Systems, devices, and methods for delivery of pulsed electric field ablative energy to endocardial tissue

Abstract

To provide a system for ablating tissue through irreversible electroporation.SOLUTION: A system comprises: a signal generator configured for generating a pulse waveform: and an ablation device coupled to the signal generator and configured to receive the pulse waveform. The ablation device includes a set of leads, each lead of the set of leads having insulation associated therewith, each lead of the set of leads configured to form a loop at a distal portion such that the ablation device including a set of loops, each loop of the set of loops including an uninsulated portion as an electrode such that the ablation device includes a set of electrodes at the distal portion, the ablation device configured to deliver the pulse waveform to tissue during use via the set of electrodes.SELECTED DRAWING: Figure 5

Description

[Technical field]

[0001] The present disclosure relates to systems, devices, and methods for delivering pulsed electric field ablation energy to endocardial tissue. [Background technology]

[0002] The generation of pulsed electric fields for tissue therapy has been moving from laboratory to clinical applications for the past 20 years, but the effects of short pulses of high voltage and large electric fields on tissues have been investigated for over 40 years. The application of a short, high DC voltage to tissue can generate localized high electric fields, typically in the range of hundreds of V / cm, that disrupt cell membranes by generating pores in the membrane. The exact mechanism of this electrically driven pore generation or electroporation is still being investigated, but it is believed that the application of a large electric field for a relatively short period of time causes instability in the lipid bilayer of the cell membrane, resulting in the formation of localized voids or pores in the cell membrane. This electroporation can be irreversible if the electric field applied to the membrane is greater than a threshold value and the pores do not close but remain open, thereby allowing the exchange of biomolecular material across the membrane, resulting in necrosis and / or apoptosis (cell death). The surrounding tissue can then heal naturally.

[0003] Although pulsed DC voltage can facilitate electroporation under appropriate circumstances, an unmet need remains for a thin, flexible, atraumatic device that effectively delivers high DC voltage electroporative ablation therapy selectively to endocardial tissue in targeted areas while minimizing damage to healthy tissue. Summary of the Invention

[0004] Described herein are systems, devices, and methods for ablating tissue by irreversible electroporation. In general, a system for delivering a pulse waveform to tissue includes a signal generator configured to generate a pulse waveform and an ablation device coupled to the signal generator and configured to receive the pulse waveform. The ablation device may include a set of spines. The ablation device may be configured to deliver the pulse waveform to tissue during use via one or more spines of the set of spines. Each spine may include a set of independently addressable electrodes formed on a surface of the spine. Each electrode of the set of electrodes may have an insulated lead associated therewith. The insulated lead may be disposed on a respective body of the spine.

[0005] In some embodiments, the insulated lead wires can be configured to maintain a voltage potential of at least about 700V without breakdown of the corresponding insulation. The system can further include a cardiac stimulation device configured to generate a pacing signal for cardiac stimulation during use. The cardiac stimulation device can 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 can be further configured to generate a pulse waveform in synchronization with the indication of the pacing signal. The signal generator can be further configured to generate a pulse waveform with a time offset relative to the indication of the pacing signal. The ablation device can further include a distal cap configured to tether the set of spines to form a distal end of the ablation device. The ablation device can further include a spine wire configured to electrically couple an electrode between a pair of spines of the set of spines. The pair of spines can be adjacent to one another. The spine wire can be a first spine wire of the set of spine wires. Each spine wire of the set of spine wires can couple an electrode between a different pair of spines of the set of spines. The set of spine wires can form a continuous loop between electrodes coupled thereto. The set of spine wires can be a first set of spine wires coupling electrodes across the set of spines. The ablation device can further include a second set of spine wires coupling electrodes across the set of spines. The second set of spine wires can couple different electrodes than the first set of spine wires across the set of spines. The first set of spine wires can form a first continuous loop between electrodes coupled thereto and the second set of spine wires can form a second continuous loop between electrodes coupled thereto. The first continuous loop can be electrically insulated from the second continuous loop. The first spine wire of the set of spine wires can couple electrodes between a first spine and a second spine of the set of spines. The second spine wire of the set of spine wires can couple electrodes between a first spine and a third spine of the set of spines.A first spine wire of the set of spine wires can couple an electrode between a first spine and a second spine of the set of spines, and a second spine wire of the set of spine wires can couple an electrode between a third spine and a fourth spine of the set of spines.

[0006] In some embodiments, the electrodes can be electrically connected together (so that they are at the same potential) at the proximal portion of the shaft of the device or in the device handle. In these embodiments, the electrical connection between the electrodes can be similar to the variants described herein. For example, a loop of electrodes at the same potential can be formed, adjacent electrodes on adjacent spines can be at the same potential, or in general, a first set of electrodes on a spine can be maintained at the same potential as a second set of electrodes on a spine by appropriate electrical connections between leads in the proximal portion of the shaft of the device or in the device handle.

[0007] In some embodiments, the set of spines can include between 3 spines and 20 spines. The set of electrodes can include between 2 electrodes and 64 electrodes. Each electrode in the set of electrodes is about 0.5 mm 2 ~about 20mm 2 Each spine in the set of spines can have a surface area of ​​about 0.2 mm 2 ~about 15mm 2 The set of spines can form a delivery assembly at a distal portion of the ablation device. The delivery assembly can be configured to transform between a first configuration in which the set of spines bend radially outward from the longitudinal axis of the ablation device, and a second configuration in which the set of spines are generally disposed generally parallel to the longitudinal axis of the ablation device. The delivery assembly can have a cross-sectional area of ​​about 1 mm. 2 ~about 25mm 2The system may further include a handle coupled to the set of spines. The handle may be configured to affect deformation of the set of spines between a first configuration and a second configuration. The set of spines may include a first spine and a second spine adjacent to the first spine. The electrode of the first spine may be located closer to the distal end of the ablation device relative to the electrode of the second spine. The set of spines may be present at a distal portion of the ablation device. At least two electrode leads of the set of electrodes may be electrically coupled to or near a proximal portion of the ablation device.

[0008] In some embodiments, the set of spines can form an expanded structure during use. A cross-sectional area of ​​the expanded structure in a first plane can be different from a cross-sectional area of ​​the expanded structure in a second plane. At least one electrode of the set of electrodes, or at least a portion thereof, can be disposed on a distal end surface of the expanded structure. The set of spines can converge to their distal ends at a point inside the expanded structure.

[0009] In some embodiments, the pulse waveform may include a first level hierarchy of pulse waveforms including pulses. Each pulse may have a pulse duration and a first time interval separating successive pulses. A second level hierarchy of pulse waveforms includes a plurality of first pulses as a set of second pulses and a second time interval separating successive sets of second pulses. The second time interval may be at least three times the duration of the first time interval. A third level hierarchy of pulse waveforms includes a plurality of second pulses as a set of third pulses and a third time interval separating successive sets of third pulses. The third time interval may be at least 30 times the duration of the second level time interval.

[0010] Also described herein are methods for treating atrial fibrillation by irreversible electroporation. In general, these methods include generating a pulse waveform and delivering the pulse waveform to a pulmonary vein ostium of a patient's heart via one or more spines of a set of spines of an ablation device. Each spine may include a set of independently addressable electrodes formed on a surface of the spine. Each electrode of the set of electrodes may have an insulated lead associated therewith. The insulated lead may be disposed on the body of the spine.

[0011] In some embodiments, the ablation device can be positioned in the endocardial space of the left atrium of the heart and in contact with the ostium of a pulmonary vein. Each insulated lead can be configured to maintain a voltage potential of at least about 700V without breakdown of the corresponding insulation. A pacing signal can be generated for cardiac stimulation of the heart. The pacing signal can be applied to the heart and a pulse waveform is generated synchronously to the pacing signal. The pulse waveform can include a time offset relative to the pacing signal, such offset being understood to be encompassed by the term "synchronization" as used herein. The set of electrodes of the spines can include a set of electrodes for each spine of the set of spines. The method can further include configuring a first electrode of the set of electrodes as an anode and a second electrode of the set of electrodes as a cathode, and delivering the pulse waveform to the first electrode and the second electrode.

[0012] In some embodiments, the method may further include configuring a first set of electrodes of a first spine of the set of spines as an anode and a second set of electrodes of a second spine of the set of spines 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 spine wires and a second set of spine wires. Each spine wire may be configured to electrically couple an electrode between a pair of spines of the set of spines. The second set of spine wires may couple a different electrode to the first set of spine wires across the set of spines. The first set of spine wires may form a first continuous loop between the electrodes that are coupled, and the second set of spine wires may form a second continuous loop between the electrodes that are coupled. The first continuous loop may be electrically isolated from the second continuous loop. The method may further include configuring an electrode coupled to the first continuous loop as an anode and an electrode coupled to the second continuous loop as a cathode, and delivering a pulse waveform to the electrode coupled to the first continuous loop and the electrode coupled to the second continuous loop.

[0013] In some embodiments, the spine wires, or the first and second sets of spine wires, can be replaced by an electrical connection between appropriate leads (so that they are at the same potential) in the proximal portion of the shaft of the device or in the handle of the device. In these embodiments, the electrical connection between the electrodes can be similar to the variants described above. For example, by forming a loop of electrodes at the same potential, or by having adjacent electrodes on adjacent spines at the same potential, the first set of electrodes on the spines can generally be maintained at the same potential as the second set of electrodes on the spines by an appropriate electrical connection between the leads in the proximal portion of the shaft of the device or in the handle of the device.

[0014] In some embodiments, the ablation device may further include a first spine wire connecting an electrode between the first spine and the second spine of the set of spines. The second spine wire may connect an electrode between the first spine and the third spine of the set of spines. The method may further include configuring the electrode connected by the first spine wire and the second spine wire as an anode or a cathode and delivering a pulse waveform to the electrode connected by the first spine wire and the second spine wire. The ablation device may further include a first spine wire connecting an electrode between the first spine and the second spine of the set of spines. The second spine wire may connect an electrode between the third spine and the fourth spine of the set of spines. The method may further include configuring the electrodes connected by the first spine wire as anodes and the electrodes connected by the second spine wire as cathodes, and delivering a pulse waveform to the anodes and cathodes. In some embodiments, the spine wires, or the first and second spine wires, may be replaced by electrical connections between appropriate leads (so that they are at the same electrical potential) in the proximal portion of the shaft of the device or in the handle of the device. In these embodiments, the electrical connections between the electrodes may be similar to the variants described above, and the method may further include configuring the first set of electrically connected electrodes as anodes and the second set of electrically connected electrodes as cathodes, and delivering a pulse waveform to the anodes and cathodes.

[0015] The set of spines can form a delivery assembly at a distal portion of the ablation device. The delivery assembly can be configured to transform between a first configuration in which the set of spines bend radially outward from a longitudinal axis of the ablation device. The method can further include placing the delivery assembly in the first configuration in contact with a pulmonary vein ostium and transforming the delivery assembly to a second configuration prior to delivering the pulse waveform. The set of spines can be present at the distal portion of the ablation device. At least two electrode leads of the set of electrodes can be electrically coupled to or near a proximal portion of the ablation device.

[0016] In some embodiments, the pulse waveforms can include a first level hierarchy of pulse waveforms that includes a set of first pulses. Each pulse can have a pulse duration and a first time interval separating successive pulses. A second level hierarchy of pulse waveforms can include a plurality of the first set of pulses as a set of second pulses. A second time interval can separate successive sets of first pulses. The second time interval can be at least three times the duration of the first time interval. A third level hierarchy of pulse waveforms can include a plurality of the second set of pulses as a set of third pulses. A third time interval can separate successive sets of second pulses. The third time interval can be at least 30 times the duration of the second level time interval.

[0017] In some embodiments, a system for ablating tissue described herein can include a signal generator configured to generate a pulse waveform. The system also includes an ablation device coupled to the signal generator and configurable to deliver the pulse waveform to tissue. The ablation device can include a set of spines, and the ablation device can be configured to deliver the pulse waveform to tissue during use via one or more spines of the set of spines. Each spine can include a set of independently addressable electrodes formed on a surface of the spine. Each electrode of the set of electrodes can have an insulated lead associated therewith. The insulated lead can be disposed on the body of the spine.

