Adjusting delivery of irreversible electroporation pulses according to transferred energy

Abstract

A medical device includes a probe configured for insertion into a body of a patient and including a plurality of electrodes configured to contact tissue within the body. An electrical signal generator applies a train of bipolar pulses between at least one pair of the electrodes in contact with the tissue, each bipolar pulse having a voltage amplitude of at least 200 V and a duration of less than 20 μs, thereby causing irreversible electroporation of the tissue between the at least one pair of the electrodes. One or more electrical sensors sense energy dissipated between the at least one pair of the electrodes during the train of pulses. A controller controls, in response to the one or more electrical sensors, an electrical parameter and a temporal parameter of the train of pulses applied by the electrical signal generator such that the dissipated energy satisfies a predefined criterion.

Description

Technical Field

[0001] The present invention relates generally to medical devices, and more particularly to methods and apparatus for monitoring the total electrical energy injected during an irreversible electroporation (IRE) procedure. Background Art

[0002] Irreversible electroporation (IRE) is a soft tissue ablation technique that applies short pulses of strong electric fields to create permanent and therefore lethal nanopores in cell membranes, thereby disrupting cell homeostasis (internal physical and chemical conditions). Cell death after IRE is due to apoptosis (programmed cell death) rather than necrosis (cell damage that leads to the destruction of the cell through the action of its own enzymes), as in all other ablation techniques based on heat or radiation. IRE is typically used to ablate tumors in areas where precision and preservation of the extracellular matrix, blood flow, and nerves are important. Summary of the Invention

[0003] The exemplary embodiments of the present invention described below provide improved methods and apparatus for performing IRE procedures.

[0004] Therefore, according to an exemplary embodiment of the present invention, a medical device is provided, which includes a probe configured for insertion into a patient's body and including a plurality of electrodes configured to contact tissue in the body. An electrical signal generator is coupled to at least one pair of electrodes in the electrodes to apply a bipolar pulse train having a voltage amplitude of at least 200V and a duration of less than 20μs between the electrodes in contact with the tissue, thereby causing irreversible electroporation of the tissue between the at least one pair of electrodes in the electrodes. One or more electrical sensors are coupled to the output end of the electrical signal generator and are configured to sense energy dissipated between the at least one pair of electrodes in the electrodes during the pulse train. A controller is coupled to control the electrical parameters and time parameters of the pulse train applied by the electrical signal generator in response to the one or more electrical sensors so that the dissipated energy meets predefined criteria.

[0005] In one exemplary embodiment, the electrical parameter controlled by the controller comprises voltage.Alternatively or additionally, the electrical parameter controlled by the controller comprises current.

[0006] In some exemplary embodiments, the controller is configured to control the electrical parameters so that the energy dissipated between each pair of electrodes meets a specified target value. In one exemplary embodiment, the controller is configured to adjust the peak amplitude of the pulses applied between at least one pair of electrodes so that the dissipated energy meets a predefined standard.

[0007] Typically, the one or more electrical sensors are configured to measure a voltage and a current flowing between at least one pair of the electrodes during a sequence of time intervals, and the controller is configured to measure the dissipated energy by calculating the sum of the products of the voltage and current over the sequence of time intervals.

[0008] In another exemplary embodiment, the controller is configured to control the time parameter so that the energy dissipated between each pair of electrodes in the electrodes meets a specified target value. In an exemplary embodiment, the controller is configured to adjust the number of pulses applied between the at least one pair of electrodes in the electrodes so that the energy dissipated meets a predefined standard. Alternatively or in addition, the controller is configured to adjust the duration of the pulses applied between the at least one pair of electrodes in the electrodes so that the energy dissipated meets a predefined standard.

