Generating ire with a ramp

Abstract

The invention is entitled "IRE generation initiated with ramps." A method for ablating tissue in a subject, comprising: providing a probe having an electrode, the probe inserted into a lumen of the subject such that the electrode is proximate to tissue to be ablated; injecting a fixation signal into the subject via the electrode, the fixation signal fixing the subject; while the subject is fixed, injecting an ablation signal into the subject via the electrode, the ablation signal configured to ablate tissue of the subject by irreversible electroporation. The ablation signal has at least one train of first pulses, each of the first pulses in the at least one train having a first pulse absolute amplitude, and the fixation signal has one or more trains of second pulses, each of the second pulses in the one or more trains having a second pulse absolute amplitude that is less than the first pulse absolute amplitude.

Description

[0001] Cross-references to related applications This application claims the benefit of U.S. Provisional Patent Application 63 / 159,412, filed March 10, 2021, which is incorporated herein by reference. Technical Field

[0002] This disclosure relates in general to ablation for surgical procedures, and more specifically to ablation performed using irreversible electroporation (IRE). Background Technology

[0003] Intracellular respiration (IRE) is a soft tissue ablation technique that applies short pulses of a strong electric field to create permanent and therefore lethal nanopores in the cell membrane, thereby disrupting cellular homeostasis (internal physical and chemical conditions). The cell death following IRE is due to apoptosis (programmed cell death) rather than necrosis (cell damage, which leads to cell destruction through the action of its own enzymes), as in all other heat- or radiation-based ablation techniques. IRE is commonly used for tumor ablation in areas where the precision and preservation of the extracellular matrix, blood flow, and nerves are crucial. Some examples of systems using IRE are provided below.

[0004] U.S. Patent 9,867,652 to Sano et al. describes an IRE that is applied through the vascular system of an organ to treat tumors deeply embedded in tissue or organ, or to decellularize an organ to create a scaffold from existing animal tissue while the existing vascular system remains intact. The patent states that "the point at which irreversible electroporation occurs can be determined by gradually increasing the voltage and testing the cells in a given tissue." U.S. Patent Application 20180289417 A1, granted to Schweitzer et al., describes an electroporation system and method for pretreating tissue for electroporation therapy. The electroporation generator includes electroporation circuitry and pretreatment circuitry. The pretreatment circuitry is configured to be coupled to a pretreatment electrode for stimulating skeletal muscle tissue in a patient and is further configured to transmit a pretreatment signal to the pretreatment electrodery.

[0005] U.S. Patent 10,286,108, granted to Davalos, describes how IRE can be used to form tissue scaffolds. The scaffolds are derived from natural tissue and formed using non-thermal irreversible electroporation.

[0006] This disclosure will be more fully understood through the following detailed description of examples of this disclosure, taken in conjunction with the accompanying drawings, wherein: Attached Figure Description

[0007] Figure 1 This is a schematic diagram of an IRE (Irreversible Electroporation) system used in ablation procedures; Figure 2 This is a schematic voltage-to-time plot of a bipolar IRE pulse; Figure 3 This is a schematic voltage-time plot of a bipolar pulse burst; Figure 4 This is a schematic diagram of the fixed signal and the IRE ablation signal; and Figure 5 This is a flowchart illustrating the steps of the IRE ablation procedure using a fixed signal. Detailed Implementation

[0008] Overview A fundamental problem with IRE ablation is that the subject may jump or spasm when the IRE pulse is initially applied. Spasm is caused by the high electric field of the high-voltage IRE pulse causing contractions in the subject's muscles, bones, or diaphragm. For example, if the catheter probe was initially positioned at the desired location in the myocardium, spasm can lead to traumatic conditions.

[0009] The example disclosed incorporates a ramp period into pulse generation, rather than initially applying the IRE pulse at its full voltage amplitude. During the ramp period, the pulse amplitude gradually increases while remaining below the effective IRE voltage. During the ramp period, the pulse amplitude is low enough that IRE does not occur. After the ramp period, the full IRE voltage amplitude can be applied, causing IRE to occur.