[0018] In some embodiments, the 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 be 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 of the set of electrodes may have an insulated lead associated therewith. Each insulated lead may be configured to maintain a voltage potential of at least about 700V without breakdown of the corresponding insulation. In some embodiments, the system may further include a cardiac stimulation device configured to generate a pacing signal for cardiac stimulation during use. The cardiac stimulation device 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 in synchronization with the indication of the pacing signal.

[0019] In some embodiments, the signal generator may be further configured to generate a pulse waveform with a time offset relative to a representation of the pacing signal. In other embodiments, the system may further include a guidewire having a nonlinear distal portion. The ablation device may be configured to be disposed on the guidewire during use. In some other embodiments, the ablation device may include a nonlinear distal portion having one or more electrodes of the electrode set disposed thereon. The pulse waveform may include a first level hierarchy of pulse waveforms including pulses. Each pulse may have a pulse duration and a first time interval separating successive pulses. The second level hierarchy of pulse waveforms may include a plurality of the first pulse set as a second pulse set. A second time interval may separate successive first pulse sets. The second time interval may be at least three times the duration of the first time interval. The third level hierarchy of pulse waveforms may include a plurality of the second pulse set as a third pulse set. A third time interval may separate successive second pulse sets. The third time interval may be at least 30 times the duration of the second level time interval. In some embodiments, a system for delivering a pulse waveform to tissue may include a signal generator configured to generate a pulse waveform and a guidewire coupled to the signal generator and configured to receive the pulse waveform. The guidewire may include a proximal section and a nonlinear distal section. The nonlinear distal section may be configured to deliver the pulse waveform to tissue during use. The proximal section may have an insulator associated therewith, the insulator may be configured to maintain a voltage potential of at least about 700V without dielectric breakdown. In some embodiments, the system may further include a cardiac stimulation device configured to generate a pacing signal for cardiac stimulation during use. The cardiac stimulation device may be communicatively coupled to the signal generator and may be 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 in synchronization with the indication of the pacing signal. A first level hierarchy of pulse waveforms may include a set of pulses. Each pulse may have a pulse duration and a first time interval separating successive pulses. A second level hierarchy of pulse waveforms may include a plurality of first pulse sets as a second set of pulses. A second time interval may separate successive sets of first pulses. The second time interval may be at least three times the duration of the first time interval. A third level hierarchy of pulse waveforms may include a set of multiple second pulses as a set of third pulses. A third time interval may separate successive sets of second pulses. The third time interval may be at least 30 times the duration of the second level time interval.

[0020] In some embodiments, a system for delivering a pulse waveform to tissue can include a signal generator configured to generate a pulse waveform and an ablation device coupled to the signal generator. The ablation device can include a set of leads and be configured to receive the pulse waveform. Each lead of the set of leads can have insulation associated therewith. Each lead of the set of leads can 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 of the set of loops can have a non-insulated portion as an electrode, such that the ablation device includes a set of electrodes at a distal portion of the ablation device. The ablation device can be configured to deliver the pulse waveform to tissue via the set of electrodes during use. The system can further include a cardiac stimulation device configured to generate a pacing signal for cardiac stimulation during use. The cardiac stimulation device can 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 can be further configured to generate the pulse waveform in synchronization with the indication of the pacing signal.

[0021] In some embodiments, the set of loops in the distal portion of the ablation device may be configured to deliver a pulse waveform to tissue. In other embodiments, each lead of the set of leads may be configured to maintain a voltage potential of at least about 700V without breakdown of the corresponding insulation. In yet another embodiment, the ablation device is further configured to deliver a pulse waveform to tissue during use via the set of electrodes 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. The first level hierarchy of pulse waveforms may include a first set of pulses. Each pulse has a pulse duration and a first time interval separating successive pulses. The second level hierarchy of pulse waveforms may include a plurality of the first set of pulses as the second set of pulses. A second time interval may separate successive first sets of pulses. The second time interval may be at least three times the duration of the first time interval. The third level hierarchy of pulse waveforms may include a plurality of the second set of pulses as the third set of pulses. A third time interval may separate successive second sets of pulses. The third time interval may be at least 30 times the duration of the second level time interval.

[0022] In some embodiments, a system for delivering a pulse waveform to tissue may include a signal generator configured to generate a pulse waveform and an ablation device coupled to the signal generator and configured to receive the pulse waveform. The ablation device may include a set of spines. The ablation device may be configured to deliver a pulse waveform to tissue during use via one or more spines of the set of spines. Each spine may include a set of independently addressable electrodes formed on a surface of each of the one or more spines. Each electrode of the set of electrodes may have an insulated lead associated therewith. The insulated lead may be disposed on a respective body of the one or more spines. The set of spines may include a first spine and a second spine adjacent to the first spine. The electrode of the first spine may be disposed closer to a distal end of the ablation device relative to the electrode of the second spine. [Brief description of the drawings]

[0023] [Figure 1] FIG. 1 is a block diagram of an electroporation system according to an embodiment. [Diagram 2] FIG. 1 is a perspective view of an ablation catheter according to an embodiment. [Diagram 3] FIG. 13 is a perspective view of an ablation catheter according to another embodiment. [Figure 4] FIG. 13 is a perspective view of an ablation catheter according to another embodiment. [Diagram 5] FIG. 13 is a detailed perspective view of a distal portion of an ablation catheter according to another embodiment. [Figure 6] FIG. 13 is a side view of an ablation catheter according to another embodiment. [Figure 7] FIG. 13 is a side view of an ablation catheter according to another embodiment. [Figure 8] 8A and 8B are side and front cross-sectional views, respectively, of an ablation catheter according to another embodiment. [Figure 9A]FIG. 13 is a side view of an ablation catheter according to another embodiment. [Figure 9B] FIG. 13 is a side view of an ablation catheter according to another embodiment. [Figure 9C] FIG. 13 is a side view of an ablation catheter according to another embodiment. [Figure 9D] FIG. 13 is a side view of an ablation catheter according to another embodiment. [Figure 9E] FIG. 13 is a side view of an ablation catheter according to another embodiment. [Figure 10] FIG. 1 is a perspective view of a balloon ablation catheter positioned in the left atrium of the heart, according to another embodiment. [Figure 11] 1 is a cross-sectional view of a balloon ablation catheter positioned in the left atrium of the heart, according to another embodiment. [Figure 12] 12A-12B are schematic diagrams of a return electrode of an ablation system according to an embodiment. [Figure 13] 1 illustrates a method for ablation of tissue, according to an embodiment. [Figure 14] 1 illustrates a method for ablation of tissue, according to another embodiment. [Figure 15] 3 is a diagram of the ablation catheter shown in FIG. 2 positioned in the left atrium of the heart. [Figure 16] FIG. 4 is a diagram of the ablation catheter shown in FIG. 3 positioned in the left atrium of the heart. [Figure 17] FIG. 5 is a diagram of the two ablation catheters shown in FIG. 4 positioned in the left atrium of the heart. [Figure 18] FIG. 6 is a diagram of the ablation catheter shown in FIG. 5 positioned in the left atrium of the heart. [Figure 19A] FIG. 13 is a schematic perspective view of a set of electrodes placed at the ostium of a pulmonary vein, according to another embodiment. [Figure 19B] 13 is a schematic cross-sectional view of a set of electrodes positioned at the ostium of a pulmonary vein, according to another embodiment. [Figure 20A]FIG. 13 is a schematic perspective view of an electric field generated by electrodes placed at the ostium of a pulmonary vein, according to another embodiment. [Figure 20B] 11 is a schematic cross-sectional view of an electric field generated by an electrode placed at the ostium of a pulmonary vein, according to another embodiment; [Figure 21] 1 is an exemplary waveform illustrating a sequence of voltage pulses with a defined pulse width for each pulse, according to an embodiment. [Figure 22] 1 illustrates a schematic diagram of a hierarchy of pulses showing pulse widths, spacing between pulses, and pulse groups, according to an embodiment. [Diagram 23] 1 provides a schematic diagram of a nesting hierarchy of monophasic pulses displaying different levels of nesting hierarchy, according to an embodiment. [Figure 24] 1A-1C are schematic diagrams of nesting hierarchy of biphasic pulses showing different levels of nesting hierarchy, according to an embodiment. [Diagram 25] 1A-1C are schematic diagrams illustrating time sequences of electrocardiogram and cardiac pacing signals, together with atrial and ventricular refractory periods, showing the time window for irreversible electroporation ablation. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] Described herein are systems, devices, and methods for selectively and rapidly applying a pulsed electric field to ablate tissue by irreversible electroporation. In general, the systems, devices, and methods described herein can be used to generate high electric field strengths in desired target regions and reduce peak electric field values ​​elsewhere to reduce unwanted tissue damage and electrical arcing. The irreversible electroporation systems described herein can 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 device to deliver energy to the target region (e.g., ablation energy for a set of tissue at the ostium of a pulmonary vein). The pulse waveforms disclosed herein can aid in the therapeutic treatment of various cardiac arrhythmias (e.g., atrial fibrillation). One or more electrodes of the ablation device can have insulated leads configured to maintain a voltage potential of at least about 700V without breakdown of the corresponding insulation to deliver the pulse waveforms generated by the signal generator. The electrodes may be independently addressable such that each electrode can be controlled (e.g., to deliver energy) independently of any other electrodes of the device. In this manner, the electrodes can synergistically deliver different energy waveforms at different times for electroporation of tissue.

[0025] The term "electroporation" as used herein refers to the application of an electric field to a cell membrane, which changes the permeability of the cell membrane to the extracellular environment. The term "reversible electroporation" as used herein refers to the application of an electric field to a cell membrane, which temporarily changes the permeability of the cell membrane to the extracellular environment. For example, a cell undergoing reversible electroporation may temporarily and / or intermittently form one or more pores in the cell membrane that close upon removal of the electric field. The term "irreversible electroporation" as used herein refers to the application of an electric field to a cell membrane, which permanently changes the permeability of the cell membrane to the extracellular environment. For example, a cell undergoing irreversible electroporation may temporarily and / or intermittently form one or more pores in the cell membrane that persist when the electric field is removed.

[0026] The pulse waveforms for electroporation energy delivery disclosed herein can improve the safety, efficiency and effectiveness of energy delivery to tissue by lowering the threshold of the electric field associated with irreversible electroporation, thereby reducing the total energy delivered and providing more effective lesion ablation. In some embodiments, the voltage pulse waveforms disclosed herein can be hierarchical and can have a nested structure. For example, the pulse waveforms can include a hierarchical grouping of pulses having related time scales. In some embodiments, the methods, systems, and devices disclosed herein can include one or more of the methods, systems, and devices 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.

[0027] In some embodiments, the system may further include a cardiac stimulation device, which is used to synchronize the generation of the pulse waveform with the paced heartbeat. The cardiac stimulation device may electrically pace the heart with the cardiac stimulation device, reliably capturing the pacing to establish periodicity and predictability of the cardiac cycle. A time window within the refractory period of the periodic cardiac cycle may be selected for the voltage pulse waveform delivery. Thus, the voltage pulse waveform may be delivered during the refractory period of the cardiac cycle to avoid interruption of the sinus rhythm of the heart. In some embodiments, the ablation device may include one or more catheters, guidewires, balloons, and electrodes. The ablation device may be transformed into different configurations (e.g., compact and expanded) to place the device in the endocardial space. In some embodiments, the system may optionally include one or more return electrodes.

[0028] In general, to ablate tissue, one or more catheters can be advanced in a minimally invasive manner through the vasculature to a target location. In cardiac applications, electrodes that deliver a voltage pulse waveform can be located on an epicardial or endocardial device. The methods described herein can include introducing a device into the endocardial space of the left atrium of the heart and placing the device in contact with a pulmonary vein ostium. A pulse waveform can be generated and delivered to one or more electrodes of the device to ablate tissue. In some embodiments, the pulse waveform can be generated synchronously with a cardiac pacing signal to avoid interruption of the cardiac sinus rhythm. In some embodiments, the electrodes can be configured with an anode-cathode subset. The pulse waveform can include hierarchical waveforms to aid in ablation of tissue and reduce damage to healthy tissue.

[0029] I. System overview Disclosed herein are systems and devices configured for tissue ablation by selectively and rapidly applying a voltage pulse waveform to assist in tissue ablation, resulting in irreversible electroporation. In general, 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 devices may be placed epicardially and / or endocardially to treat atrial fibrillation. Voltage may be applied to a selected subset of electrodes with independent subset selection to select anode and cathode electrodes. A pacing signal for cardiac stimulation may be generated and used to generate a pulse waveform by a signal generator synchronized with the pacing signal.

