Systems, devices and methods for delivering ablative energy to tissue

Abstract

The present disclosure relates to systems, apparatus and methods for delivering ablative energy to tissue. A system includes a pulse waveform generator and an ablation device coupled to the pulse waveform generator. The ablation device includes at least one electrode, the at least one electrode being configured to deliver ablative pulses to tissue during use. The pulse waveform generator is configured to deliver voltage pulses to the ablation device in the form of a pulse waveform. A first level of the hierarchy of the pulse waveform includes a first pulse group, each pulse having a pulse duration, wherein a first time interval separates consecutive pulses. A second level of the hierarchy of the pulse waveform includes a plurality of first pulse groups as second pulse groups, a second time interval separating consecutive first pulse groups, the second time interval being at least three times the duration of the first time interval.

Description

[0001] This application is a divisional application of an application filed on October 19, 2016, with application number 201680077941.2, and invention name “Systems, devices and methods for delivering ablation energy to tissue”.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Application No. 62 / 274,926, filed on January 5, 2016, entitled “SYSTEMS, APPARATUSES AND DEVICES FOR DELIVERY OF PULSED ELECTRIC FIELD ABLATIVE ENERGY TO ENDOCARDIAL TISSUE,” the entire disclosure of which is incorporated herein by reference in its entirety. Background Art

[0004] In the past two decades, the generation of pulsed electric fields for tissue treatment has been transferred from the laboratory to clinical applications, and the effects of short pulses of high voltage and large electric fields on tissues have been studied for the past four decades or more. The application of a short high DC voltage to tissues can produce a local high electric field, usually in the range of several hundred volts / cm, which may damage the cell membrane by creating pores in the cell membrane. Although the exact mechanism of this electrically driven pore generation or electroporation is unclear, it is believed that the application of a relatively large electric field will produce instability in the lipid bilayer in the cell membrane, causing the distribution of local gaps or pores in the membrane. If the electric field applied at the membrane is greater than a threshold, electroporation may be irreversible, and the pores remain open, allowing biomolecular materials to pass through the membrane for exchange and causing necrosis and / or apoptosis (cell death). The surrounding tissue then heals in a natural process.

[0005] Thus, known electroporation applications in medication and delivery methods do not address high voltage application, tissue selectivity, and safe energy delivery, particularly in the context of ablation therapy for cardiac arrhythmias utilizing catheter devices. Furthermore, there is an unmet need for a thin, flexible, non-invasive device that can simultaneously and effectively deliver high DC voltage electroporation ablation therapy selectively to tissue in a region of interest while minimizing damage to healthy tissue, and for a device design and drug delivery waveform that involves minimal or no device repositioning, allowing for an effective, safe, and rapid clinical procedure. Summary of the invention

[0006] A system includes a pulse waveform generator and an ablation device coupled to the pulse waveform generator. The ablation device includes at least one electrode, the at least one electrode being configured to deliver ablative pulses to tissue during use. The pulse waveform generator is configured to deliver voltage pulses to the ablation device in the form of a pulse waveform. A first level of the hierarchy of the pulse waveform includes a first pulse group, each pulse having a pulse duration, wherein a first time interval separates consecutive pulses. A second level of the hierarchy of the pulse waveform includes a plurality of first pulse groups as second pulse groups, a second time interval separating consecutive first pulse groups, the second time interval being at least three times the duration of the first time interval. BRIEF DESCRIPTION OF THE DRAWINGS

[0007] 1 is a schematic diagram of a catheter having a plurality of electrodes disposed along its distal axis, disposed epicardially such that it snugly surrounds a pulmonary vein of the cardiac anatomy, in accordance with an embodiment.

[0008] Figure 2 is an exemplary waveform illustrating a train of voltage pulses with a defined pulse width for each pulse according to an embodiment.

[0009] Figure 3 Schematically illustrated is a pulse hierarchy showing pulse width, spacing between pulses, and grouping of pulses according to an embodiment.

[0010] Figure 4 A schematic diagram of a nested hierarchy of monophasic pulses showing different levels of nested hierarchy according to an embodiment is provided.

[0011] Figure 5 is a schematic diagram of nested hierarchies of biphasic pulses showing different levels of nested hierarchies, according to an embodiment.

[0012] Figure 6 Schematically illustrates circles of numbered catheter electrodes, wherein groups of electrodes may be sequentially selected for application of corresponding sequences of voltage pulse waveforms, in accordance with an embodiment.

[0013] Figure 7 Electrocardiogram and cardiac pacing signals as well as a time series of atrial and ventricular refractory periods are schematically shown and indicate the time window for irreversible electroporation ablation according to an embodiment.

[0014] Figure 8 Schematically illustrates a temporal sequence of electrode group activations delivered as a series of waveform packets within a corresponding series of consecutive heartbeats, in accordance with an embodiment.

[0015] Fig. 9is a schematic diagram of an irreversible electroporation system according to an embodiment, the electroporation system comprising a system console, which in turn comprises a voltage / signal generator, a controller configured to apply voltage to a selected subset of electrodes and communicatively connected to a computer or processor together with a user interface, and a switching unit configured to electrically isolate other devices from voltage pulses that can be delivered from the voltage generator to the ablation catheter.

[0016] Fig.10 is a schematic diagram of a user interface in an initial configuration according to an embodiment.

[0017] Fig.11 is a schematic diagram of a user interface showing engagement of an initialization function according to an embodiment.

[0018] Fig.12 is a schematic diagram of a user interface showing required steps after initialization, according to an embodiment.

[0019] Fig.13 is a schematic diagram of a user interface showing a configuration in which the system is ready for delivering ablative energy after completing the previous steps. In the configuration, according to an embodiment, the user interface includes a button for ablation. DETAILED DESCRIPTION

[0020] The term "about" or "approximately" used in conjunction with a reference number herein means the reference number plus or minus up to 10% of the reference number. For example, the language "about 50" units or "approximately 50" units means from 45 units to 55 units.