[0010] The initial low-voltage pulse locks the subject's muscles without inducing IRE, thus immobilizing the subject and preventing spasms when the full IRE voltage is reached.

[0011] The ramp can be any convenient shape, such as linear or exponential. The typical length of the ramp period is about 0.5 s.

[0012] System Description See now Figure 1 This figure is a schematic illustration of a multichannel IRE (irreversible electroporation) system 20 used in an IRE ablation procedure. In the illustrated example, physician 22 uses IRE system 20 to perform a multichannel IRE ablation procedure. Physician 22 uses ablation catheter probe 26 to perform the procedure on the heart 52 of subject 24, the distal end 28 of which includes a plurality of ablation electrodes 30 arranged along the length of the distal end.

[0013] IRE system 20 includes processor 32 and IRE module 34, and the IRE module includes IRE generator 36 and IRE controller 38. An IRE generator similar to generator 36 is described in U.S. Patent Application 16 / 701,989. As described in detail below, IRE generator 36 generates electrical pulse trains that are directed to selected electrodes 30 to generate a current 72 between the two electrodes to perform IRE procedures. The waveform (timing and amplitude) of the electrical pulse train is controlled by IRE controller 38. Processor 32 also describes in detail below, operating the input and output interface between IRE system 20 and physician 22.

[0014] Processor 32 and IRE controller 38 typically each include a programmable processor programmed in software and / or firmware to perform the functions described herein. Alternatively or additionally, the processor and controller may include hard-wired and / or programmable hardware logic circuitry to perform at least some of these functions. Although processor 32 and IRE controller 38 are shown in the accompanying drawings, for simplicity, they are represented as separate monolithic functional blocks; in reality, some of these functions may be combined in a single processing and control unit. In some examples, IRE controller 38 resides within IRE module 34 because high-speed control signals are typically transmitted from IRE controller to IRE generator 36. However, if signals can be transmitted from processor 32 to IRE generator 36 at a sufficiently high speed, IRE controller 38 may reside within the processor.

[0015] Processor 32 and IRE module 34 are typically located within console 40. Console 40 includes input devices 42 operated by physician 22, such as a keyboard and mouse. Display screen 44 is positioned close to console 40. Display screen 44 may optionally include a touchscreen, thus providing another input device.

[0016] IRE system 20 may additionally include one or more of the following modules (typically residing within console 40): • An electrocardiogram (ECG) module 46 is coupled via a cable 48 to an ECG electrode 50 attached to a subject 24. The ECG module 46 is configured to measure the electrical activity of the subject 24's heart 52.

[0017] • The temperature module 54 is coupled to a temperature sensor 56 (such as a thermocouple) located near each electrode 30 on the distal end 28 of the catheter 26 and is configured to measure the temperature of adjacent tissue 58.

[0018] • The tracking module 60 is coupled to one or more electromagnetic position sensors 61 in the distal end 28. In the presence of an external magnetic field generated by the magnetic field generator 62, the electromagnetic position sensors output signals that vary with the sensor's position. Based on these signals, the tracking module 60 can determine the position of the electrode 30 within the heart 52.

[0019] The position tracking method using an external magnetic field was applied to CARTO, manufactured by Biosense Webster Inc. (Irvine, California). ™ The system is implemented and described in detail in U.S. Patents 5,391,199, 6,690,963, 6,484,118, 6,239,724, 6,618,612 and 6,332,089, PCT Patent Publication WO 96 / 05768 and U.S. Patent Application Publications 2002 / 0065455 A1, 2003 / 0120150 A1 and 2004 / 0068178 A1.

[0020] Alternatively or otherwise, module 60 may use a tracking system based on the current transmitted through electrode 30 or the impedance seen by the electrode. In such a system, module 60 estimates the position of a given electrode 30 in response to the current or impedance between a given electrode and a plurality of surface electrodes 63 coupled to the skin of subject 24. The Advanced Current Positioning (ACL) system manufactured by Biosense-Webster (Irvine, California) and described in U.S. Patent 8,456,182 is such a tracking system.