[0030] In general, the systems and devices described herein include one or more catheters configured to ablate tissue in the left atrium of the heart. FIG. 1 illustrates an ablation system (100) configured to deliver a voltage pulse waveform. The system (100) may include an instrument (120) including a signal generator (122), a processor (124), a memory (126), and a cardiac stimulation device (128). The instrument (120) may be coupled to an ablation device (110), and an optional pacing device (130) and / or an optional return electrode (140) (e.g., a return pad shown therein in dotted lines).

[0031] The signal generator (122) can be configured to generate a pulse waveform for irreversible electroporation of tissue, such as the ostium of a pulmonary vein. For example, the signal generator (122) can be a voltage pulse waveform generator and can deliver a pulse waveform to the ablation device (110). The return electrode (140) can be coupled to the patient (e.g., positioned on the patient's back) to allow current to pass from the ablation device (110) through the patient and then to the return electrode (140) to provide a safe current return path (not shown) from the patient. The processor (124) can incorporate data received from the memory (126), the cardiac stimulation device (128), and the pacing device (130) to determine parameters (e.g., amplitude, width, duty cycle, etc.) of the pulse 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 for pulse waveform generation and / or cardiac pacing synchronization. For example, the memory (126) may be configured to store pulse waveform and / or cardiac pacing data for pulse waveform generation and / or cardiac pacing, respectively.

[0032] In some embodiments, the ablation device (110) may include a catheter configured to receive and / or deliver pulsed waveforms, as described in more detail below. For example, the ablation device (110) may be positioned to be introduced into the endocardial space of the left atrium, position one or more electrodes (112) at one or more pulmonary vein ostia, and then deliver a pulsed waveform 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 700V without breakdown of the corresponding insulation. In some embodiments, the insulation of each lead may be capable of maintaining a potential difference across its thickness of about 200V to about 1,500V without breakdown. For example, the electrodes (112) may be grouped into one or more anode-cathode subsets, such as, for example, 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, or a subset including three anodes and two cathodes.

[0033] The pacing device (130) is suitably coupled to a patient (not shown) and configured to receive a cardiac pacing signal generated by a cardiac stimulating device (128) of the instrument (120) for cardiac stimulation. A representation of the pacing signal can be transmitted by the cardiac stimulating device (128) to the signal generator (122). Based on the pacing signal, a representation of a voltage pulse waveform can be selected, calculated, and / or otherwise identified by the processor (124) and generated by the signal generator (122). In some embodiments, the signal generator (122) is configured to generate a pulse waveform in synchronization with a representation of the pacing signal (e.g., within a common refractory window). For example, in some embodiments, the common refractory window can begin substantially immediately (or only slightly after) the ventricular pacing signal and then last for a duration of about 130 ms or less. In such embodiments, the entire pulse waveform may be delivered within this duration.

[0034] The processor (124) may be any suitable processing device configured to operate and / or execute a set of instructions or code. The processor may 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 may be configured to operate and / or execute application processes and / or other modules, processes and / or functions associated with the system and / or its associated network (not shown). The underlying device technology may comprise a variety of component types, for example, metal oxide semiconductor field effect transistor (MOSFET) technology such as complementary metal oxide semiconductor (CMOS), bipolar technology such as emitter coupled logic (ECL), polymer technology (e.g., silicon conjugated polymer-metal structures, and metal conjugated polymer-metal structures), mixed analog and digital, etc.

[0035] The memory (126) may include a database (not shown) and may be, for example, a random access memory (RAM), a memory buffer, a hard drive, an erasable programmable read only memory (EPROM), an electrically erasable programmable 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 generating pulse waveforms and / or cardiac pacing.

[0036] The system (100) can communicate with other devices (not shown), for example, through one or more networks, each of which may be any type of network. A wireless network can refer to any type of digital network that is not connected by any type of cable. However, a wireless network can be connected to a wired network to interface with the Internet, other carrier voice and data networks, business networks, and personal networks. Wired networks are typically transmitted over copper twisted pair cables, coaxial cables, or fiber optic cables. There are many types of wired networks, examples of which include wide area networks (WANs), metropolitan area networks (MANs), local area networks (LANs), campus area networks (CANs), global area networks (GANs) such as the Internet, and virtual private networks (VPNs). In the following, a network refers to any combination of combined wireless, wired, public, and private data networks that are typically interconnected via the Internet to provide an integrated networking and information access solution.

[0037] Ablation Device The systems described herein may include one or more multi-electrode ablation devices configured to ablate tissue in the left atrium of the heart to treat atrial fibrillation. FIG. 2 is a perspective view of an ablation device (200) (e.g., structurally and / or functionally similar to ablation device (110)) including a catheter (210) and a guidewire (220) slidable within a cavity 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 over the guidewire (220) during use. The distal portion (222) of the guidewire (220) may be shaped to aid in positioning the catheter (210) within the cavity of the patient. For example, the shape of the distal portion (222) of the guidewire (220) may be configured for positioning at and / or near the ostium of a pulmonary vein, as described in more detail with respect to FIG. 15. The distal portion (222) of the guidewire (220) can include and / or be formed with an atraumatic shape that reduces trauma to tissue (e.g., prevents and / or reduces the possibility of tissue puncture). For example, the distal portion (222) of the guidewire (220) can include a non-linear shape, such as a circle, a loop (as shown in FIG. 2), an ellipsoid, or any other geometric shape. In some embodiments, the guidewire (220) can be configured to be elastic such that the guidewire having a non-linear shape can conform to the lumen of the catheter (210) when placed within the catheter (210) and the non-linear shape can reform / otherwise return upon advancement from the catheter (210). In other embodiments, the catheter (210) can be similarly configured to be elastic to aid in advancing the catheter (210) through a sheath (not shown). The shaped distal portion (222) of the guidewire (220) can be angled relative to the guidewire (220) and other portions of the catheter (210). The catheter 210 and guidewire 220 can be sized for advancement into an endocardial cavity (e.g., the left atrium). The diameter of the shaped distal portion 222 of the guidewire 220 can be approximately the same as the diameter of the cavity in which the catheter 230 is to be placed.

[0038] The catheter (210) can be slidably advanced over the guidewire (220) so that it is positioned over the guidewire (220) during use. A distal portion (222) of the guidewire (220) positioned in the cavity (e.g., near the pulmonary vein ostium) can serve as a backstop for advancing the distal portion of the catheter (210). The distal portion of the catheter (210) can include a set of electrodes (e.g., structurally and / or functionally similar to the electrode(s) (112)) configured to contact the inner diameter surface of the cavity (pulmonary vein ostium). For example, the electrodes (212) can include a generally circular electrode arrangement configured to contact the pulmonary vein ostium. As shown in FIG. 2, the one or more electrodes (212) can include a series of metal bands or rings positioned along the catheter shaft and electrically connected together. For example, the ablation device (200) can include a single electrode with multiple bands, one or more electrodes, each with its own band, and combinations thereof. In some embodiments, the electrodes (212) can be shaped to match the shape of the distal portion (222) of the guidewire (220). The catheter shaft can include a flexible section between the electrodes to increase flexibility. In other embodiments, one or more of the electrodes (212) can include a helical winding to increase flexibility.

[0039] Each of the electrodes of the ablation devices discussed herein may be connected to an insulated lead (not shown) that leads to a handle (not shown) that is coupled to the proximal portion of the catheter. The insulation of each lead may be capable of sustaining a potential difference of at least 700V across its thickness without dielectric breakdown. In other embodiments, the insulation of each lead may be capable of sustaining a potential difference of about 200V to about 2000V across its thickness, including all values ​​and subranges therebetween, without dielectric breakdown. This allows the electrodes to effectively deliver electrical energy and cauterize tissue by irreversible electroporation. The electrodes may receive a pulsed waveform generated by a signal generator (122), for example, as described above with respect to FIG. 1. In other embodiments, the guidewire (220) may be separate from the ablation device (200) (e.g., the ablation device (200) includes a catheter (210) but does not include a guidewire (220)). For example, guidewire (220) may itself be advanced into the endocardial space, and then catheter (210) may be advanced over guidewire (220) into the endocardial space.

[0040] FIG. 3 is a perspective view of another embodiment of an ablation device (300) (e.g., structurally and / or functionally similar to ablation device (110)) including a catheter (310) having a set of electrodes (314) disposed along a distal portion (312) of the catheter (310). The distal portion (312) of the catheter (310) may be non-linear and form a generally circular shape. The set of electrodes (314) may be disposed along the non-linear distal portion (312) of the catheter (310) to form a generally circular array of electrodes (314). In use, the electrodes (314) may be positioned at the ostium of a pulmonary vein to deliver a pulsed waveform to ablate tissue, as described in more detail with respect to FIG. 16. The shaped distal portion (312) of the catheter (310) may be angled relative to the remainder of the catheter (310). For example, the distal portion (312) of the catheter (310) may be approximately perpendicular to the adjacent portion 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 pull wires (not shown)) configured to change the shape of the distal portion (312) of the catheter (310). For example, manipulation of the pull wires 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 the electrode (314) to be positioned near and / or in contact with (e.g., the inner diameter surface of) the ostium of a pulmonary vein. The electrode (314) may include a series of metal bands or rings and may be independently addressable.

[0041] In some embodiments, the pulse waveforms may be applied between electrodes (314) configured in an anode and cathode set. For example, adjacent or approximately diametrically opposed pairs of electrodes may be operated together as an anode-cathode set. It should be understood that any of the pulse waveforms disclosed herein may be applied incrementally or sequentially across a series of anode-cathode electrodes.

[0042] FIG. 4 is a perspective view of yet another embodiment of an ablation device (400) (e.g., structurally and / or functionally similar to ablation device (110)) including a catheter (410) and a guidewire (420) having a shaped, non-linear distal portion (422). The guidewire (420) may be slidable within a lumen of the catheter (410). The guidewire (420) advances through a lumen of the catheter (410), and the distal portion (422) of the guidewire (420) may be substantially circular. The shape and / or diameter of the distal portion (422) of the guidewire (420) may be altered using a bending mechanism as described above with respect to FIG. 3. The catheter (410) may be flexible so that it can flex. In some embodiments, the catheter (410) and / or the guidewire (420) may be configured to be resilient so that they conform to the lumen in which they are located and assume a secondary shape as they advance out of the lumen. By varying 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 ostium of a pulmonary vein. The distal end (412) of the catheter (410) can be sealed except where the guidewire (420) begins to extend, allowing the catheter (410) to electrically insulate a 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) can include a seal having an opening that allows the guidewire (420) to pass therethrough upon application of a force that forms a compressive hold (which can be liquid-tight) between the seal and the guidewire (420).

[0043] In some embodiments, the exposed distal portion (422) of the guidewire (420) can be coupled to an electrode and configured to receive a pulse waveform from a signal generator and deliver the pulse waveform to tissue during use. For example, the proximal end of the guidewire (420) can be coupled to a suitable lead and connected to the signal generator (122) of FIG. 1. The distal portion (422) of the guidewire (420) can be sized to be placed at the ostium of a pulmonary vein. For example, the diameter of the shaped distal portion (422) of the guidewire (420) can be approximately the same as the diameter of the ostium of a pulmonary vein. The shaped distal portion (422) of the guidewire (420) can be angled relative to the rest of the guidewire (420) and the catheter (410).

[0044] 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 for delivery of a voltage pulse waveform. Platinum is radiopaque and may be used to increase flexibility to aid in the advancement and positioning of the ablation device (400) within the endocardial space.

[0045] FIG. 5 is a detailed perspective view of a petal-shaped distal portion of an ablation device (500) (e.g., structurally and / or functionally similar to ablation device (110)) that includes a set of electrodes (520, 522, 524, 526), ​​each extending from a pair of insulated lead segments (510, 512, 514, 516). Each pair of adjacent insulated lead segments coupled to a non-insulated electrode (e.g., lead segment (510, 512) and electrode (526)) forms a loop (FIG. 5 shows a set of four loops). The set of loops at the distal portion of the ablation device (500) can be configured to deliver a pulse waveform to tissue. The ablation device (500) can include a set of insulated lead segments (510, 512, 514, 516) that branch off at the distal end of the device (500) and connect to respective exposed electrodes (520, 522, 524, 526) as shown in FIG. 5. The electrodes (520, 522, 524, 526) can include exposed portions of electrical conductors. In some embodiments, one or more of the electrodes (520, 522, 524, 526) can include platinum coils. One or more of the segments (510, 512, 514, 516) can be coupled to a bending mechanism (e.g., struts, pull wires, etc.) controlled from a handle (not shown) to control the size and / or shape of the distal portion of the device (500).