[0021] In some embodiments, a system includes a pulse waveform generator and an ablation device coupled to the pulse waveform generator. The ablation device includes at least one electrode, the at least one electrode being configured to deliver ablation pulses to tissue during use. The pulse waveform generator is configured to deliver voltage pulses to the ablation device in the form of a pulse waveform. The first level of the hierarchy of the pulse waveform includes a first pulse group, each pulse having a pulse duration, and a first time interval separating consecutive pulses. The second level of the hierarchy of the pulse waveform includes a plurality of first pulse groups as second pulse groups, a second time interval separating consecutive first pulse groups, and the second time interval being at least three times the duration of the first time interval. The third level of the hierarchy of the pulse waveform includes a plurality of second pulse groups as third pulse groups, a third time interval separating consecutive second pulse groups, and the third time interval being at least 30 times the duration of the second time interval.

[0022] In some embodiments, the pulses in each first pulse group include monophasic pulses having a voltage amplitude of at least 800 volts. In some embodiments, the pulse duration of each monophasic pulse is in a range from about 1 microsecond to about 300 microseconds.

[0023] In some embodiments, the pulses in each first pulse set include biphasic pulses each having a voltage amplitude of at least 800 volts. In some embodiments, the pulse duration of each biphasic pulse is in a range from about 0.5 nanoseconds to about 20 microseconds.

[0024] In some embodiments, each second pulse group includes at least 2 first pulse groups and less than 40 first pulse groups. In some embodiments, each third pulse group includes at least 2 second pulse groups and less than 30 second pulse groups. In some embodiments, the second time interval is at least ten times the pulse duration.

[0025] In some embodiments, the ablation device comprises an ablation catheter configured for epicardial placement. In some embodiments, the ablation device comprises an ablation catheter configured for endocardial placement.

[0026] In some embodiments, a system includes a pulse waveform generator and an ablation device coupled to the pulse waveform generator, the ablation device including at least one electrode, the at least one electrode being configured to deliver ablation pulses to tissue during use. The pulse waveform generator is configured to deliver voltage pulses to the ablation device in the form of a pulse waveform. The first level of the hierarchy of the pulse waveform includes a first pulse group, each pulse having a pulse duration, and a first time interval separating consecutive pulses. The second level of the hierarchy of the pulse waveform includes a plurality of first pulse groups as second pulse groups, and a second time interval separates consecutive first pulse groups. In some embodiments, the second time interval is at least three times the duration of the first time interval. The third level of the hierarchy of the pulse waveform includes a plurality of second pulse groups as third pulse groups, and a third time interval separates consecutive second pulse groups. In some embodiments, the third time interval is at least thirty times the duration of the second time interval. The pulse waveform generator is configured to apply a plurality of the third pulse groups to the ablation device, wherein there is a time delay of up to about 5 milliseconds between consecutive third pulse groups applied to different electrode groups.

[0027] In some embodiments, the ablation device comprises an ablation catheter configured for epicardial placement. In some embodiments, the ablation catheter comprises at least four electrodes.

[0028] In some embodiments, each second pulse group includes at least 2 first pulse groups and less than 40 first pulse groups. In some embodiments, each third pulse group includes at least 2 second pulse groups and less than 30 second pulse groups. In some embodiments, the pulses in each first pulse group have a voltage amplitude of at least 800 volts.

[0029] In some embodiments, a system includes a pulse waveform generator and an ablation device coupled to the pulse waveform generator, the ablation device including at least one electrode, the at least one electrode being configured to deliver ablation pulses to tissue during use. The system also includes a cardiac stimulator coupled to the pulse waveform generator, the cardiac stimulator being configured to generate a pacing signal for cardiac stimulation during use. The pulse waveform generator is configured to deliver voltage pulses to the ablation device in the form of a pulse waveform, the pulse waveform being synchronized with the pacing signal. A first level of the hierarchy of the pulse waveform includes a first pulse group, each pulse having a pulse duration, and a first time interval separating consecutive pulses. A second level of the hierarchy of the pulse waveform includes a plurality of first pulse groups as second pulse groups, and a second time interval separates consecutive first pulse groups. A third level of the hierarchy of the pulse waveform includes a plurality of second pulse groups as third pulse groups, and a third time interval separates consecutive second pulse groups. The pulse waveform generator is configured to generate the pulse waveform so that each of the first pulse groups and each of the second pulse groups, the multiple second pulse groups, the predetermined number of electrode groups, the time delay, the pulse duration, the first time interval, the second time interval and the third time interval are jointly constrained by the Diophantine inequality.

[0030] In some embodiments, the Diophantine inequality constraint is further characterized by a refractory time window. In some embodiments, the number of the first pulse groups and the number of the second pulse groups are predetermined.

[0031] In some embodiments, the pulse waveform generator is further configured to deliver the pulse waveform spaced apart from the pacing signal at a time offset that is less than about 25 milliseconds. In some embodiments, the third time interval corresponds to a pacing cycle associated with the pacing signal. In some embodiments, the second time interval is at least three times the duration of the first time interval. In some embodiments, the third time interval is at least thirty times the duration of the second time interval. In some embodiments, the second time interval is at least ten times the duration of the pulse duration.

[0032] In some embodiments, the ablation device comprises an ablation catheter configured for epicardial placement. In some embodiments, the ablation device comprises an ablation catheter configured for endocardial placement.

[0033] In some embodiments, a system includes a pulse waveform generator and an ablation device coupled to the pulse waveform generator, the pulse waveform generator including a user interface, the ablation device including a plurality of electrodes configured to deliver ablation pulses to patient tissue during use. The system also includes a cardiac stimulator coupled to the pulse waveform generator, the cardiac stimulator being configured to generate a pacing signal for cardiac stimulation of the patient during use. The pulse waveform generator is configured to deliver voltage pulses to the ablation device in the form of a pulse voltage waveform having at least three levels. The pulse waveform generator is further configured to deliver the pulse voltage waveform synchronously with the pacing signal and to deliver the pulse voltage waveform upon receiving a user confirmation indication.