[0021] The catheter 26 is coupled to the console 40 via an electrical interface 64 (such as a port or socket). The IRE signal is thus carried to the distal end 28 via the interface 64. Similarly, signals for tracking the position of the distal port 28 and / or for tracking the temperature of the tissue 58 can be received by the processor 32 via the interface 64 and applied by the IRE controller 38 to control the pulses generated by the IRE generator 36.

[0022] External electrode 65 or “return patch” may be additionally externally coupled between subject 24 (typically on the skin of the subject’s torso) and IRE generator 36.

[0023] The following text is for reference only. Figure 2 and Figure 3 Table I describes the IRE signals generated by the IRE module. In addition to the descriptions below, the signals generated by the module are used by the selected electrode 30 to ablate tissue 58 adjacent to the electrode.

[0024] Figure 2This is a schematic diagram of the voltage versus time of a bipolar IRE pulse 100 according to an example of this disclosure.

[0025] Figure 2 The voltage V of the bipolar IRE pulse 100 as a function of time t is depicted. The bipolar IRE pulse includes a positive pulse 104 and a negative pulse 106, where the terms "positive" and "negative" refer to the arbitrary polarity of the two selected electrodes 30 to which the bipolar pulse is applied. The amplitude of the positive pulse 104 is denoted as V+, and the pulse's duration is denoted as t+. Similarly, the amplitude of the negative pulse 106 is denoted as V-, and the pulse's duration is denoted as t-. The time between the positive pulse 104 and the negative pulse 106 is denoted as t. 间隔 Typical values ​​for the parameters of the bipolar pulse 100 are given in Table 1 below.

[0026] Figure 3 This is a schematic diagram of the voltage versus time plot of a bipolar pulse burst 200 according to an example of this disclosure.

[0027] In IRE procedures, IRE signals are typically transmitted as one or more bursts 200 between a pair of selected electrodes 30 (by... Figure 3 (Depicted) such that one electrode in the pair can be considered as acting as an injection electrode, while the other electrode in the pair acts as a return electrode. Alternatively, the IRE signal can be transmitted between a selected electrode 30 and an external electrode 65, in which case the selected electrode 30 can be considered as acting as an injection electrode, and the external electrode 65 acts as a return electrode.

[0028] Sudden onset 200 includes N T There are 204 pulse trains, each consisting of N pulses. P One bipolar pulse 100, and N T N P It is a positive integer. The length of pulse train 204 is denoted as t. T The period of the bipolar pulse 100 within pulse train 204 is denoted as t. PP And the time interval between consecutive strings is marked as Δ. T No signal is applied during this time interval. Typical values ​​for the signal limiting parameters of a burst 200 IRE ablation signal are given in Table 1 below: parameter symbol Typical value Pulse amplitude V+, V- 500V-2000V Pulse width t+, t- 0.5µs-5µs The interval between positive and negative pulses <![CDATA[t 间隔 ]]> 0.1µs-5µs Period of bipolar pulses in a pulse train <![CDATA[t PP ]]> 1µs-20µs pulse train length <![CDATA[t T ]]> 10µs-100µs Number of bipolar pulses in a pulse train <![CDATA[N P ]]> 1-100 Interval between continuous pulse trains <![CDATA[Δ T ]]> 0.3ms-1000ms Number of pulse trains in burst <![CDATA[N T ]]> 1-100 Length of burst 0ms-500ms Energy of each channel ≤200J Total time for IRE signal delivery ≤10s Table I Fixed signal from Figure 2 and Figure 3As is evident in Table I, the IRE signal delivered to the subject 24 via one or a pair of selected electrodes 30 comprises a high-voltage pulse, i.e., a pulse with an amplitude of up to 2000V. The inventors have observed that the subject may experience spasms when the IRE signal is initially delivered, and it is believed that the spasms are caused by skeletal or diaphragmatic contractions of the subject's muscles due to the high voltage / field of the IRE pulse.

[0029] Spasms in the subject can lead to trauma. Spasms can also cause electrode 30 to move from its initial position, thus requiring electrode repositioning, which increases the time required for the ablation procedure.