[0046] The electrodes (520, 522, 524, 526) can be flexible and form a compact first configuration for advancement into an endocardial cavity, such as adjacent a pulmonary vein ostium. Once positioned in a desired location, the electrodes (520, 522, 524, 526) can be deformed to an expanded second shape upon advancement out of a cavity, such as a sheath, to form a flower-shaped distal portion, as shown in FIG. 5. In other embodiments, the insulated lead segments (510, 512, 514, 516) and the electrodes (520, 522, 524, 526) can be biased (e.g., spring open) to expand outwardly into the second configuration upon advancement out of a cavity (e.g., a sheath) carrying the device (500). The electrodes (520, 522, 524, 526) can be independently addressable, each having an insulated lead configured to maintain a voltage potential of at least about 700V without breakdown of the corresponding insulation. In other embodiments, the insulation of each lead is capable of sustaining a potential difference of about 200V to about 2000V across its thickness without breakdown.

[0047] In some embodiments, the ablation device (5000) can be configured to deliver a pulsed waveform to tissue during use via the set of electrodes (520, 522, 524, 526). In some embodiments, the pulsed waveform may be applied between the electrodes (520, 522, 524, 526) configured in an anode and cathode set. For example, a pair of electrodes that are approximately diametrically opposed (e.g., electrodes (520, 524) and (522, 526)) may be operated together as an anode-cathode pair. In other embodiments, adjacent electrodes may be configured as an anode-cathode pair. By way of example, a first electrode (520) of a set of electrodes may be configured as an anode and a second electrode (522) may be configured as a cathode.

[0048] 6-9E illustrate additional embodiments of ablation devices (e.g., structurally and / or functionally similar to ablation device (110)) that can be configured to deliver a voltage pulse waveform using a set of electrodes to cauterize tissue and electrically isolate a pulmonary vein. In some of these embodiments, the ablation device can be transformed from a first configuration to a second configuration, causing the electrodes of the ablation device to expand outwardly into contact with a cavity in the tissue (e.g., the ostium of a pulmonary vein).

[0049] 6 is a side view of an embodiment of an ablation device (600) including a catheter shaft (610) at a proximal end of the device (600), a distal cap (612) of the device (600), and a set of spines (614) coupled thereto. The distal cap (612) may include an atraumatic shape to reduce trauma to tissue. A proximal end of the set of spines (614) may be coupled to a distal end of the catheter shaft (610), and a distal end of the set of spines (614) may be tethered to the distal cap (612) of the device (600). The ablation device (600) may be configured to deliver a pulsed waveform to tissue via one or more spines of the set of spines (614) during use.

[0050] Each spine (614) of the ablation device (600) can include one or more independently addressable electrodes (616) formed on the surface of the spine (614). Each electrode (616) can include an insulated lead configured to maintain a voltage potential of at least about 700V without breakdown of the corresponding insulator. In other embodiments, the insulator of each lead can maintain a potential difference of about 200V to about 2000V across its thickness without breakdown. Each spine (614) can include an insulated lead for each electrode (616) formed within the body of the spine (614) (e.g., within a cavity of the spine (614)). FIG. 6 illustrates a set of spines (614) where each spine (614) includes a pair of electrodes (616) having approximately the same size, shape, and spacing as the electrodes (616) of the adjacent spine (614). In other embodiments, the size, shape, and spacing of the electrodes (616) can be different.

[0051] For each of the ablation devices described herein, and for the ablation devices depicted in Figures 6-9 in particular, each spine of the set of spines can include a flexible curvature. The minimum radius of curvature of the spines can range from about 1 cm or greater. For example, the set of spines can be configured to form a delivery assembly at the distal portion of the ablation device and to transform between a first configuration in which the set of spines bend radially outward from the longitudinal axis of the ablation device, and a second configuration in which the set of spines are disposed generally parallel to the longitudinal axis of the ablation device. In this manner, the spines can more easily conform to the geometry of the endocardial cavity. In general, the "basket" of spines can have an asymmetric shape along the entire length of the shaft such that one end of the basket (e.g., the distal end) is more bulbous than the other end of the basket (e.g., the proximal end). The delivery assembly can be placed in a first configuration in contact with the pulmonary vein ostium and transformed to a second configuration prior to delivery of the pulse waveform. In some of these embodiments, a handle can be coupled to the set of spines, the handle configured to affect deformation of the set of spines between a first configuration and a second configuration. In some embodiments, the leads of at least two electrodes of the set of electrodes can be electrically coupled at or near a proximal portion of the ablation device, for example, in the handle.

[0052] In one embodiment, each electrode (616) of a spine (614) may be configured as an anode, and each electrode (616) of an adjacent spine (614) may be configured as a cathode. In another embodiment, the electrodes (616) of one spine may alternate between an anode and a cathode with the electrodes of an adjacent spine having the opposite configuration (e.g., cathode and anode). The ablation device (600) may include any number of spines, for example, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, or more spines, including subranges therebetween. In some embodiments, the ablation device (600) may include between 3 and 20 spines. For example, the ablation device (600) may include between 6 and 12 spines.

[0053] FIG. 7 is a side view of another embodiment of an ablation device (700) including a catheter shaft (710) at a proximal end of the device (700), a distal cap (712) of the device (700), and a set of spines (714) coupled thereto. The distal cap (712) can include an atraumatic shape. A proximal end of the set of spines (714) can be coupled to a distal end of the catheter shaft (710), and a distal end of the set of spines (714) can be tethered to the distal cap device (712) of the device (700). Each spine (714) of the ablation device (700) can include one or more independently addressable electrodes (716) formed on a surface of the spine (714). Each electrode (716) can include an insulated lead configured to maintain a voltage potential of at least about 700V without breakdown of the corresponding insulation. In other embodiments, the insulation of each lead can sustain a potential difference of about 200V to about 1500V across its thickness without dielectric breakdown. Each spine (714) can include an insulated lead for each electrode (716) formed in the body of the spine (714) (e.g., within a cavity of the spine (714)). The spine wire sets (718, 719) can be electrically conductive and can be electrically coupled to adjacent electrodes (716) disposed on different spines (714), such as electrodes (716) between a pair of spines (718, 719) of a spine set. For example, the spine wires (718, 719) can extend transversely to the longitudinal axis of the ablation device (700).

[0054] 7 shows a set of spines (714) where each spine (714) includes a pair of electrodes (716) having approximately the same size, shape, and spacing as the electrodes (716) of the adjacent spine (714). In other embodiments, the size, shape, and spacing of the electrodes (716) may be different. For example, the electrode (716) electrically coupled to a first spine wire (718) may be a different size and / or shape than the electrode (716) electrically coupled to a second spine wire (719).

[0055] In some embodiments, the first spine wire (718) can include a first set of spine wires (720, 721, 722, 723), where each spine wire in the set of spine wires (720, 721, 722, 723) can couple an electrode (716) between a different pair of spines in the set of spines (714). In some of these embodiments, the sets of spine wires (720, 721, 722, 723) can form a continuous loop between the electrodes (716) coupled thereto. Similarly, the second spine wire (719) can include a second set of spine wires (724, 725, 726), where each spine wire in the set of spine wires (724, 725, 726) can couple an electrode (716) across the set of spines (714). The second set of spine wires (724, 725, 726) can couple different electrodes (716) than the first set of spine wires (720, 721, 722, 723) across the set of spines (714). In some of these embodiments, the first set of spine wires (720, 721, 722, 723) can form a first continuous loop between the electrodes (716) coupled thereto, and the second set of spine wires (724, 725, 726) can form a second continuous loop between the electrodes (716) coupled thereto. The first continuous loop can be electrically isolated from the second continuous loop. In some of these embodiments, the electrode (716) coupled to the first continuous loop can be configured as an anode, and the electrode (716) coupled to the second continuous loop can 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, the spine wires such as 721, 722, 723 can be replaced by similar electrical connections in the proximal portion of the device (e.g., the handle of the device). For example, the electrodes 716 can all be electrically wired together in the handle of the device.

[0056] In another embodiment, a first spine wire (721) of the set of spine wires (720, 721, 722, 723) can couple an electrode (716) between a first spine (711) and a second spine (713) of the set of spines (714), and a second spine wire (720) of the set of spine wires (720, 721, 722, 723) can couple an electrode (716) between a first spine (711) and a third spine (715) of the set of spines (714). The electrodes (716) coupled by the first spine wire (721) and the second spine wire (720) can be configured as an anode and a cathode (or vice versa). In yet another embodiment, a first spine wire (721) of the set of spine wires (720, 721, 722, 723) can couple an electrode (716) between a first spine (711) and a second spine (713) of the set of spines (714), and a second spine wire (723) of the set of spines (720, 721, 722, 723) can couple an electrode (716) between a third spine (715) and a fourth spine (717) of the set of spines (714). A pulse waveform may be delivered to the electrode (716) coupled by the first spine wire (721) and the second spine wire (723). In some embodiments, instead of spine wires, at least two electrode leads of the set of electrodes are electrically coupled at or near a proximal portion of the ablation device, such as in a handle.

[0057] In other embodiments, one or more spine wires (718, 719) can form a continuous loop between the electrically coupled electrodes (716). For example, a first set of spine wires (718) can form a first continuous loop between the electrodes (716) coupled thereto, and a second set of spine wires (719) can form a second continuous loop between the electrodes (716) coupled thereto. In this case, the first continuous loop can be electrically isolated from the second continuous loop. In one embodiment, each of the electrodes (716) coupled to the first set of spine wires (718) can be configured as an anode, while each of the electrodes (716) coupled to the second set of spine wires (719) can be configured as a cathode. Each group of electrically coupled electrodes (716) can be independently addressable. In some embodiments, instead of spine wires, the leads of at least two electrodes of a set of electrodes are electrically coupled to or near the proximal portion of the ablation device, for example in the handle.

[0058] In some embodiments, as described in more detail below with respect to FIGS. 8A-8B, the spine 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 spine 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 spines, for example, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, or more spines. In some embodiments, the ablation device (700) can include 3-20 spines. For example, in one embodiment, the ablation device (700) can include 6-9 spines.

[0059] 8A-8B are side and front cross-sectional views, respectively, of an ablation catheter (800). FIG. 8A is a side view of an embodiment of an ablation device (800) including a catheter shaft (810) at a proximal end of the device (800), a distal cap (812) of the device (800), and a set of spines (814) coupled thereto. The distal cap (812) can include an atraumatic shape. A proximal end of the set of spines (814) can be coupled to a distal end of the catheter shaft (810), and a distal end of the set of spines (814) can be tethered to the distal cap device (812) of the device (800). Each spine (814) of the ablation device (800) can include one or more independently addressable electrodes (816, 818) formed on a surface of the spine (814). Each electrode (816, 818) can include an insulated lead configured to maintain a voltage potential of at least about 700V without breakdown of the corresponding insulation. In other embodiments, the insulation of each lead can maintain a potential difference of about 200V to about 2000V across its thickness, including all values ​​and subranges therebetween, without breakdown. Each spine (814) can include an insulated lead for each electrode (816, 818) formed in the body of the spine (814) (e.g., within the cavity of the spine (814)). One or more spine wires (817, 819) can be electrically conductive and electrically couple adjacent electrodes (816, 818) disposed on different spines (814). For example, the spine wires (817, 819) can extend transversely to the longitudinal axis of the ablation device (800).