[0034] In some embodiments, the first level of the hierarchy of the pulse waveform includes a first pulse group, each pulse having a pulse duration, and a first time interval separates consecutive pulses. In some embodiments, the second level of the hierarchy of the pulse waveform includes a plurality of first pulse groups as second pulse groups, and a second time interval separates consecutive first pulse groups. In some embodiments, the third level of the hierarchy of the pulse waveform includes a plurality of second pulse groups as third pulse groups, and a third time interval separates consecutive second pulse groups. In some embodiments, the pulse waveform generator is further configured to apply a plurality of third pulse groups to a predetermined number of electrode groups of the ablation device, wherein there is a time delay between consecutive third pulse groups. In some embodiments, each of the first pulse groups and each of the second pulse groups, the predetermined number of electrode groups, the time delay, the pulse duration, the first time interval, the second time interval, and the third time interval are jointly constrained by Diophantine inequalities.

[0035] In some embodiments, the pulse waveform generator is configured to deliver the pulse waveform only after a predetermined time interval after the user confirms the indication. In some embodiments, the user interface includes a control input device, and the pulse waveform generator is configured to deliver the pulse waveform upon user engagement of the control input device.

[0036] In some embodiments, a method includes generating a pulse waveform. The pulse waveform includes a first level of a hierarchy of the pulse waveform including a first pulse group, each pulse having a pulse duration, and a first time interval separating consecutive pulses. The pulse waveform also includes a second level of the hierarchy of the pulse waveform including a plurality of first pulse groups as a second pulse group, a second time interval separating consecutive first pulse groups, and the second time interval being at least three times the duration of the first time interval. The pulse waveform also includes a third level of the hierarchy of the pulse waveform including a plurality of second pulse groups as a third pulse group, a third time interval separating consecutive second pulse groups, and the third time interval being at least thirty times the duration of the second level time interval. The method also includes delivering the pulse waveform to an ablation device.

[0037] In some embodiments, a method includes generating a pulse waveform. The pulse waveform includes a first level of a hierarchy of the pulse waveform including a first pulse group, each pulse having a pulse duration, and a first time interval separating consecutive pulses. The pulse waveform also includes a second level of the hierarchy of the pulse waveform including a plurality of first pulse groups as a second pulse group, a second time interval separating consecutive first pulse groups, and the second time interval being at least three times the duration of the first time interval. The pulse waveform also includes a third level of the hierarchy of the pulse waveform including a plurality of second pulse groups as a third pulse group, a third time interval separating consecutive second pulse groups, and the third time interval being at least thirty times the duration of the second level time interval. The method also includes generating a pacing signal using a cardiac stimulator. The method also includes delivering the pulse waveform to an ablation device synchronously with the pacing signal.

[0038] Disclosed herein are methods, systems, and devices for selectively and rapidly applying pulsed electric fields / waveforms to achieve tissue ablation with irreversible electroporation. Some embodiments relate to pulsed high voltage waveforms together with sequential delivery schemes for delivering energy to tissues through electrode groups. In some embodiments, the electrodes are catheter-based electrodes or multiple electrodes arranged along the length of an elongated medical device. In some embodiments, a system that can be used for irreversible electroporation includes a voltage / signal generator and a controller that can be configured to apply a pulsed voltage waveform to a selected plurality of electrodes or electrode subgroups of an ablation device. In some embodiments, the controller is configured to control inputs, whereby anode-cathode subgroups of selected pairs of electrodes can be sequentially triggered based on a predetermined sequence, and in one embodiment, the sequential delivery can be triggered from a cardiac stimulator or pacing system / device. In some embodiments, the ablation pulse waveform is applied during the refractory period of the cardiac cycle to avoid interruptions in the regularity of the heart's rhythm. An exemplary method of enforcing this approach is to electrically pace the heart with a cardiac stimulator and ensure pacing capture to establish periodicity and predictability of the cardiac cycle, and then define a time window within the refractory period of this periodic cycle during which the ablation waveform is delivered.

[0039] In some embodiments, the pulse voltage waveform disclosed herein is hierarchical in organization and has a nested structure. In some embodiments, the pulse waveform includes hierarchical groupings of pulses having a variety of associated time scales. In addition, the associated time scales and pulse widths and the number of pulses and hierarchical groupings can be selected so as to satisfy one or more of a set of Diophantine inequalities related to cardiac pacing frequency.

[0040] The pulse waveforms for electroporation energy delivery as disclosed herein can enhance the safety, efficiency, and effectiveness of energy delivery by lowering the electric field threshold associated with irreversible electroporation, thereby obtaining more effective ablation lesions with reduced total energy delivery. This in turn can broaden the clinical application areas of electroporation, including therapeutic treatment of a variety of arrhythmias.

[0041] The present disclosure generally addresses the need for devices and methods for rapid, selective, and safe delivery of irreversible electroporation therapy using multiple devices, such that in some embodiments, the peak electric field value can be reduced and / or minimized while maintaining a sufficiently large electric field magnitude in the area where tissue ablation is desired. This also reduces the likelihood of excessive tissue damage or arcing, and localized hyperthermia increases.

[0042] FIG. 1 is a schematic diagram of a catheter 15 having a plurality of electrodes disposed along its axis. The catheter is shown in FIG. 1 relative to the heart 7 and the catheter 15 is epicardially wrapped around the pulmonary veins represented by reference numerals 10, 11, 12, and 13 (upper left, lower left, upper right, and lower right in FIG. 1, respectively) of the left atrium and has electrodes (such as those represented by reference numeral 17 in FIG. 1) indicated by dark bands wrapped and / or encircled around the outline of the pulmonary veins 10, 11, 12, 13 of the left atrium. In some embodiments, the catheter ends 8 and 9 are tightly pulled together and held within a tie-down tool (not shown) to ensure that the catheter electrodes are snugly wrapped around the pulmonary veins 10, 11, 12, 13. A method and apparatus for placing a multi-electrode ablation catheter around a pulmonary vein using a subxiphoid pericardial access site and a guidewire-based delivery method is described in PCT patent application publication number WO2014 / 025394, entitled “Catheters, Catheter Systems and Methods for Puncturing Through a Tissue Structure and Ablating a Tissue Region,” the entire disclosure of which is incorporated herein by reference in its entirety.