[0030] This disclosure illustrates an example of preventing subject spasms by injecting a fixation signal into the subject 24 prior to the injection of the IRE ablation signal. The fixation signal locks the subject's muscles so that the subject no longer spasms when the IRE ablation signal is injected. Typically, the fixation signal is similar to the IRE ablation signal, except that the fixation signal has a lower absolute amplitude. The fixation signal is described in detail below.

[0031] In the examples of this disclosure, the fixed signal comprises a train of pulses with monotonically increasing amplitudes, all of which have absolute values ​​less than the absolute value of the amplitude of the ablation IRE signal. See below for reference. Figure 4 Describe a fixed signal.

[0032] Figure 4 Figure 300 is a schematic diagram of a fixed signal and an IRE ablation signal according to an example of this disclosure. Figure 300 is a voltage-to-time diagram, and segment 302 of the diagram includes the fixed signal, which is also referred to herein as fixed signal 302. Segment 306 of the diagram includes the IRE ablation signal, as shown, which is located after the fixed signal in time. The IRE ablation signal is also referred to herein as IRE ablation signal 306.

[0033] The parameters of the IRE ablation signal 306 are configured according to Table I. For example, it is assumed that signal 306 comprises four pulse trains 310, and are referred to herein as bursts 306. The parameters of each pulse train 310 are V+, V-, t+, t-, t... 间隔 t PP t T N P They are configured to be identical, as illustrated in Table I. The interval Δ between consecutive pulse trains 310 T As illustrated in Table I.

[0034] The fixed signal 302 includes one or more pulse trains 314A, 314B, 314C, ..., generally referred to as pulse trains 314. By way of example, assume that signal 302 includes three pulse trains 314. In examples of the present disclosure, pulse train 314 has the same parameters as pulse train 310, except for the pulse amplitudes V+, V-. Furthermore, the intervals between pulse trains 314 are the same as the intervals between pulse trains 310, and the spacing between the final pulse train of the fixed signal and the initial pulse train of the ablation signal is also the same.

[0035] For the ablation signal 306, the amplitude of the pulses within a given pulse train of the fixed signal is constant. However, compared with the ablation signal 306, the amplitudes of consecutive pulse trains of the fixed signal 302 (referred to herein as V+ imm and V- imm ) are not equal to each other, but vary monotonically over time. That is, V+ imm increases monotonically over time, and V- imm decreases monotonically over time. Therefore, the absolute value of the amplitude of consecutive pulse trains of the fixed signal increases monotonically in a ramp-like manner.

[0036] In the disclosed example, the amplitude of the fixed signal pulse trains varies from a lower limit fraction "b" of the amplitudes V+, V- of the ablation signal 306 to an upper limit fraction "u" of the amplitudes V+, V-, where 0<b<u<1. The variation may be linear or non-linear, for example, exponential. In the disclosed example, b=20% and u=70%, but other values of u and b are possible, provided that they follow the above inequality. Generally, and as Figure 4 shown, the total time ΔT of the fixed signal 302 imm is about 0.5s, but total times greater than or less than 0.5s are possible.

[0037] Typical values for the amplitudes of the fixed signal pulse trains and the total time of the fixed signal are given in Table II, which lists the signal-defining parameters of the fixed signal: Table II Figure 5 is a flowchart of steps of an IRE ablation procedure according to an example of the present disclosure, which illustrates the use of the fixed signal.

[0038] An IRE ablation procedure typically includes multiple bursts 200 of IRE signals applied between different pairs of selected electrodes 30 and / or between different selected electrodes 30 and an external electrode 65. (Each burst is typically applied sequentially to a first pair of electrodes, a second pair of electrodes, a third pair of electrodes, and so on.) In the examples of this disclosure, a fixed signal 302 may be applied prior to each burst in the burst; alternatively, a fixed signal 302 may be applied prior to selected bursts in the burst; and even more alternatively, a fixed signal 302 may be applied prior to only the first burst in the burst.