[0060] FIG. 8B is a front cross-sectional view of FIG. 8A taken along line 8B-8B. Each spine wire (817, 819, 821, 823) electrically couples a pair of adjacent electrodes (816, 818, 820, 822) of different spines. In some embodiments, each coupled electrode pair may be electrically insulated from one another. In some embodiments, the coupled electrode pairs may be configured with a common polarity. Adjacent pairs of electrodes may be configured with opposite polarities (e.g., a first electrode pair configured as an anode and an adjacent second electrode pair configured as a cathode). For example, the electrodes (816) coupled to the first set of spine wires (817) may be configured as an anode, while each of the electrodes (818) coupled to the second set of spine wires (819) may be configured as a cathode. In some embodiments, each electrode formed on a spine (814) may share a common polarity (e.g., configured as an anode or a cathode). Each linked electrode pair may be independently addressable. In some embodiments, the ablation device (800) may include an even number of spines. The ablation device (800) may include any number of spines, for example, 4, 6, 8, 10, or more spines. In some embodiments, the ablation device may include 4-10 spines. For example, in one embodiment, the ablation device may include 6-8 spines. As previously mentioned, in some embodiments, the spine wires such as 817, 819 may be replaced by similar electrical connections in the proximal portion of the device (e.g., the device handle). For example, the electrodes 816 may be electrically wired together in the device handle so that they are at the same electrical potential during ablation.

[0061] FIG. 9A is a side view of yet another embodiment of an ablation device (900) including a catheter shaft (910) at a proximal end of the device (900), a distal cap (912) of the device (900), and a set of spines (914) coupled thereto. The distal cap (912) can include an atraumatic shape. A proximal end of the set of spines (914) can be coupled to a distal end of the catheter shaft (910), and a distal end of the set of spines (914) can be tethered to the distal cap (912) of the device (900). Each spine (914) of the ablation device (900) can include one or more independently addressable electrodes (916, 918) formed on a surface of the spine (914). Each electrode (916, 918) can include an insulated lead configured to maintain a voltage potential of at least about 700V without breakdown of the corresponding insulation. In other embodiments, the insulation of each lead can sustain a potential difference of about 200V to about 2000V across its thickness without dielectric breakdown. Each spine (914) can include an insulated lead for each electrode (916, 918) formed in the body of the spine (914) (e.g., within the cavity of the spine (914)). Figure 9A shows a set of spines (914) in which each spine (914) includes an electrode (916, 918) that is spaced apart from the electrodes (916, 918) of adjacent spines (914). For example, the set of spines (914) may include a first spine (920) and a second spine (922) adjacent to the first spine (920), with the electrode (916) of the first spine (920) positioned closer to the distal end (912) of the ablation device (900) than the electrode (918) of the second spine (922). In other embodiments, the size and shape of the electrodes (916, 918) may also differ.

[0062] In some embodiments, adjacent distal electrode (916) and proximal electrode (918) can form an anode-cathode pair. For example, distal electrode (916) can be configured as an anode and proximal electrode (918) can be configured as a cathode. In some embodiments, the ablation device (900) can include 6-12 spines. In FIG. 9A, one electrode (916, 918) is formed on the surface of each spine (914) such that each spine (914) includes one insulated lead. Thus, the cavity of the spine (914) can be of smaller diameter, allowing the spine (914) to be thicker and more mechanically robust. Thus, dielectric breakdown of the insulation can be further reduced, thereby improving the reliability and lifespan of each spine (914) and the ablation device (900). The ablation device (900) may include any number of spines, e.g., 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20 or more spines. In some embodiments, the ablation device (900) may include 3-20 spines. For example, in one embodiment, the ablation device (900) may include 6-10 spines. Additionally, in some embodiments, the shape of the bulbous expansion structure (930) of the set of expanded spines (914) may be asymmetric, e.g., its distal portion may be more bulbous or rounded than its proximal portion (see, e.g., FIGS. 9B-9E). Such a bulbous distal portion may facilitate placement of the device at the ostium of a pulmonary vein.

[0063] With reference to Figures 9B-9E, it is understood that components having similar reference numbers as Figure 9A (e.g., electrode (916) in Figure 9A and electrode (916') in Figure 9B) may be structurally and / or functionally similar unless otherwise specified. Figure 9B illustrates spine wires (914', 920', 922') that form an expanded structure (930') during use, such as during deployment. The first plane (924A') of the expanded structure (930'), sometimes referred to as the primary plane, has a different cross-sectional area than the cross-sectional area in the second plane (924B') of the expanded structure (930'). As shown in Figure 9B, in some embodiments, the cross-sectional area of ​​the expanded structure (930') in the second plane (924B') is greater than the cross-sectional area in the first plane (924A'). The terms "first plane" and "second plane" as used with respect to Figure 9B may refer to planes perpendicular to the longitudinal axis of the catheter shaft (910') formed about 1 cm, about 2 cm, and about 3 cm or more, respectively, from the distal end of the catheter shaft (910') and the proximal end of the distal cap (912'), including all values ​​and subranges therebetween. Similar to Figure 9A, the electrode (916') of the first spine (920') is positioned closer to the distal cap (912') of the ablation device (900') than the electrode (918') of the second spine (922').

[0064] FIG. 9C illustrates the spine wires (914'', 920'', 922'') forming the expansion structure (930'') during use, such as during deployment. The first plane (924A'') of the expansion structure (930''), sometimes referred to as the primary plane, has a different cross-sectional area than the cross-sectional area in the second plane (924B'') of the expansion structure (930''). As shown in FIG. 9C, in some embodiments, the cross-sectional area of ​​the expansion structure (930'') in the second plane (924B'') is greater than the cross-sectional area in the first plane (924A''). The terms "first plane" and "second plane" as used with respect to FIG. 9C can refer to planes perpendicular to the longitudinal axis of the catheter shaft (910'') and formed from the distal end of the catheter shaft (910'') and the proximal end of the distal cap (912'') to about 1 cm, about 2 cm, and about 3 cm, or more, respectively (including all values ​​and sub-ranges therebetween). Unlike Figures 9A-9B, multiple electrodes may be present on each spine wire, and some electrodes may be equidistant from the distal cap (912''). In this manner, more distal electrodes such as 932'' and 934'' may be placed proximal / antral to the pulmonary vein ostium while being used to deliver ablation to create peri-ostial lesions around the pulmonary vein.

[0065] FIG. 9D illustrates the spine wires (914''', 920''', 922''') forming the expansion structure (930''') during use, such as during deployment. The spine wires (914''', 920''', 922''') converge at their distal ends to a point (928''') located inside / within the expansion structure (930'''). As shown in FIG. 9D, in such a configuration, at least some of the electrodes (932''', 934''') of the spine wires (914''', 920''', 922''') may reside at a distal end surface (926''') of the expansion structure (930'''). The term "distal end surface" as used with respect to FIG. 9D may refer to a plane perpendicular to the longitudinal axis of the catheter shaft (910''') that passes through the distal boundary of the expansion structure (930'''). In this manner, the expansion structure (930'') can be pressed against, for example, the posterior wall of the left atrium to directly create a lesion by activation of appropriate electrodes on the distal end face using any suitable polarity combination. For example, electrodes 932''' and 934'''' may be configured with opposite polarities.

[0066] FIG. 9E illustrates the spine wires (944, 940, 942) that form the expansion structure (950) during use, such as during deployment. The spine wires (944, 940, 942) converge to a distal end at the proximal end of the inner / internal distal cap (912'''') of the expansion structure (950). As shown in FIG. 9E, in such a configuration, at least some of the electrodes (952, 954) of the spine wires (944, 940) may be located at the distal end face (946) of the expansion structure (950). The term "distal end face" as used with respect to FIG. 9E may refer to a plane perpendicular to the longitudinal axis of the catheter shaft (910'''') that passes through the distal boundary of the expansion structure (950). In this manner, the expansion structure (950) may be pressed against, for example, the posterior wall of the left atrium to directly create lesions by activation of appropriate electrodes at the distal end face (946) using any suitable polarity combination. For example, electrodes 952 and 954 may be configured with opposite polarities. Compared to the expandable structure (930'''') of Figure 9D, the expandable structure (950) of Figure 9E has an orthogonal (e.g., flat) shape that can be pressed against, for example, the posterior wall of the left atrium to cauterize tissue. In other words, the cross-sectional area of ​​the expandable structure (930'''') at the distal end surface (926'''') is smaller than the cross-sectional area of ​​the expandable structure 950 at the distal end surface (946).

[0067] For each of the ablation devices described herein, each of the spines can include a polymer and define a cavity to form a hollow tube. One or more electrodes of the ablation devices described herein can include 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 can include 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 order using any pulse waveform sufficient to ablate tissue by irreversible electroporation. For example, different sets of electrodes can deliver different sets of pulses (e.g., hierarchical pulse waveforms), as described in more detail below. It should be understood that the size, shape, and spacing of the electrodes on and between the spines can be configured to deliver sequential / transmural energy to electrically isolate one or more pulmonary veins. In some embodiments, alternating electrodes (e.g., all distal electrodes) can be at the same potential, as can all other electrodes (e.g., all proximal electrodes). Thus, ablation can be delivered rapidly with all electrodes activated simultaneously. A variety of such electrode pairing options exist and may be implemented based on their convenience.

[0068] balloon In some embodiments, the ablation device may include one or more balloons for delivering energy to ablate tissue by irreversible electroporation. FIG. 10 illustrates an embodiment of a balloon ablation device (1010) (e.g., structurally and / or functionally similar to the ablation device (110)) positioned in the left atrium (1000) of a heart. The ablation device (1010) may include a first balloon (1012) and a second balloon (1014) that may be configured to be positioned at the ostium (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 first balloon (1012) to be positioned near and / or at the ostium (1002) of the pulmonary vein (1004) while the second balloon (1014) can be advanced and positioned further into the pulmonary vein (1014). The inflated second balloon helps stabilize the position of the first balloon in the ostium 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, for example, saline. The first balloon (1012) and the second balloon (1014) may be electrically insulated from one another. For example, each balloon (1012, 1014) may include an insulated lead wire associated therewith, each lead having sufficient electrical insulation to maintain a potential difference of at least 700V across its thickness without dielectric breakdown. In other embodiments, the insulation of each lead wire may maintain a potential difference of about 200V to about 2500V across its thickness without dielectric breakdown, including all values ​​and subranges therebetween. For example, the lead wire of the second balloon (1014) may be insulated as it extends through the first balloon (1012).

[0069] In some embodiments, the first and second balloons (1012, 1014) can form an anode-cathode pair. For example, the first balloon (1012) can be configured as a cathode and the second balloon (1014) can be configured as an anode, or vice versa, and electrical energy can be capacitively coupled across the balloons or the saline-filled electrodes. The device (1010) can receive a pulse waveform (1002) to be delivered to tissue. For example, one or more of a biphasic signal and a monophasic signal can be applied such that tissue can be ablated between the first balloon (1012) and the second balloon (1014) at a desired location in the pulmonary vein (1004). The first and second balloons (1012, 1014) can substantially confine the electric field between the first and second balloons (1012, 1014) to reduce the electric field and damage to tissue away from the ostium (1002) of the pulmonary vein (1004). In some embodiments, one or more of the balloons (1012, 1014) can include a wire mesh.

[0070] FIG. 11 is a cross-sectional view of another embodiment of a balloon ablation device (1110) (e.g., structurally and / or functionally similar to ablation device (110)) positioned in the left atrium (1100) and right atrium (1104) of the heart. The ablation device (1110) can include a balloon (1112) that can be configured to be advanced and positioned in the right atrium (1104). For example, the balloon (1112) can be positioned in contact with the septum (1106) of the heart. The balloon (1112) can be filled with saline. The device (1110) can further include an electrode (1120) that can be advanced from the right atrium (1104), through the balloon (1112) and septum (1106), and into the left atrium (1100). For example, the electrode (1120) may extend from the balloon (1112) and be advanced through the septum (1106) into the left atrium (1100). Once the electrode (1120) enters the left atrium (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 a circle, an ellipse, or any other geometric shape. In FIG. 11, the distal portion of the electrode (1120) forms a loop that may encircle a single ostium or two or more ostia of a pulmonary vein (1102) of the left atrium (1100). In other embodiments, the distal portion of the electrode (1120) may have approximately the same diameter as the ostium (1102) of the pulmonary vein.

[0071] The balloon (1112) and the electrode (1120) may be electrically insulated from one another. For example, the balloon (1112) and the electrode (1120) may each include an insulated lead (1114, 1122), each lead (1114, 1122) having sufficient electrical insulation to maintain a potential difference of at least 700V across its thickness without dielectric breakdown. In other embodiments, the insulation of each lead may maintain a potential difference of about 200V to about 2000V across its thickness without dielectric breakdown, including all values ​​and subranges therebetween. The lead (1122) of the electrode (1120) may be insulated through 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 a cathode and the electrode (1120) may be configured as an anode. The device (1110) can receive a pulse waveform that is delivered to the ostium (1102) of the pulmonary vein. For example, one or more of a biphasic and monophasic signal can be applied to ablate tissue. The pulse waveform can generate a strong electric field around the electrode (1120) while the applied current is capacitively coupled to the balloon (1112) to complete the circuit. In some embodiments, the electrode (1120) can include a fine gauge wire and the balloon (1112) can include a wire mesh.