[0009] According to an exemplary embodiment of the present invention, a method for ablating tissue in a patient's body is also provided. The method includes inserting a probe into the body, wherein the probe includes a plurality of electrodes configured to contact the tissue. A bipolar pulse train having a voltage amplitude of at least 200V and a duration of less than 20μs is applied between at least one pair of electrodes in the electrodes in contact with the tissue, thereby causing irreversible electroporation of the tissue between the at least one pair of electrodes in the electrodes. The energy dissipated between the at least one pair of electrodes in the electrodes during the pulse train is measured, and the electrical parameters and time parameters of the pulse train applied by the electrical signal generator are controlled in response to the measured energy so that the dissipated energy meets a predefined standard. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] The present invention will be more fully understood through the following detailed description of embodiments of the present invention in conjunction with the accompanying drawings, in which:

[0011] Figure 1 is a schematic illustration of a multi-channel IRE system for use in an IRE ablation procedure according to an exemplary embodiment of the present invention;

[0012] Figure 2 is a schematic illustration of a bipolar IRE pulse according to an exemplary embodiment of the present invention;

[0013] Figure 3 is a schematic diagram of a burst of bipolar pulses according to an exemplary embodiment of the present invention;

[0014] Figures 4A to 4B is a schematic diagram of an IRE signal with a combined RF signal according to an exemplary embodiment of the present invention;

[0015] Figure 5is a block diagram schematically illustrating an IRE module and its connections with other modules according to an exemplary embodiment of the present invention;

[0016] Figure 6 According to the exemplary embodiment shown in the figure Figure 5 Schematic diagram of the pulse routing and metering components in the IRE module;

[0017] Figure 7 According to an exemplary embodiment of the present invention Figure 6 A circuit diagram of two adjacent modules in a pulse routing and metering assembly;

[0018] Figure 8 is a circuit diagram of a pulse generating circuit, a transformer, and a high-voltage power supply according to an exemplary embodiment of the present invention;

[0019] Figure 9 is a circuit diagram of a switching device according to an exemplary embodiment of the present invention; and

[0020] Figure 10 FIG. 1 is a flow chart schematically illustrating a method for controlling an IRE procedure according to an exemplary embodiment of the present invention. DETAILED DESCRIPTION

[0021] Overview

[0022] IRE is a primarily non-thermal process, resulting in a tissue temperature increase of at most a few degrees within milliseconds. This differs from RF (radiofrequency) ablation, which raises tissue temperature by 20°C to 70°C and destroys cells through heating. IRE utilizes bipolar pulses—a combination of positive and negative pulses—to avoid muscle contraction due to direct current voltage. The pulses are applied, for example, between two bipolar electrodes in a catheter.

[0023] In order for an IRE pulse to generate the desired nanopore in tissue, the field strength E of the pulse must exceed the tissue-dependent threshold E th Thus, for example, for cardiac cells, the threshold is approximately 500 V / cm, while for bone, the threshold is approximately 3000 V / cm. These differences in threshold field strengths enable IRE to be applied selectively to different tissues. To achieve the required field strength, the voltage to be applied to a pair of electrodes depends both on the target tissue and on the spacing between the electrodes. The applied voltage can be as high as 2000 V, which is much higher than the typical voltage of 10 V to 200 V used in thermal radiofrequency ablation.

[0024] Bipolar IRE pulses comprise a positive pulse and a negative pulse applied between two electrodes, with a pulse width of 0.5 to 5 μβ, and a spacing between the positive and negative pulses of 0.1 to 5 μβ. (In this document, the terms "positive" and "negative" refer to an arbitrary choice of polarity between the two electrodes.) Bipolar pulses are assembled into pulse trains, each pulse train comprising one to one hundred bipolar pulses with a period between pulses of 1 to 20 μβ. To perform IRE ablation at a given location, one to one hundred pulse trains are applied between a pair of electrodes at that location, with an interval between successive pulse trains of 0.3 ms to 1000 ms. The total energy delivered per channel (pair of electrodes) in one IRE ablation is typically less than J60, and the ablation can last up to 10 s.

[0025] When a multi-electrode catheter is used in an IRE procedure, the successive pairs of electrodes can be cycled during the procedure. Using a 10-electrode catheter as an example, the pairs of electrodes can be energized in an adjacent fashion (1-2, 2-3,... 9-10) or in an interleaved fashion (1-3, 2-4,... 8-10). Energization of the adjacent pairs, for example, is performed in two stages, first energizing the odd-even pairs 1-2, 3-4, 5-6, 7-8, and 9-10, and then energizing the even-odd pairs 2-3, 4-5, 6-7, and 8-9.