[0039] For simplicity in the following description, it is assumed that the IRE procedure includes a burst 200 transmitted between a pair of electrodes, such that one electrode 30 acts as the injection electrode, and the other electrode in the pair (which may be electrode 30 or electrode 65) acts as the return electrode. For other cases described above, i.e., for multiple bursts 200 applied to more than one pair of electrodes, those skilled in the art will be able to modify the description with the necessary changes.

[0040] In the initial setup step 400, physician 22 selects the IRE signal parameters to be used in the procedure. These are listed in Table I and referenced above. Figure 2 and Figure 3 The values ​​are selected as described above. Furthermore, physician 22 is listed in Table II and referenced above. Figure 4 The value of the fixed signal parameter is selected. The selection can be performed by any convenient method, such as by displaying a protocol with preset values ​​of the IRE signal parameter and the fixed signal parameter on screen 44 and allowing the physician to select a specific protocol.

[0041] During the setup process, the physician also selects a pair of electrodes to be used for injecting the IRE signal and fixing the signal. This pair of electrodes may include one electrode 30 acting as the injection electrode and another electrode 30 acting as the return electrode. Alternatively, the pair may include one electrode 30 acting as the injection electrode and an external electrode 65 acting as the return electrode. For signal parameters, selection can also be made by displaying a preset protocol on screen 44, allowing the physician to select the pair of electrodes to be used for IRE ablation.

[0042] In insertion step 404, to begin the procedure, physician 22 inserts catheter 26 into the subject's body through the lumen of subject 24 and then navigates the catheter using control handle 70 so that the selected injection electrode 30 approaches a selected portion of the tissue 58 to be ablated (referred to herein as the target tissue). Processor 32 uses tracking module 60 for navigation. The module typically displays the position of the distal end 28 and the electrode 30 (including the injection electrode 30 selected in step 400) on an image of the heart 52 presented on screen 44.

[0043] Once the injection electrode has been positioned close to the target tissue, the physician 22 initiates IRE ablation by providing a control signal to the processor 32 through any convenient means, such as using a control handle 70, input device 42, or foot switch (not shown).

[0044] Upon receiving a control signal, the processor 32 performs fixed step 408 and continuously performs the final ablation step 412.

[0045] In the fixing step 408, the processor uses the IRE module 34 to generate a fixing signal 302, which is based on the setting step 400 and is generally as follows: Figure 4 Configure the settings as shown by the selected values. The processor directs the fixation signal to the injection electrode 30, causing the electrode to inject the fixation signal into the subject 24. The fixation signal immobilizes the subject 24.

[0046] Upon completion of the fixation signal injection, while subject 24 is fixed, the processor proceeds to ablation step 412. In step 412, the processor uses IRE module 34 to generate ablation signal 308, which is also based on the setup step 400 and typically as follows: Figure 4 The selected values ​​are configured as shown. For step 408, in step 412, the processor directs the ablation signal to the injection electrode 30, causing the electrode to inject the ablation signal into the subject 24, thereby ablating the target tissue.

[0047] As used herein, the term “about” or “approximately” for any numerical value or range of an entity indicates a suitable dimensional tolerance that allows the entity to achieve its intended purpose as described herein. More specifically, “about” or “approximately” can refer to a range of ±20% of the stated value; for example, “about 90%” can refer to a value range of 72% to 108%, and “about 0.5s” can refer to a value range of 0.4s to 0.6s. Example

[0048] Example 1. A method for ablating tissue (58) in a subject (24), comprising: A probe (26) is provided, which includes an electrode (30), and is configured to be inserted into the lumen of the subject such that the electrode is close to the tissue to be ablated; A fixation signal is injected into the subject via the electrode, the fixation signal being configured to fix the subject; and While the subject is immobilized, an ablation signal is injected into the subject's body via the electrode. This ablation signal is configured to ablate the subject's tissue through irreversible electroporation. The ablation signal includes at least one string of first pulses, each of the first pulses in the at least one string having a first pulse absolute amplitude, and the fixed signal includes one or more strings of second pulses, each of the second pulses in the one or more strings having a second pulse absolute amplitude smaller than the first pulse absolute amplitude.