[0072] In another embodiment, the electrode (1120) can be advanced into the pulmonary vein (1102) and positioned at one or more pulmonary vein ostia without advancing the balloon (1112) and / or the septum (1106). The balloon (1112) and electrode (1120) can be configured as a cathode-anode pair to receive a pulsed waveform in the same manner as described above.

[0073] Return electrode Some embodiments of the ablation system described herein may further include a return electrode or a set of distributed return electrodes coupled to the patient to reduce the risk of unintended damage to healthy tissue. Also, FIGS. 12A-12B are schematic diagrams of a set of return electrodes (1230) (e.g., return pads) of an ablation system positioned on a patient (1200). A set of four ostia (1210) of the pulmonary veins in the left atrium are shown in FIGS. 12A-12B. The electrodes (1220) of the ablation device may be positioned around one or more of the ostia (1210) of the pulmonary veins. In some embodiments, the set of return electrodes (1230) may be positioned on the back of the patient (1200) such that current passes from the electrodes (1220) through the patient (1200) and then to the return electrodes (1230).

[0074] For example, one or more return electrodes may be placed on the skin of the patient (1200). In one embodiment, eight return electrodes (1230) may be placed on the patient's back to surround the pulmonary vein ostia (1210). To improve contact, a conductive gel may be used between the return electrodes (1230) and the skin. It should be understood that any of the ablation devices described herein may be used with one or more return electrodes (1230). In Figures 12A-12B, the electrodes (1220) are positioned around the four ostia (1210).

[0075] 12B shows a current-carrying electrode (1220) forming an electric field (1240) around the pulmonary vein ostium (1210). A return electrode (1230) can then receive the pulsed monophasic and / or biphasic waveform delivered by the electrode (1220). In some embodiments, the number of return electrodes (1230) can be inversely proportional to the surface area of ​​the return electrodes (1230).

[0076] For each of the ablation devices discussed herein, the electrodes (e.g., ablation electrodes, return electrodes) may comprise a biocompatible metal, such as titanium, palladium, silver, platinum, or a platinum alloy. For example, the electrodes may preferably comprise platinum or a platinum alloy. Each electrode may include a lead having electrical insulation sufficient to maintain a potential difference of at least 700 V across its thickness without dielectric breakdown. In other embodiments, the insulation of each lead may maintain a potential difference of about 200 V to about 2500 V across its thickness without dielectric breakdown, including all values ​​and subranges therebetween. The insulated lead may extend to a proximal handle portion of the catheter, which may be connected to an appropriate electrical connector. The catheter shaft may be made of a flexible polymeric material, such as Teflon, Nylon, Pebax, etc.

[0077] II Method Also described herein are methods of ablating tissue within a cardiac chamber using the above-described systems and devices. The cardiac chamber may be the left atrium and may include its associated pulmonary vein. In general, the methods described herein include introducing and positioning a device in contact with one or more pulmonary vein ostia. A pulse waveform may be delivered by one or more electrodes of the device for ablation of tissue. In some embodiments, a cardiac pacing signal may synchronize the delivered pulse waveform with the cardiac cycle. Additionally or alternatively, the pulse waveform may include multiple levels of hierarchy to reduce total energy delivery. Ablation of tissue thus performed may be delivered with less energy delivery in synchronization with the paced heartbeat to reduce damage to healthy tissue. It should be understood that any of the ablation devices described herein may be used to ablate tissue using the methods described below as appropriate.

[0078] FIG. 13 is a method (1300) for one embodiment of a tissue ablation process. In some embodiments, a voltage pulse waveform as described herein may be applied during a refractory period of the cardiac cycle to avoid interruption of the sinus rhythm of the heart. The method (1300) includes, at step (1302), introducing a device (e.g., an ablation device such as ablation device (110) and / or any ablation device (200, 300, 400, 500, 600, 700, 800, 900, 1010, 1110) into the endocardial space of the left atrium. The device may be advanced (1304) to be placed in contact with a pulmonary vein ostium. For example, an electrode of the ablation device may be placed in contact with an inner diameter surface of the pulmonary vein ostium to form a generally circular electrode arrangement. In some embodiments, a pacing signal may be generated (1306) for stimulation of the heart. The pacing signal may then be generated (1307) for stimulation of the heart. A pacing signal may be applied to the heart (1308). For example, the heart may be electrically paced with a cardiac stimulator to reliably capture pacing and establish periodicity and predictability of the cardiac cycle. One or more of an atrial pacing and a ventricular pacing may be applied. An indication of the pacing signal may be transmitted (1310) to a signal generator. A time window within a refractory period of the cardiac cycle may then be defined within which one or more voltage pulse waveforms may be delivered. In some embodiments, the pacing signal may be followed by a refractory time window. For example, a common refractory time window may exist between both the atrial refractory time window and the ventricular refractory time window.

[0079] A pulse waveform may be generated 1312 in synchronization with the pacing signal. For example, the voltage pulse waveform may be applied at a common refractory time window. In some embodiments, the pulse waveform may be generated with a time offset relative to a representation of the pacing signal. For example, the beginning of the refractory time window may be offset from the pacing signal by a time offset. The voltage pulse waveform(s) may be applied over a series of heartbeats spanning a corresponding common refractory time window. The generated pulse waveform may be delivered 1314 to tissue. In some embodiments, the pulse waveform may be delivered to a pulmonary vein ostium of the patient's heart via one or more spines of a set of spines of the ablation device. In other embodiments, the voltage pulse waveforms described herein may be selectively delivered to a subset of electrodes, such as an anode-cathode subset, for ablation and isolation of a pulmonary vein. For example, a first electrode of the group of electrodes may be configured as an anode and a second electrode of the group of electrodes may be configured as a cathode. These steps may be repeated to ablate the desired number of pulmonary vein ostia (eg, 1, 2, 3 or 4 ostia).

[0080] In some embodiments, hierarchical voltage pulse waveforms having nested structures and time interval hierarchies described herein may be useful for irreversible electroporation, providing control and selectivity in different tissue types. Figure 14 is a flow chart (1400) of another embodiment of a tissue ablation process. The method (1400) includes introducing (1402) a device (e.g., an ablation device such as ablation device (110) and / or any of the ablation devices (200, 300, 400, 500, 600, 700, 800, 900, 1010, 1110) into the endocardial space of the left atrium. The device can be advanced (1404) to be positioned at the ostium of a pulmonary vein. In embodiments where the device can include first and second configurations (e.g., compact and expanded), the device can be introduced in the first configuration and transformed into the second configuration to contact tissue at or near the ostium of the pulmonary vein (1406). The device can include electrodes, which can be configured in anode-cathode subsets as described in detail above (1408). For example, a subset of the electrodes of the device can be selected as anodes while another subset of the electrodes of the device can be selected as cathodes, and a voltage pulse waveform can be applied between the anodes and cathodes.

[0081] The pulse waveform can be generated by a signal generator (e.g., signal generator 122) and can include multiple levels in a hierarchy (1410). Various hierarchical waveforms can be generated by a signal generator as disclosed herein. For example, the pulse waveform can include a first level hierarchy of pulse waveforms including a first set of pulses. Each pulse has a pulse duration and a first time interval separating successive pulses. A second level hierarchy of pulse waveforms can include a set of multiple first pulses as a set of second pulses. A second time interval can separate successive sets of first pulses. The second time interval can be at least three times the duration of the first time interval. A third level hierarchy of pulse waveforms can include a set of multiple second pulses as a set of third pulses. A third time interval can separate successive sets of second pulses. The third time interval can be at least 30 times the duration of the second level time interval.

[0082] It is understood that although the examples herein specify separate monophasic and biphasic waveforms, it should be recognized that combined waveforms may also be generated where some portions of the waveform hierarchy are monophasic while other portions are biphasic. Voltage pulse waveforms having a hierarchical structure may be applied across different anode-cathode subsets, possibly with a time delay. As described above, one or more waveforms applied across the anode-cathode subsets may be applied during the refractory period of the cardiac cycle. The pulse waveforms may be delivered to the tissue (1412). It is understood that the steps described in Figures 13 and 14 may be combined and modified as necessary.

[0083] 15-18 illustrate an embodiment of a method for ablating tissue in the left atrium of the heart as described above using an ablation device described herein (e.g., FIGS. 2-5). FIG. 15 illustrates a cross-sectional view of an embodiment of a method for ablating tissue disposed in the left atrium of the heart using an ablation device (1500) corresponding to the ablation device (210) illustrated in FIG. 2. The left atrium (1502) is shown having four pulmonary veins (1504), and the ablation device (1500) may be used to sequentially ablate tissue to electrically isolate one or more of the pulmonary veins (1504). As illustrated in FIG. 15, the ablation device (1500) may be introduced into an endocardial cavity, such as the left atrium (1502), using a transseptal approach (e.g., extending from the right atrium through the septum to the left atrium (1502)). The ablation device (1500) may include a catheter (1510) and a guidewire (1520) slidable within a lumen of the catheter (1510). A distal portion of the catheter (1510) may include a set of electrodes (1512). A distal portion (1522) of the guidewire (1520) may be advanced into the left atrium (1502) to be positioned near the ostium of the pulmonary vein (1504). The catheter (1510) may then be advanced over the guidewire (1520) to position the electrodes (1512) near the ostium of the pulmonary vein (1504). Once the electrodes (1512) are in contact with the ostium of the pulmonary vein (1504), the electrodes (1512) may be configured into an anode-cathode subset. A voltage pulse waveform generated by a signal generator (not shown) is delivered to the tissue using the electrodes (1512) in synchronization with the paced heartbeat and / or may include a waveform hierarchy. After completion of ablation of tissue in one of the pulmonary veins (1504), the catheter (1510) and guidewire (1520) may be repositioned to another pulmonary vein (1504) to ablate tissue in the remaining pulmonary vein or veins (1504).

[0084] FIG. 16 is a cross-sectional view of an embodiment of a method for ablating tissue disposed in the left atrium of the heart using an ablation device (1600) corresponding to the ablation device (310) shown in FIG. 3. The left atrium (1602) is shown having four pulmonary veins (1604), and the ablation device (1600) may be used to sequentially ablate tissue to electrically isolate one or more of the pulmonary veins (1604). As shown in FIG. 16, the ablation device (1600) may be introduced into an endocardial cavity, such as the left atrium (1602), using a transseptal approach. The ablation device (1600) may include a sheath (1610) and a catheter (1620) slidable within the cavity of the sheath (1610). A distal portion (1622) of the catheter (1620) may include a set of electrodes. A distal portion (1622) of the catheter (1620) can be advanced into the left atrium (1602) to position electrodes near the ostium of the pulmonary vein (1604). Once the electrodes are in contact with the ostium of the pulmonary vein (1604), the electrodes can be configured into an anode-cathode subset. A voltage pulse waveform generated by a signal generator (not shown) can be delivered to tissue using the electrodes in synchronization with the paced heartbeat and / or can include a waveform hierarchy. After completion of ablation of tissue in the pulmonary vein (1604), the catheter (1620) can be repositioned to another pulmonary vein (1604) to ablate tissue in one or more remaining pulmonary veins (1604).