[0043] In some embodiments, the catheter electrode 17 can be constructed in the form of a metal belt or ring. In some embodiments, each electrode 17 can be constructed to be flexible. For example, the electrode 17 can be in the form of a metal coil spring or a spiral winding wrapped around the axis of the catheter 15. As another example, the electrode 17 can be in the form of a series of metal belts or rings arranged along the axis and electrically connected together, wherein the flexible portion of the catheter shaft between the electrodes provides flexibility to the entire electrode. In some embodiments, at least a portion of the electrode 17 may include a biocompatible metal, such as but not limited to titanium, palladium, silver, platinum and / or a platinum alloy. In some embodiments, at least a portion of the electrode 17 includes platinum and / or a platinum alloy. In some embodiments, the catheter shaft can be made of a flexible polymer material, such as (for the purpose of non-limiting examples only) polytetrafluoroethylene, polyamide, such as nylon or polyether block amide. The electrode 17 can be connected to an insulated electrical lead (not shown) leading to the proximal handle portion (not shown) of the catheter 15, wherein the insulator on each of the leads can maintain a potential difference of at least 700V across its thickness without being broken down by the dielectric. Although catheter 15 is shown in FIG. 1 for epicardial placement, ie, beneath the pericardium, in alternative embodiments, an ablation catheter may additionally or alternatively be used for endocardial placement.

[0044] Figure 2A pulsed voltage waveform is shown in the form of a rectangular double pulse train, wherein each pulse (such as pulse 101) is 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. Figure 2 The pulse waveform shows a set of monophasic pulses, in which all pulses have the same polarity (in Figure 2 In some embodiments, such as for irreversible electroporation applications, the height of each pulse 101 or the voltage amplitude of pulse 101 can be about 400 volts, about 1000 volts, about 5000 volts, about 10,000 volts, about 15,000 volts, including all values ​​and subranges therebetween. Figure 2 As shown, pulses 101 are separated from adjacent pulses by a time interval 102, sometimes referred to as a first time interval. To produce irreversible electroporation, the first time interval can be about 10 microseconds, about 50 microseconds, about 100 microseconds, about 200 microseconds, about 500 microseconds, about 800 microseconds, about 1 millisecond, including all values ​​and subranges therebetween.

[0045] Figure 3 A pulse waveform with a hierarchical structure of nested pulses is introduced. Figure 3 A series of monophasic pulses, such as pulse 115 having a pulse width / pulse duration w, are shown, with pulses 115 separated by time intervals (sometimes also referred to as first time intervals), such as a duration t between consecutive pulses. 1 118, quantity m 1 The pulses are arranged to form a pulse group 121 (sometimes also referred to as a first pulse group). In addition, the waveform has a number m 2 Such pulse groups (sometimes also called second pulse groups) are composed of a duration t between consecutive groups. 2 The time interval 119 (sometimes also referred to as the second time interval) is separated. Figure 3 The m marked by 122 2 The collection of such pulse groups constitutes the next level of the hierarchy, which may be referred to as a group and / or a third pulse set. The pulse width and time interval t between pulses 1 can be in the range of a few microseconds to hundreds of microseconds, including all values ​​and subranges therebetween. In some embodiments, the time interval t 2 Comparable time interval t 1 In some embodiments, the ratio t 2 / t 1 Can be in the range between about 3 and about 300 including all values ​​and subranges therebetween.

[0046] Figure 4 The structure of the nested pulse level waveform is further explained. In this figure, a series of m 1 The pulses (individual pulses are not shown) form a pulse group 130 (eg, a first pulse group). The duration t between one group and the next 2 A series of m separated by an inter-group time interval 142 (eg, a second time interval) 2 Such groups form a packet 132 (eg, a second pulse group). The duration t between one packet and the next 3 A series of m separated by a time interval 142 (eg, a third time interval) 3 Such groups form the next level in the hierarchy, a super group (e.g., the third pulse group) labeled 134 in the figure. In some embodiments, the time interval t 3 Comparable time interval t 2 In some embodiments, the time interval t 3 Comparable time interval t 2 In some embodiments, the ratio t 3 / t 2 The amplitude of the individual voltage pulses in the pulse level may be anywhere in the range of 500 volts to 7,000 volts or more, including all values ​​and subranges therebetween.

[0047] Figure 5 An example of a biphasic waveform sequence having a layered structure is provided. In the example shown in the figure, a biphasic pulse such as 151 has a positive voltage portion and a negative voltage portion to complete one cycle of the pulse. The duration t 1 There is a time delay 152 (eg, a first time interval) between adjacent cycles of n 1 Such cycles form a pulse group 153 (eg, the first pulse group). The duration t between one group and the next 2 A series of n groups separated by an inter-group time interval 156 (eg, a second time interval) 2 Such groups form a packet 158 ​​(eg, a second pulse group). The figure also shows a second packet 162 with a duration t between the packets. 3 The time delay t160 (e.g., the third time interval) of the pulses may be formed. As with the monophasic pulses, higher levels of the hierarchical structure may also be formed. The amplitude of each pulse or the voltage amplitude of the biphasic pulses may be anywhere in the range of 500 volts to 7,000 volts or more, including all values ​​and subranges therebetween. The pulse width / pulse duration may be in the range of nanoseconds or even sub-nanoseconds to tens of microseconds, while the delay t 1It can be in the range of zero to a few microseconds. The time interval between groups t 2 The time interval t may be at least ten times greater than the pulse width. 3 Comparable time interval t 2 In some embodiments, the time interval t 3 Comparable time interval t 2 At least fifty times bigger.