[0049] Example 2. According to the method of Example 1, the fixed signal includes a plurality of strings of these second pulses, and the absolute amplitude of the second pulse in each of the plurality of strings increases monotonically with time.

[0050] Example 3. The method according to Example 2, wherein the monotonically increasing is linear.

[0051] Example 4. The method according to Example 2, wherein the monotonically increasing is non-linear.

[0052] Example 5. According to the method of Example 1, wherein each of the at least one string of the first pulse and the one or more strings of the second pulse includes a plurality of pulses.

[0053] Example 6. According to the method described in Example 1, wherein the absolute amplitude of the second pulse is between 20% and 70% of the absolute amplitude of the first pulse.

[0054] Example 7. The method according to Example 1, wherein the first pulses and the second pulses include bipolar pulses.

[0055] Example 8. The method according to Example 1, wherein the total time of the fixed signal is in the range of 0.4s to 0.6s.

[0056] Example 9. The method according to Example 1, wherein the probe includes another electrode (30) configured to receive an injected ablation signal and an injected fixation signal.

[0057] Example 10. The method according to Example 1, and including an external electrode (65) located on the skin of the subject and configured to receive an injected ablation signal and an injected fixation signal.

[0058] Example 11. An apparatus for ablating tissue (58) in a subject (24), comprising: A probe (26), comprising an electrode (30), configured to be inserted into the lumen of the subject such that the electrode is close to the tissue to be ablated; and Processor (32), which is configured to: A fixation signal is injected into the subject's body via the electrode; the fixation signal is configured to fix the subject in place. While the subject is immobilized, an ablation signal is injected into the subject's body via the electrode. This ablation signal is configured to ablate the subject's tissue through irreversible electroporation. The ablation signal includes at least one string of first pulses, each of the first pulses in the at least one string having a first pulse absolute amplitude, and the fixed signal includes one or more strings of second pulses, each of the second pulses in the one or more strings having a second pulse absolute amplitude smaller than the first pulse absolute amplitude.

[0059] It should be understood that the above embodiments are cited by way of example, and this disclosure is not limited to the content specifically shown and described above. Rather, the scope of this disclosure includes combinations and sub-combinations of the various features described above, as well as variations and modifications thereof, which should be apparent to those skilled in the art upon reading the above description, and which are not disclosed in the prior art.

Claims

1. A device for ablating tissue within a subject, comprising: A probe including electrodes, the probe being configured to be inserted into the lumen of the subject such that the electrodes are close to the tissue to be ablated; as well as Processor, the processor being configured to: A fixation signal is injected into the subject via the electrodes, the fixation signal being configured to fix the subject in place. While the subject is immobilized, an ablation signal is injected into the subject's body via the electrode. This ablation signal is configured to ablate the subject's tissue via irreversible electroporation (IRE). The ablation signal comprises at least one sequence of first pulses, each of the first pulses in the at least one sequence having a first pulse absolute amplitude, and The fixed signal comprises multiple strings of second pulses, and the absolute amplitude of each second pulse increases monotonically with time, and is less than the absolute amplitude of the first pulse during the monotonically increasing period, while remaining less than the effective IRE voltage.

2. The device according to claim 1, wherein, The monotonically increasing phenomenon is linear.

3. The device according to claim 1, wherein, The monotonically increasing phenomenon is non-linear.

4. The device according to claim 1, wherein, The at least one string of the first pulse and each of the plurality of strings of the second pulse include a plurality of pulses.

5. The device according to claim 1, wherein, The absolute amplitude of the second pulse is between 20% and 70% of the absolute amplitude of the first pulse.

6. The device according to claim 1, wherein, The first pulse and the second pulse include bipolar pulses.

7. The device according to claim 1, wherein, The total duration of the fixed signal is in the range of 0.4s to 0.6s.

8. The device according to claim 1, wherein, The probe includes another electrode configured to receive an injected ablation signal and an injected fixation signal.

9. The device of claim 1, further comprising an external electrode located on the skin of the subject and configured to receive an injected ablation signal and an injected fixation signal.

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