[0085] FIG. 17 is a cross-sectional view of an embodiment of a method for ablating tissue disposed in the left atrium of a heart using an ablation device corresponding to the ablation device (410) shown in FIG. 4. The left atrium (1702) is shown having four pulmonary veins (1704), and the ablation device (1700) can be used to ablate tissue to electrically isolate one or more of the pulmonary veins (1704). As shown in FIG. 17, the ablation device (1700) can be introduced into an endocardial cavity, such as the left atrium (1702), using a transseptal approach. The ablation device (1700) can include a sheath (1710) and multiple catheters (1720, 1721) slidable within the cavity of the sheath (1710). Each of the catheters (1720, 1721) can include a respective guidewire (1722, 1723) slidable within the catheter (1720, 1721). The distal portions of the guidewires (1722, 1723) may include electrodes configured to deliver a voltage pulse waveform. Each of the catheters (1720, 1721) and corresponding guidewires (1722, 1723) may be advanced into the left atrium (1702) to be positioned near the ostium of a respective pulmonary vein (1704). When the guidewire electrodes (1722, 1723) contact the ostium of the pulmonary vein (1704), the electrodes may be configured in an anode-cathode subset. For example, the first guidewire (1722) may be configured as an anode while the second guidewire (1723) may be configured as a cathode. In this configuration, a voltage pulse waveform generated by a signal generator (not shown) may be delivered for ablation and simultaneous isolation of a pair of pulmonary veins (1704). Additionally or alternatively, a voltage pulse waveform may be delivered to the tissue using the electrodes in synchronization with the paced heartbeat and / or may include a waveform hierarchy. After completion of ablation of tissue in the two pulmonary veins (1704), the catheters (1720, 1721) may be repositioned to ablate tissue in the remaining two pulmonary veins (1704). In some embodiments, the sheath (1710) may include three or four catheters positioned in the pulmonary veins (1704).

[0086] FIG. 18 is a cross-sectional view of an embodiment of a method for ablating tissue located in the left atrium of the heart using an ablation device (1800) corresponding to the ablation device (500) shown in FIG. 5. The left atrium (1802) is shown having four pulmonary veins (1804), and the ablation device (1800) may be used to sequentially ablate tissue to electrically isolate one or more of the pulmonary veins (1804). As shown in FIG. 18, the ablation device may be introduced into an endocardial cavity, such as the left atrium (1802), using a transseptal approach. The ablation device may include a sheath (1820) and a catheter (1810) slidable within the cavity of the sheath (1820). A distal portion (1812) of the catheter (1810) may be flower-shaped, as described in detail with respect to FIG. 5. The distal portion 1812 of the catheter 1810 can be advanced into the left atrium 1802 in a compact first configuration and positioned near the ostium of the pulmonary vein 1804. The distal portion 1812 of the catheter 1810 can then be deformed to an expanded second shape to form a flower-shaped distal portion as shown in FIG. 18 such that the distal portion 1812 of the catheter 1810 is positioned near the ostium of the pulmonary vein 1804. Once the electrodes are in contact with the ostium of the pulmonary vein 1804, the electrodes can be configured in an anode-cathode subset. A voltage pulse waveform generated by a signal generator (not shown) can be delivered to tissue using the electrodes in synchronization with the paced heartbeat and / or can include a waveform hierarchy. After completion of the ablation of tissue in a pulmonary vein (1804), the catheter (1810) may be repositioned to another pulmonary vein (1804) to ablate tissue in one or more remaining pulmonary veins (1804).

[0087] Any of the methods described herein (e.g., Figures 13-18) can further include coupling a return electrode (e.g., one or more return electrodes (1230) shown in Figures 12A-12B) to the patient's back and configured to safely remove current from the patient during application of the voltage pulse waveform.

[0088] 19A-20B show embodiments of electrodes placed in contact around the ostium of a pulmonary vein and the electric field generated therefrom. Figure 19A is a schematic diagram (1900) of an embodiment of a set of electrodes (1910) placed at the ostium of a pulmonary vein (1904). The left atrium (1902) can include a blood pool (1906) and the pulmonary vein (1904) can include a blood pool (1908). The left atrium (1902) and pulmonary vein (1904) can each have a wall thickness of up to about 4 mm.

[0089] FIG. 19B is another schematic diagram (1900) of a set (1910) of electrodes arranged radially along the inner surface of a pulmonary vein (1904). The pulmonary vein (1904) can include an arterial wall (1905) that includes a blood pool (1908). Adjacent electrodes (1910) can be separated by a predetermined distance (1911). In some embodiments, the pulmonary vein (1904) can have an inner diameter of about 16 mm. In FIGS. 19A-19B, the electrodes (1910) can have a length of about 10 mm and can be spaced about 4 mm apart from one another. It should be understood that in other embodiments, the electrodes (1910) can be any of the electrodes disclosed herein. For example, the electrodes (1910) can include the flower-shaped distal electrodes of FIG. 5 and / or the generally circular arrangement of electrodes shown in FIG. 3.

[0090] 20A-20B are schematic diagrams (2000) of an embodiment of an electric field (2020) generated by a set of electrodes (2010) positioned at the ostium of a pulmonary vein (2002). FIG. 20A is a perspective view of the pulmonary vein (2002) and the outer wall of the left atrium (2004), while FIG. 20B is a cross-sectional view. The shaded electric field (2020) indicates where the electric field (2020) exceeds a threshold when adjacent electrodes (2010) deliver energy (e.g., a voltage pulse waveform) to ablate tissue. For example, the electric field (2020) represents a 1500V potential difference applied between adjacent electrodes (2010). Under this applied voltage, the magnitude of the electric field (2020) exceeds a threshold of at least 500V / cm in the shaded volumetric electric field (2020) and may be sufficient to cause irreversible ablation in cardiac tissue. As described in detail above, by sequencing pulse waveforms on adjacent pairs of electrodes (2010), the ostium of the pulmonary vein (2002) can be cauterized to electrically isolate the pulmonary vein (2002) from the left atrium (2004).

[0091] Pulse Waveform Disclosed herein are methods, systems and devices for selectively and rapidly applying pulsed electric fields / waveforms to effect tissue ablation in irreversible electroporation. The pulse waveform(s) disclosed herein can be used in any of the systems (100), devices (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 are directed to high voltage pulse waveforms with a series of delivery schemes to deliver energy to tissue via a set of electrodes. In some embodiments, peak electric field values ​​can be reduced and / or minimized while maintaining a sufficiently large electric field strength in the area where tissue ablation is desired. This also reduces the likelihood of excessive tissue damage or electrical arcing resulting in high localized temperature rise. In some embodiments, a system useful for irreversible electroporation includes a signal generator and a processor that can be configured to apply a pulse voltage waveform to a selected plurality of electrodes or a subset of electrodes of an ablation device. In some embodiments, the processor is configured to control inputs whereby selected pairs of the anode-cathode subset of electrodes can be triggered sequentially based on a predefined sequence, in one embodiment, a sequence of deliveries can be triggered from a cardiac stimulation device and / or a pacing device. In some embodiments, the ablation pulse waveform is applied during a refractory period of the cardiac cycle to avoid interruption of the sinus rhythm of the heart. One exemplary method of doing this is to electrically pace the heart with a cardiac stimulation device, reliably capture the pacing to establish periodicity and predictability of the cardiac cycle, and then define a time window well within the refractory period of this periodic cycle to deliver the ablation waveform.

[0092] In some embodiments, the pulse voltage waveforms disclosed herein are hierarchical and nested in organization. In some embodiments, the pulse waveforms include hierarchical groups of pulses at various associated time scales. Furthermore, the associated time scales and pulse widths, and the number of pulses and hierarchical groups can be selected to satisfy a set of one or more Diophantine inequalities, including the frequency of cardiac pacing.

[0093] The pulse waveforms for electroporation energy delivery disclosed herein can improve the safety, efficiency and effectiveness of energy delivery by lowering the electric field threshold associated with irreversible electroporation, resulting in more effective ablation lesions with reduced total energy delivered, which in turn can broaden the scope of clinical applications of electroporation, including therapeutic treatment of various cardiac arrhythmias.

[0094] FIG. 21 shows a pulse voltage waveform in the form of a series of rectangular double pulses, with each pulse, such as pulses (2100) associated with a pulse width or duration. The pulse width / duration may be about 0.5 microseconds, about 1 microsecond, about 5 microseconds, about 10 microseconds, about 25 microseconds, about 50 microseconds, about 100 microseconds, about 125 microseconds, about 140 microseconds, about 150 microseconds, including all values ​​and subranges therebetween. The pulse waveform in FIG. 21 shows a set of monophasic pulses in which all pulses have the same polarity (all positive in FIG. 21, measured from a baseline of zero). In some embodiments, such as for applying irreversible electroporation, the height of each pulse (2100) or the voltage amplitude of the pulse (2100) may range from about 400 volts, about 1,000 volts, about 5,000 volts, about 10,000 volts, about 15,000 volts, including all values ​​and subranges therebetween. As shown in Figure 21, pulses (2100) are separated from adjacent pulses by a time interval (2102), sometimes referred to as a first time interval. The first time interval may 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 therebetween, to produce irreversible electroporation.

[0095] FIG. 22 introduces a pulse waveform with a structure of a hierarchy of nested pulses. FIG. 22 shows a series of monophasic pulses, such as pulse (2200), having pulse width / pulse duration w separated by a time interval t1 (sometimes also referred to as a first time interval), such as duration (2202) between successive pulses, adapted to form a pulse group (2210) (sometimes also referred to as a first pulse group) of m1 number. The waveform further has m2 number of such pulse groups (sometimes also referred to as a second set of pulses) separated by a time interval (2212) (sometimes also referred to as a second time interval) t2 of duration between successive groups. A collection of m2 such pulse groups constitutes the next level of the hierarchy, which can be referred to as a packet and / or a third set of pulses, as shown at (2220) in FIG. 22. Both the pulse width and the time interval t1 between pulses can range from microseconds to hundreds of microseconds, including all values ​​and partial ranges in between. In some embodiments, the time interval t2 can be at least three times greater than the time interval t1, in some embodiments, the ratio t2 / t1 can be in the range from about 3 to about 300, including all values ​​and subranges therebetween.

[0096] FIG. 23 further details the structure of a nested pulse hierarchical waveform. In this figure, a series of m1 pulses (individual pulses not shown) forms a pulse group (2300) (e.g., a first set of pulses). A series of m2 such groups separated by an inter-group time interval (2310) t2 of duration between one group and the next (e.g., a second time interval) forms a packet 132 (e.g., a second set of pulses). A series of m3 such packets separated by a time interval (2312) t3 of duration between one packet and the next (e.g., a third time interval) forms the next level in the hierarchy, labeled superpacket (2320) (e.g., a third set of pulses) in the figure. In some embodiments, the time interval t3 can be at least about 30 times greater than the time interval t2. In some embodiments, the time interval t3 can be at least about 50 times greater than the time interval t2. In some embodiments, the ratio t3 / t2 can be in the range of about 30 to about 800, including all values ​​and subranges therebetween. The amplitude of the individual voltage pulses in the pulse hierarchy can be anywhere within the range of 500 volts to 7,000 volts or more, including all values ​​and sub-ranges therebetween.

[0097] FIG. 24 provides an example of a biphasic waveform sequence with a hierarchical structure. In the example shown in the figure, a biphasic 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) t1 between adjacent cycles of duration, and n1 such cycles form a pulse group (2410) (e.g., a first set of pulses). A series of n2 such groups separated by an inter-group time interval (2412) (e.g., a second time interval) t2 of duration between one group and the next group forms a packet (2420) (e.g., a second set of pulses). The figure also shows a second packet (2430) with a time delay (2432) (e.g., a third time interval) t3 of duration between the packets. As with the monophasic pulses, higher level hierarchical structures can also be formed. The amplitude of each pulse or the voltage amplitude of the biphasic pulse can be anywhere within the range of 500 volts to 7,000 volts or more, including all values ​​and subranges therebetween. The pulse width / pulse duration can be in the range of nanoseconds or subnanoseconds to tens of microseconds, while the delay t1 can be in the range of zero to several microseconds. The intergroup time interval t2 can be at least 10 times greater than the pulse width. In some embodiments, the time interval t3 can be at least about 20 times greater than the time interval t2. In some embodiments, the time interval t3 can be at least 50 times greater than the time interval t2.

[0098] The embodiments disclosed herein include waveforms structured as hierarchical waveforms that include waveform elements / pulses at various hierarchical levels. Individual pulses, such as (2200) in FIG. 22, comprise a first level of hierarchy and have associated pulse durations and a first time interval between successive pulses. A set of pulses, or elements of the first level structure, form a second level of hierarchy, such as a pulse group / second pulse group (2210) in FIG. 22. Among other parameters associated with the waveform are parameters such as the total duration of the second set of pulses (not shown), the total number of first level elements / first set of pulses, and a second time interval between successive first level elements that describe the second level structure / second set of pulses. In some embodiments, the total duration of the second set of pulses can be from about 20 microseconds to about 10 milliseconds, including all values ​​and subranges in between. A set of groups, a set of second pulses, or elements of the second level structure form a third level of hierarchy, such as a packet of groups / third set of pulses (2220) in FIG. 22. Among other parameters are the total duration of the third set of pulses (not shown), the total number of second level elements / second set of pulses, and the third time interval between successive second level elements describing the third level structure / third set of pulses. In some embodiments, the total duration of the third set of pulses can be from about 60 microseconds to about 200 milliseconds, including all values ​​and subranges therebetween. The overall repeating or nested structure of the waveform can continue into multiple higher levels, such as a 10 level or more structure.