[0048] Embodiments disclosed herein include waveforms constructed as layered waveforms that include waveform elements / pulses at different levels of the hierarchy. Individual pulses such as Figure 3 115 comprises a first level of the hierarchy and has associated pulse durations and first time intervals between consecutive pulses. The pulse groups or elements of the first level structure form a second level of the hierarchy, such as Figure 3 Among other parameters, associated with the waveform are parameters such as a total duration of the second pulse group describing the second level structure / second pulse group (not shown), a total number of first level elements / first pulse groups, and a second time interval between consecutive first level elements. In some embodiments, the total duration of the second pulse group may be between about 20 microseconds and about 10 milliseconds, including all values ​​and subranges therebetween. A group, second pulse group, or element of the second level structure forms a third level of the hierarchy, such as Figure 3 The grouping / third pulse group 122 of the waveform. Among other parameters, there is a total duration of the third pulse group (not shown), a total number of second level elements / second pulse groups, and a third time interval between consecutive second level elements that describe the third level structure / third pulse group. In some embodiments, the total duration of the third pulse group may be between about 60 microseconds and about 200 milliseconds, including all values ​​and subranges therebetween. The general iterative or nested structure of the waveform may continue to multiple levels higher, such as a ten-level structure or more.

[0049] In some embodiments, layered waveforms with nested structures and time interval hierarchies as described herein are useful for irreversible electroporation ablation energy delivery, thereby providing a good degree of control and selectivity for application in different tissue types. A variety of layered waveforms can be generated using a suitable pulse generator. It should be understood that although the examples herein identify separate monophasic waveforms and biphasic waveforms for clarity, it should be noted that combined waveforms can also be generated / implemented in which some portions of the waveform hierarchy are monophasic and other portions are biphasic.

[0050] In embodiments involving treatment of cardiac ablation, the above-described pulse waveform may be applied bipolarly using electrodes selected from a set of electrodes on a catheter, such as an ablation catheter. A subset of the electrodes of the catheter may be selected as anodes, and another subset of the electrodes of the ablation catheter may be selected as cathodes, wherein the voltage waveform is applied between the anodes and cathodes. As a non-limiting example, where the ablation catheter is an epicardially placed ablation catheter, the catheter may be wrapped around a pulmonary vein, and one electrode may be selected as an anode and another electrode may be selected as a cathode. Figure 6 An exemplary circular catheter configuration is shown in which substantially diametrically opposed electrode pairs (e.g., electrodes 603 and 609, electrodes 604 and 610, electrodes 605 and 611, and electrodes 606 and 612) can be activated as an anode-cathode group. Any of the disclosed pulse waveforms can be applied gradually or sequentially to a sequence of such electrode groups. As a non-limiting example, Figure 6 Describe the sequence of electrode subgroup activation. As a first step, electrodes 603 and 609 are selected as anodes and cathodes, respectively, and a voltage waveform having a layered structure as described herein is applied across these electrodes. In the case of a small time delay (e.g., less than about 5 milliseconds), as a next step, electrodes 604 and 610 are selected as anodes and cathodes, respectively, and the waveform is applied across the group of electrodes again. After a small time delay, as a next step, electrodes 605 and 611 are selected as anodes and cathodes for the next application of the voltage waveform, respectively. In the next step, after a small time delay, electrodes 606 and 612 are selected as anodes and cathodes for voltage waveform application, respectively. In some embodiments, one or more waveforms applied across electrode pairs are applied during the refractory period of the cardiac cycle, as described in more detail herein.

[0051] In some embodiments, the ablation pulse waveforms described herein are applied during the refractory period of the cardiac cycle to avoid interruption of the sinus rhythm of the heart. In some embodiments, the treatment method includes electrically pacing the heart with a cardiac stimulator to ensure pacing capture to establish periodicity and predictability of the cardiac cycle, and then defining a time window within the refractory period of the cardiac cycle within which one or more pulse ablation waveforms can be delivered. Figure 7 An example of applying atrial and ventricular pacing (e.g., where pacing leads or catheters are located in the right atrium and right ventricle, respectively) is shown. With time represented on the horizontal axis, Figure 7 A series of ventricular pacing signals (such as 64 and 65) and a series of atrial pacing signals (such as 62 and 63) are shown, as well as a series of ECG waveforms 60 and 61 driven by the pacing signals. Figure 7 As indicated by the thick arrows in FIG. 1 , there are an atrial refractory period time window 68 and a ventricular refractory period time window 69 that follow the atrial pacing signal 62 and the ventricular pacing signal 64, respectively. Figure 7As shown, the duration T r The common refractory time window 66 can be defined as being between the atrial refractory time window 68 and the ventricular refractory time window 69. In some embodiments, the electroporation ablation waveform can be applied in this common refractory time window 66. The starting point of this refractory time window 68 is offset from the pacing signal 64 by a time offset 59, such as Figure 7 As shown. In some embodiments, the time offset 59 may be less than about 25 milliseconds. At the next heartbeat, a similarly defined common refractory time window 67 is the next time window available for application of the ablation waveform. In this way, the ablation waveform can be applied over a series of heartbeats, each heartbeat remaining within the common refractory time window. In one embodiment, each grouping of pulses as defined above in the pulse waveform hierarchy can be applied over a heartbeat, such that for a given electrode group, a series of groups are applied over a series of heartbeats.

