveform includes a first pulse group, each pulse having a pulse duration, and a first time interval separating consecutive pulses; The second level of the hierarchical structure of the pulse waveform includes a plurality of first pulse groups as second pulse groups, with a second time interval separating consecutive first pulse groups, the second time interval being at least three times the duration of the first time interval; and The third level of the hierarchical structure of the pulse waveform includes a plurality of second pulse groups as a third pulse group, and a third time interval separates the consecutive second pulse groups, the third time interval being at least thirty times the duration of the second level time interval.

42. A system comprising: A signal generator configured to generate pulse waveforms; An ablation device coupled to the signal generator and configured to receive the pulse waveform, the ablation device including a set of electrical leads, each of the electrical leads having an associated insulator, each of the electrical leads being configured to form a loop at a distal portion of the ablation device, such that the ablation device includes a set of loops, each loop including a non-insulated portion as an electrode, such that the ablation device includes a set of electrodes located at the distal portion of the ablation device, the ablation device being configured to deliver the pulse waveform to tissue via the set of electrodes during use; as well as A cardiac stimulator configured to generate a pacing signal for cardiac stimulation during use, the cardiac stimulator being communicatively coupled to the signal generator and further configured to transmit an indication of the pacing signal to the signal generator; The signal generator is further configured to generate the pulse waveform in synchronization with the indication of the pacing signal.

43. The system of claim 42, wherein the set of rings at the distal portion of the ablation device is configured to deliver the pulse waveform to the tissue.

44. The system of claim 42, wherein each of the set of electrical leads is configured to maintain a voltage potential of at least about 700 V without dielectric breakdown of its corresponding insulation.

45. The system of claim 42, wherein the ablation device is further configured to deliver the pulse waveform to tissue via the set of electrodes during use by configuring a first electrode of the set of electrodes as an anode and a second electrode of the set of electrodes as a cathode.

46. ​​The method according to any one of claims 42-45, wherein the pulse waveform comprises: The first level of the hierarchical structure of the pulse waveform includes a first pulse group, each pulse having a pulse duration, and a first time interval separating consecutive pulses; The second level of the hierarchical structure of the pulse waveform includes a plurality of first pulse groups as second pulse groups, with a second time interval separating consecutive first pulse groups, the second time interval being at least three times the duration of the first time interval; and The third level of the hierarchical structure of the pulse waveform includes a plurality of second pulse groups as a third pulse group, and a third time interval separates the consecutive second pulse groups, the third time interval being at least thirty times the duration of the second level time interval.

47. The system of claim 1, wherein the set of ridges is present in the distal portion of the ablation device, and the electrical leads of at least two of the electrodes in the set of electrodes are electrically coupled in or near the proximal portion of the ablation device.

48. The method of claim 23, wherein the set of ridges is present in the distal portion of the ablation device, wherein the electrical leads of at least two of the electrodes in the set of electrodes are electrically coupled in or near the proximal portion of the ablation device.

49. A system comprising: A signal generator configured to generate pulse waveforms; as well as An ablation device coupled to the signal generator and configured to receive the pulse waveform, the ablation device including a set of ridges, the ablation device being configured to deliver the pulse waveform to tissue via one or more of the set of ridges during use, each ridge including: A set of independently addressable electrodes formed on the surface of each of the one or more ridges, each electrode having an associated insulated electrical lead disposed in the body of each of the one or more ridges, the set of ridges including a first ridge and a second ridge adjacent to the first ridge, wherein the electrode of the first ridge is positioned closer to the distal end of the ablation device relative to the electrode of the second ridge.

50. The system of claim 22, wherein the set of ridges forms an expansion structure during use, and wherein the cross-sectional area at a first plane of the expansion structure is different from the cross-sectional area at a second plane of the expansion structure.

51. The system of claim 1, wherein the set of ridges forms an expansion structure during use, and wherein the cross-sectional area at a first plane of the expansion structure is different from the cross-sectional area at a second plane of the expansion structure.

52. The system of claim 1, wherein the set of ridges forms an expansion structure during use, wherein at least one electrode of the set of electrodes or at least a portion thereof is disposed in the distal end plane of the expansion structure.

53. The system of claim 52, wherein the set of ridges converges at a point within the expansion structure at its distal end.

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