[0099] In some embodiments, the hierarchical waveforms and time interval hierarchy with nesting described herein are useful for ablation energy delivery in irreversible electroporation, providing a good degree of control and selectivity for application in different tissue types. Various hierarchical waveforms can be generated with an appropriate pulse generator. It will be appreciated that while separate monophasic and biphasic waveforms are identified in the examples herein for clarity, it should be noted that combination waveforms can also be generated / implemented where some portions of the waveform hierarchy are monophasic, while other portions are biphasic.

[0100] In some embodiments, the ablation pulse waveforms described herein are applied during the refractory period of the cardiac cycle to avoid interruption of the heart's sinus rhythm. In some embodiments, the therapeutic method electrically paces the heart with a cardiac stimulator to reliably capture pacing to establish periodicity and predictability of the cardiac cycle, and then defines a time window within the refractory period of the cardiac cycle during which one or more ablation pulse waveforms can be delivered. FIG. 25 illustrates an example in which both atrial and ventricular pacing are applied (e.g., with pacing leads or catheters located in the right atrium and right ventricle, respectively). FIG. 25 illustrates time on the horizontal axis, and shows a series of ventricular pacing signals, such as (2500) and (2510), and a series of atrial pacing signals (2520, 2530), along with a series of ECG waveforms (2540, 2542) driven by the pacing signals. As shown in FIG 25 by the wide arrows, there is an atrial refractory period time window (2522) and a ventricular refractory period time window (2502) following the atrial pacing signal (2522) and the ventricular pacing signal (2500), respectively. As shown in FIG 25, there is a time window of duration T rA common refractory time window (2550) of pulses may be defined. In some embodiments, the electroporation ablation waveform(s) may be applied during this common refractory time window (2550). The start of this refractory time window (2522) is offset from the pacing signal (2500) by a time offset (2504), as shown in FIG. 25. The time offset (2504) may be less than about 25 milliseconds in some embodiments. At the next heartbeat, the similarly defined common refractory time window (2552) is the next time window available for application of the ablation waveform(s). In this manner, the ablation waveform(s) may be applied over a series of heartbeats, with each heartbeat remaining within the common refractory time window. In one embodiment, each packet of pulses as described above in the pulse waveform hierarchy may be applied over a heartbeat, such that a series of packets is applied over a series of heartbeats to a given set of electrodes.

[0101] As used herein, when used in connection with numerical values ​​and / or ranges, the terms "about" and / or "approximately" generally refer to numerical values ​​and / or ranges that are close to the stated numerical values ​​and / or ranges. In some instances, the terms "about" and "approximately" can mean within ±10% of the recited value. For example, in some cases, "about 100 [units]" can mean within ±10% of 100 (e.g., 90 to 110). The terms "about" and "approximately" can be used interchangeably.

[0102] Some embodiments described herein relate to computer storage products with a non-transitory computer-readable medium (sometimes also referred to as a non-transitory processor-readable medium) having instructions or computer code for performing various computer-implemented operations. The computer-readable medium (or processor-readable medium) is non-transitory in the sense that it does not include a transitory propagating signal itself (e.g., a propagating electromagnetic wave carrying information over a transmission medium such as space or cable). The medium and computer code (sometimes also referred to as code or algorithm) may be designed and constructed for a specific purpose or purposes. Examples of non-transitory computer-readable media include, but are not limited to, magnetic storage media such as hard disks, floppy disks, magnetic tapes, optical storage media such as compact disks / digital video disks (CD / DVD), compact disk-read only memory (CD-ROM), and holographic devices, magneto-optical recording media such as optical disks, carrier wave 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.

[0103] The systems, devices, and / or methods described herein may be implemented by software (implemented in 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 (implemented in 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, machine instructions such as those produced by a compiler, code used to generate 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, encrypted code, and compressed code.

[0104] (Additional Note) As a preferred embodiment, the technical ideas that can be understood from the above embodiment will be described below. [Appendix 1] 1. A system for ablating tissue by irreversible electroporation, comprising: a signal generator configured to generate a pulse waveform; an ablation device coupled to the signal generator and configured to receive the pulse waveform, the ablation device including a set of leads, each lead of the set of leads having insulation associated therewith, each lead of the set of leads configured to form a loop at a distal portion of the ablation device, the ablation device including a set of loops, each loop of the set of loops including a non-insulated portion as an electrode, the ablation device including a set of electrodes at the distal portion, the ablation device configured to deliver the pulse waveform to tissue during use via the set of electrodes; wherein the ablation device is further configured to deliver the pulsed waveform to tissue during use via the set of electrodes 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. [Appendix 2] 2. The system of claim 1, wherein the set of loops in the distal portion of the ablation device are configured to deliver the pulse waveform to tissue. [Appendix 3] 2. The system of claim 1, wherein the set of loops is transformable from a compact first configuration for advancement into the endocardial cavity to an expanded second configuration for delivering a pulse waveform to tissue. [Appendix 4] 4. The system of claim 3, wherein the expanded second configuration is a flower configuration. [Appendix 5] 5. The system of any one of claims 1 to 4, wherein each lead of the set of leads is configured to maintain a voltage potential of at least about 700 V without breakdown of the corresponding insulation. [Appendix 6] 6. The system of any one of claims 1 to 5, further comprising a cardiac stimulation device configured to generate a pacing signal for cardiac stimulation during use, communicatively coupled to the signal generator, and further configured to transmit an indication of the pacing signal to the signal generator. [Appendix 7] 7. The system of claim 6, wherein the signal generator is further configured to generate the pulse waveform synchronously with the representation of the pacing signal. [Appendix 8] The first level hierarchy of pulse waveforms includes a first set of pulses, each pulse having a pulse duration, a first time interval separating successive pulses, and 8. The system of claim 1, wherein the hierarchy of the second level of the pulse waveform includes a plurality of first pulse sets as a second pulse set, a second time interval separating consecutive first pulse sets, the second time interval having a longer duration than a duration of the first time interval. [Appendix 9] 9. The system of claim 8, wherein the hierarchy of a third level of the pulse waveform includes a plurality of second sets of pulses as a third set of pulses, a third time interval separating consecutive second sets of pulses, the third time intervals having a duration longer than a duration of a time interval of the second level. [Appendix 10] 1. A system comprising: The system includes a signal generator configured to generate a pulse waveform; The system includes an ablation device coupled to the signal generator and configured to receive the pulse waveform, the ablation device configured to deliver the pulse waveform to tissue during use via a set of electrodes, each electrode of the set of electrodes having an insulated lead associated therewith, each insulated lead configured to maintain a voltage potential of at least about 700V without breakdown of a corresponding insulation; and The system includes a cardiac stimulation device configured to generate a pacing signal for cardiac stimulation in use, the cardiac stimulation device 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 synchronously with the representation of the pacing signal. system. [Appendix 11] 11. The system of claim 10, wherein the signal generator is further configured to generate the pulse waveform at a time offset relative to a representation of the pacing signal. [Appendix 12] 11. The system of claim 10, further comprising a guidewire having a non-linear distal portion, the ablation device being configured to overlie the guidewire during use. [Appendix 13] 11. The system of claim 10, wherein the ablation device includes a non-linear distal portion having one or more electrodes of a set of electrodes disposed on the non-linear distal portion. [Appendix 14] 11. The system of claim 10, wherein each lead is configured to form a loop at a distal portion of the ablation device such that the ablation device includes a set of loops. [Appendix 15] 15. The system of claim 14, further comprising a bending mechanism configured to control a dimension or shape of the distal portion of the ablation device. [Appendix 16] 15. The system of claim 14, wherein the electrode forms a compact first configuration for advancement into the intimal space and is configured to form an expanded second configuration upon advancement out of the sheath cavity to form a flower-shaped distal portion of the ablation device. [Appendix 17] 17. The system of claim 16, wherein the lead and electrode are biased to expand outwardly to the expanded second configuration upon advancement out of the cavity of the sheath. [Appendix 18] 11. The system of claim 10, wherein the electrodes are configured in an anode and cathode set. [Appendix 19] The pulse waveform is a first level hierarchy of pulse waveforms including a first set of pulses, each pulse having a pulse duration and a first time interval separating successive pulses; a second level hierarchy of pulse waveforms including a plurality of the first sets of pulses as a second set of pulses and a second time interval separating successive first sets of pulses, the second time interval being at least three times the duration of the first time interval; 11. The system of claim 10, comprising: The specific examples and descriptions herein are exemplary in nature and embodiments may be developed by one of ordinary skill in the art based on the material taught herein without departing from the scope of the invention, which is limited only by the appended claims.

Claims

1. 1. A system comprising: The system includes a signal generator configured to generate a pulse waveform; The system includes an ablation device connected to the signal generator and configured to receive the pulse waveform. the ablation device includes a set of spines, the ablation device being configured, in use, to deliver the pulsed waveform to tissue via one or more of the set of spines; each spine includes a set of independently addressable electrodes formed on a surface of each of the one or more spines, each electrode of the set of electrodes having a corresponding insulated electrical lead disposed within a body of each of the one or more spines, the set of spines including a first spine and a second spine adjacent to the first spine, the electrode of the first spine being positioned relatively closer to a distal end of the ablation device than the electrode of the second spine.

2. The system described in claim 1, wherein the set of spines forms an expanded structure when in use, and the cross-sectional area of ​​the expanded structure in a first plane is different from the cross-sectional area of ​​the expanded structure in a second plane.

3. The system described in claim 1, wherein the set of spines forms an extended structure when in use, and at least one electrode of the set of electrodes, or at least a portion thereof, is positioned on a distal end plane of the extended structure.

4. A system as described in claim 2 or 3, wherein the set of spines converge at their distal ends to a point within the expansion structure.

5. A system described in any one of claims 1 to 4, wherein each electrical lead of the set of electrical leads is configured to maintain a potential of at least approximately 700 V without causing dielectric breakdown of the corresponding insulator.

6. A system as described in any one of claims 1 to 5, wherein the ablation device is further configured to deliver the pulse waveform to the tissue via the set of electrodes in 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.

7. A system described in any one of claims 1 to 6, wherein the ablation device further includes a spine wire configured to electrically connect the electrode between a pair of spines of the set of spines.

8. The system described in claim 7, wherein the pair of spines are adjacent to each other.

9. The system described in claim 8, wherein the spine wire is a first spine wire of a set of spine wires, and each spine wire of the set of spine wires connects the electrodes between different pairs of spines of the set of spines.

10. The system described in claim 9, wherein the first spine wire of the set of spine wires connects the electrode between a first spine and a second spine of the set of spines, and the second spine wire of the set of spine wires connects the electrode between a third spine and a fourth spine of the set of spines.

11. A system described in any one of claims 1 to 10, wherein the set of spines includes 3 to 20 spines.

12. A system described in any one of claims 1 to 11, wherein the set of electrodes includes 2 to 64 electrodes.

13. The system of claim 1, wherein each electrode of the set of electrodes has a surface area of ​​about 0.5 mm 2 to about 20 mm 2 .

14. The system of any one of claims 1 to 13, wherein each spine of the set of spines has a cross-sectional area of ​​about 0.2 mm 2 to about 15 mm 2 .

15. The pulse waveform comprises a first level hierarchy of the pulse waveform, the first level hierarchy comprising a first set of pulses, each pulse having a pulse time duration, the first level hierarchy comprising a first time interval separating successive pulses; the pulse waveform includes a second level hierarchy of the pulse waveform, the second level hierarchy including a plurality of the first sets of pulses as second sets of pulses and a second time interval separating consecutive first sets of pulses, the second time interval being longer than the duration of the first time interval; 15. The system of claim 1, wherein the pulse waveform comprises a third level hierarchy of the pulse waveform, the third level hierarchy comprising a plurality of the second sets of pulses as a third set of pulses and a third time interval separating consecutive second sets of pulses, the third time interval being longer than a duration of the second time interval.

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