[0052] Figure 8 1 shows the timing of electrode activation on a series of electrode groups according to an embodiment. Using the exemplary scenario where a layered ablation waveform needs to be applied to j electrode groups (each electrode group typically includes at least one anode and at least one cathode), in some embodiments, cardiac pacing is utilized as described above, and a pulse group (such as including one or more pulse groups or one or more pulse groups) is first applied to electrode group 1, and only a small time delay t d (on the order of about 100 μs or less) a pulse packet is applied to electrode set 2. Subsequently, with another time delay, the pulse packet is applied to electrode set 3 and so on to electrode set j. This sequence 632 of application of pulse packets to all j electrode sets is delivered during a refractory time window of a single heartbeat (such as a common refractory time window 66 or 67), and each application to an electrode set constitutes one packet for that electrode set. Now consider the case of a monophasic layered waveform. Reference Figure 3 The example of a monophasic waveform shown has a series of monophasic pulses each having a pulse width w, the pulses being separated by a duration t between successive pulses. 1 The time intervals are separated by the number m 1 The pulses are arranged to form a pulse group. In addition, the waveform has a duration t between consecutive groups. 2 The number of time intervals separated by m 2 If this waveform is applied sequentially to groups of j electrodes as described in this paper, we can write the inequality

[0053] j[m 2 (m 1 w+t 1 (m 1 -t))+t 2(m 2 -1)]+t d (j-1)<T r (1)

[0054] Pulse waveform parameter m 1 and m 2 The given number of electrode groups j must be met so that the entire ablation pulse delivery occurs within the refractory time window. r In some embodiments, the refractory time window T r The time interval w, t may be about 140 milliseconds or less. The time offset of the starting point of the refractory window relative to the pacing signal may be less than about 10 milliseconds. 1 ,t 2 and t d can be arbitrary, and when implemented using a finite state machine such as, for example, a computer processor, they are integers measured in some suitable units (such as, for example, microseconds, nanoseconds, or multiples of the basic processor clock cycle). Given the number of electrode groups j, equation (1) represents a Diophantine inequality that constrains the pulse waveform parameters (pulse width, time interval, and number of pulses and groups) on each other so that the total duration of the waveform application on the j electrode groups is less than a given common refractory period. In some embodiments, a solution set for the Diophantine inequality can be found based on partial constraints on the pulse waveform parameters. For example, the generator may require input of some pulse waveform parameters and / or related parameters, such as pulse width w and time delay, t d Afterwards, the system console determines the remaining pulse waveform parameters. In this case, the number of electrode groups j is also an input for the system's constraint solution determination. In one embodiment, the system console may display more than one such possible solution set of waveform parameters for user selection, while in alternative embodiments, the system automatically selects or determines the waveform parameters. In some embodiments, the solution can be calculated and implemented directly in a predetermined form, such as on a pulse generator system console. For example, all pulse waveform parameters are predetermined to satisfy a Diophantine inequality similar to equation (1), and the waveform is pre-programmed on the system; the solution that may be predetermined may depend on the number of electrode groups j, or alternatively, the maximum number of electrode groups may be assumed to be predetermined. In some embodiments, more than one solution may be predetermined and made available for user selection on the system console.

[0055] Although Diophantine inequality (1) applies to the delivery of a single waveform packet within a single refractory period time window, a full waveform may sometimes involve multiple packets. The number of packets may be predetermined, and in one embodiment may be in the range of 1 to 28 packets, including all values ​​and subranges therebetween. In one embodiment, T rThe appropriate refractory time window may be predetermined and / or predefined, or in an alternative embodiment, it may be selected by a user from within some predetermined range. Although inequality (1) is explicitly written for a monophasic layered waveform, a similar inequality may be written for a biphasic waveform or for a waveform combining monophasic and biphasic elements.

[0056] Figure 8 A schematic diagram of ablation waveform delivery on multiple electrode groups j with a series of groupings at the top level of the waveform hierarchy is provided. The first waveform grouping 632 is delivered over a continuous series of j electrode groups within the entire electrode sequence; the waveform parameters of this sequence satisfy the Diophantine inequality, such as equation (1). This entire voltage waveform sequence is delivered within the defined refractory period time window of a single paced heartbeat. The grouping delay t is equal to one pacing cycle. 3 After that, the next waveform packet 633 is delivered through the consecutive j electrode groups within the entire electrode sequence with the same waveform parameters. Waveform delivery continues over a predetermined number of packets until the last waveform packet 636 is delivered over the consecutive j electrode groups. Thus, ablation delivery occurs over as many paced heartbeats as packets. As is appropriate and convenient for clinical applications, the voltage amplitude of the waveform may be in the range between about 700V and about 10,000V, and more preferably in the range between about 1,000V and about 8,000V, including all values ​​and sub-ranges therebetween.

[0057] In some embodiments, a complete sequence of electrode groups can be subdivided into smaller subsequences of electrode groups / electrode subgroups. For example, a complete sequence of j electrode groups can be subdivided into smaller subsequences of electrode groups / electrode subgroups having j electrodes in the first subsequence / first subgroup. 1 electrode groups, having j in the second subsequence / second subgroup 2 The electrode groups, etc., have j N The waveform grouping is first in the jth of the first subsequence. 1 On the electrode groups, then in the second subsequence j 2 The process may be applied to multiple electrode groups, and so on, where cardiac pacing is employed throughout the process and all waveform groups are applied within the appropriate refractory period time window.

[0058] Fig. 9is a schematic diagram of the system architecture of an ablation system 200 configured to deliver a pulse voltage waveform. The system 200 includes a system console 215, which in turn includes a pulse waveform generator and controller 202, a user interface 203, and a switch 205, which is used to isolate the connection box 210 (which can connect multiple catheters) from the voltage pulses delivered by the generator. In some embodiments, the generator / controller 202 may include a processor, which may be any suitable processing device configured to run and / or execute a set of instructions or codes. The processor can be, for example, a general-purpose processor, a field programmable gate array (FPGA), an application specific integrated circuit (ASIC), a digital signal processor (DSP), etc. The processor can be configured to run and / or execute application processes and / or other modules, processes, and / or functions associated with the system and / or a network associated therewith (not shown).

[0059] In some embodiments, the system 200 may further include a memory and / or database (not shown) configured to, for example, store pacing data, waveform information, etc. The memory and / or database may independently be, for example, a random access memory (RAM), a memory buffer, a hard drive, a database, an erasable programmable read-only memory (EPROM), an electrically erasable read-only memory (EEPROM), a read-only memory (ROM), flash memory, etc. The memory and / or database may store instructions to cause the generator / controller 202 to perform modules, processes, and / or functions associated with the system 200, such as pulse waveform generation and / or cardiac pacing.

[0060] The system 200 can communicate with other devices (not shown) via, for example, one or more networks, each of which can be any type of network implemented as a wired network and / or a wireless network, such as a local area network (LAN), a wide area network (WAN), a virtual network, a telecommunications network, and / or the Internet. As is known in the art, any or all communications can be protected (e.g., encrypted) or unprotected. The system 200 may include and / or comprise a personal computer, a server, a workstation, a tablet computer, a mobile device, a cloud computing environment, an application or module running on any of these platforms, and the like.

[0061] The system console 215 delivers ablation pulses to an ablation catheter 209, which is appropriately positioned in the patient's anatomy, such as, for example, in a loop around the patient's pulmonary veins in the pericardial space of the patient's heart. An intracardiac ECG recording and pacing catheter 212 is coupled to an ECG recording system 208 via a connection box 210. The ECG recording system 208 is connected to a cardiac stimulator or pacing unit 207. The cardiac stimulator 207 can send pacing outputs to the recording and pacing catheter 212; typically, both atrial and ventricular pacing signals can be generated as outputs from the cardiac stimulator 207, and in some embodiments, there can be separate intracardiac atrial and ventricular pacing catheters (not shown) or leads, each of which can then be set and / or positioned in the appropriate cardiac chamber. The same pacing output signal is also sent to the ablation system console 215. The pacing signal is received by the ablation system console, and based on the pacing signal, an ablation waveform can be generated by the generator / controller 202 within a common refractory window, as described herein. In some embodiments, the common refractory window may begin substantially immediately after the ventricular pacing signal (or after a very small delay) and thereafter last for a duration of about 130 ms or less. In this case, as previously described, the entire ablation waveform packet is delivered within this duration.

[0062] The user interface 203 associated with the ablation system console 215 can be implemented in a variety of forms that are convenient for use in the application. When the epicardial ablation catheter is delivered via a subxiphoid approach and placed epicardially around a pulmonary vein as shown in FIG. 1 , the ends can be tied in place at ends 8 and 9 by passing the ends through a tie tool. Depending on the size of the specific left atrial anatomy, a subset of the electrodes can be arranged around the pulmonary vein in a surrounding manner, while the remainder of the electrodes can be pulled into the tie tool (not shown in FIG. 1 ) and are therefore not exposed. In such an embodiment, the surrounded / exposed electrodes can be selectively used to deliver ablation energy. Fig.10 An embodiment of a user interface suitable for use with an ablation catheter is schematically depicted. Fig.10 6, the user selects the number of proximal electrodes within the tie tool and the number of distal electrodes within the tie tool as indicated in windows 653 and 654, respectively, where the user makes selections 650 and 651 for the corresponding number of electrodes, respectively. The complementary electrodes / subsets of electrodes on the catheter that are not within the tie tool (taken from the entire catheter electrode set) are the exposed electrodes that will be used in the delivery of the pulsed electric field for electroporation ablation. The amplitude of the waveform to be delivered is controlled by an input mechanism, such as a slider 658, which can be adjusted in Fig.10657 in the predetermined voltage range shown in FIG. Once the voltage amplitude is selected, an initialization (initialize) button 655 provided on the user interface is engaged to prepare the ablation system for energy delivery. In one example, this can take the form of a trigger for charging a capacitor bank to store energy for subsequent delivery to the catheter.

[0063] like Fig.11 As shown, the initialization button 660 can also be used as a status indicator to indicate that the initialization process is in progress. The status can be indicated by text (such as Fig.11 ” and / or a color such as yellow to indicate that initialization has not yet begun or is still in progress). Once the initialization process is complete (e.g., the capacitor bank is fully or satisfactorily charged), as shown Fig.12 As shown, the same button 663 now indicates that the process is complete ("Initialized"), and in some embodiments, as shown, it may change color (e.g., from yellow to green) and / or shape to further indicate completion of initialization. At the same time, the ablation system waits to receive a pacing signal from the cardiac stimulator or pacing unit. Once the pacing signal is detected and / or confirmed along with the completion of the initialization process, the second button 665 now becomes available for the user to engage to confirm pacing capture. If the ablation system console does not detect a pacing signal, the second button 665 is not enabled. The user can monitor the ECG display (not shown) to observe the cardiac stimulator pacing output in conjunction with the intracardiac ECG recording to confirm pacing capture (this confirms that atrial and ventricular contractions are indeed driven by the pacing signal so as to establish a predictable common refractory period window). Once the user visually confirms pacing capture from the ECG data, he can engage the "Confirm Pacing Capture" button 665 to confirm pacing capture on the ablation system.

[0064] like Fig.13As shown, once pacing capture is confirmed on the ablation system, the system can now be used for ablation or pulsed electric field delivery. The pacing capture confirmation button now changes appearance 670 (the appearance can change color, shape, etc.) and is indicated by 670 as being ready for ablation delivery. In addition, the ablation delivery button 675 now becomes available to the user. The user can engage the ablation delivery button 675 to deliver ablation synchronously with the paced rhythm. In some embodiments, the user engages the button 675 for the duration of the ablation delivery, and at the end of the ablation, the button changes shape or color to indicate the completion of the ablation delivery. In some embodiments, if the user disengages from the button 675 before the ablation delivery is completed, the ablation delivery stops immediately with only a small time lag of no more than, for example, 20ms. In some embodiments, if the user has not engaged the ablation button 675 after being displayed as available, it remains available for engagement as a safety mechanism before it is disabled, and only for a limited duration. In some embodiments, the ablation button 675 can be a software or graphical button on a user interface display, while in another embodiment, it can be a mechanical button that responds according to its activation state or availability determined by the system, or in another embodiment, the button 675 can be in the form of any variety of control input devices, such as a lever, a joystick, a computer mouse, etc., without limitation. In one embodiment, the ablation system can have a separate emergency stop button for additional safety, such as if it is desired to immediately deactivate the system. In one embodiment, the ablation console can be mounted on a rolling trolley or wheeled cart, and the user can control the system using a touch screen interface in a sterile area. The touch screen can be, for example, an LCD touch screen that can be mounted in a plastic housing of a standard medical rail or pillar, and the touch screen can have at least the above-mentioned functions. For example, the interface can be covered with a clean sterile plastic drape.

[0065] The waveform parameters described in detail herein can be determined by the design of the signal generator, and in some embodiments the parameters can be predetermined. In some embodiments, at least a subset of the waveform parameters can be determined by user control, such as may be convenient for a given clinical application. The specific examples and descriptions herein are exemplary in nature, and based on the materials taught herein, those skilled in the art may develop various variations without departing from the scope of the embodiments disclosed herein.

[0066] One or more embodiments described herein relate to computer storage products having non-transitory computer-readable media (also referred to as non-transitory processor-readable media) having thereon instructions or computer codes for performing various computer-implemented operations. Computer-readable media (or processor-readable media) are non-transitory in the sense that they do not themselves include temporary propagating signals (e.g., propagating electromagnetic waves that carry information on a transmission medium such as space or cables). The media and computer codes (also referred to as codes or algorithms) may be those designed and constructed for a specific purpose. Examples of non-transitory computer-readable storage media include, but are not limited to: magnetic media such as hard disks, floppy disks, and magnetic tapes; optical media such as compact disks / digital video disks (CD / DVD), compact disk read-only memories (CD-ROMs), and holographic devices; magneto-optical storage media such as optical disks; carrier signal processing modules; and hardware devices specifically configured for storing and executing program codes, such as application specific integrated circuits (ASICs), programmable logic devices (PLDs), read-only memories (ROMs), and random access memory (RAM) devices. Other embodiments described herein relate to computer program products, which may include, for example, instructions and / or computer codes disclosed herein.

[0067] One or more embodiments and / or methods described herein may be implemented by software (implemented on hardware), hardware, or a combination thereof. Hardware modules may include, for example, a general purpose processor (or microprocessor or microcontroller), a field programmable gate array (FPGA), and / or an application specific integrated circuit (ASIC). Software modules (implemented on hardware) may be expressed in a variety of software languages ​​(e.g., computer code), including C, C++, Ruby, Visual 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 generated by a compiler, code for generating web services, and files containing higher-level instructions executed by a computer using an interpreter. Other examples of computer code include, but are not limited to, control signals, encrypted code, and compressed code.

[0068] Although various embodiments have been described above, it should be understood that the embodiments are presented by way of example only and not by way of limitation. Although the method described above indicates that certain events occur in a certain order, the ordering of certain events may vary. In addition, certain events may be performed simultaneously in parallel processes where possible, as well as sequentially as described above.

Claims

1. A system comprising: Pulse waveform generator; as well as an ablation device coupled to the pulse waveform generator, the ablation device comprising at least one electrode configured to deliver ablative pulses to tissue during use; wherein the pulse waveform generator is configured to deliver voltage pulses to the ablation device in the form of a pulse waveform, wherein: (a) a first level of the hierarchy of pulse waveforms comprises a first pulse group, wherein pulses in the first pulse group are biphasic pulses, each pulse having a voltage amplitude ranging from 500 volts to 7000 volts and a pulse duration ranging from 0.5 nanoseconds to 20 microseconds, and a first time interval separating consecutive pulses; (b) a second level of the hierarchy of the pulse waveform comprises a plurality of first pulse groups as second pulse groups, a second time interval separating consecutive first pulse groups, the second time interval being at least ten times the pulse duration; and (c) a third level of said hierarchy of said pulse waveforms comprises a plurality of second pulse groups as third pulse groups, a third time interval separating consecutive second pulse groups, said third time interval being at least twenty times said duration of said second time interval, wherein the pulse waveform generator is configured to apply a plurality of third pulse groups to a predetermined number of electrode groups of the ablation device, wherein there is a time delay between consecutive third pulse groups, Wherein the pulse waveform generator is further configured to generate the pulse waveform so that each of the first pulse groups and each of the second pulse groups, the predetermined number of electrode groups, the time delay, the pulse duration, the first time interval, the second time interval and the third time interval are jointly constrained by the Diophantine inequality.

2. The system of claim 1, wherein each second pulse group includes at least 2 first pulse groups and less than 40 first pulse groups.

3. The system of claim 1, wherein each third pulse group includes at least 2 second pulse groups and less than 30 second pulse groups.

4. The system of claim 1, wherein the pulses in each first pulse group have a voltage amplitude of at least 800 volts.

5. The system of claim 1, wherein the ablation device comprises an ablation catheter configured for epicardial placement.

6. The system of claim 1, wherein the ablation device comprises an ablation catheter configured for endocardial placement.

7. The system of claim 1, wherein the pulse waveform generator is configured to apply a plurality of the third pulse groups to the ablation device, wherein consecutive third pulse groups have a time delay of at most 5 milliseconds between them.

8. The system of claim 1 , further comprising a cardiac stimulator coupled to the pulse waveform generator, the cardiac stimulator configured to generate a pacing signal for cardiac stimulation during use, The pulse waveform generator is configured to deliver voltage pulses to the ablation device in the form of a pulse waveform, wherein the pulse waveform is synchronized with the pacing signal.

9. The system of claim 8, wherein the pulse waveform generator is further configured to deliver the pulse waveform spaced apart from the pacing signal with a time offset that is less than 25 milliseconds.

10. The system of claim 9, the third time interval corresponding to a pacing cycle associated with the pacing signal.

11. The system of claim 1, wherein the Diophantine inequality constraint is further characterized by a refractory time window.

12. The system of claim 11, wherein the number of the first pulse groups and the number of the second pulse groups are predetermined.

Images