[0026] Prior to starting an IRE procedure, the physician sets the procedure parameters based on, for example, the volume of tissue to be ablated, the field strength required within the tissue, the catheter configuration, and the energy to be delivered during the procedure.

[0027] Once the procedure is started, the IRE ablation pulses can affect the impedance of the tissue and / or the contact impedance between the electrodes and the tissue in addition to the desired effects of the electroporation itself. Changes in either of these impedances for a fixed duration and amplitude of the pulses will affect the current delivered by the pulses, and thus the energy transferred into the tissue from each pulse. This in turn will cause the total energy dissipated in the tissue during the procedure to deviate from the amount of energy preset by the physician. Thus, the effect of the IRE ablation can differ from the intended effect. Furthermore, two procedures with the same energy settings for the IRE ablation can in fact have different amounts of energy transferred to the tissue, thus potentially affecting the repeatability of these types of procedures. In particular, energy in excess of the preset level can result in undesirable thermal effects, such as bubble formation or charring of tissue around the electrodes.

[0028] The exemplary embodiments of the invention described herein address the problem of controlling the amount of energy delivered to tissue during an IRE procedure by measuring the actual energy dissipation between electrodes. Based on this measurement, the pulses delivered to the tissue by the catheter are controlled so that the amount of energy dissipated meets a predefined criterion. For example, the criterion may specify that the amount of energy dissipated meets a certain target value (i.e., the cumulative energy dissipated at each location in the tissue is equal to the target value within a certain error range, such as ±5% or ±10%). Alternatively or in addition, other criteria may be defined.

[0029] To this end, exemplary embodiments described herein provide a medical device comprising an electrical signal generator and a controller. The medical device also includes a probe that is inserted into a patient's body and includes a plurality of electrodes that contact tissue within the body and are used to apply electrical signals to the tissue for an IRE procedure. The controller receives setup parameters for implementing an IRE ablation protocol. These parameters can be preset or adjustable by an operator of the device, such as a physician. The controller instructs the signal generator to apply a bipolar pulse train between selected electrodes on the probe. For IRE, these pulses typically have a voltage amplitude of at least 200V and a duration of less than 20μs for each bipolar pulse pair to cause irreversible electroporation of the tissue between the selected electrodes. Alternatively, other suitable pulse parameters may be selected for this purpose.

[0030] To measure the pulse energy dissipated in tissue, electrical sensors are coupled to the output of an electrical signal generator. These sensors continuously sense the energy dissipated between the bipolar electrode pairs and transmit the measurement results to a controller. The controller calculates the dissipated energy and controls the electrical and temporal parameters of the pulse train applied by the electrical signal generator so that the dissipated energy reaches a target value or meets some other criteria. The electrical signal generator can be configured as a voltage source or a current source. In the former case, the electrical parameter controlled by the controller is primarily the voltage of the pulse, while in the latter case, the electrical parameter is primarily the current of the pulse.

[0031] To measure the energy dissipated, the controller receives measurements of the voltage between the electrodes and the current through the electrodes at successive intervals during the ablation procedure. From these measurements, the controller estimates the instantaneous power delivered to the tissue and, therefore, finds the cumulative energy dissipated in the tissue during the IRE procedure. The controller calculates adjustments that may be needed in the bipolar pulse train so that the total energy dissipated during the procedure meets applicable standards. To this end, the controller typically adjusts one or more of the following parameters: pulse amplitude (voltage amplitude or current amplitude, depending on whether the signal generator is a voltage source or a current source), pulse width (duration), number of pulses per pulse train, and number of pulse trains during the procedure. Alternatively, or in addition, the controller may calculate adjustments for a single bipolar pulse or pulse train so that the single pulse or pulse train will dissipate a preset amount of energy in the tissue.

[0032] In some exemplary embodiments, an electrical signal generator for IRE surgery can apply radiofrequency (RF) signals for thermal RF ablation of tissue in addition to bipolar pulses for IRE ablation. Measurement of energy dissipation by electrical sensors can also be used to monitor and control the thermal RF ablation process.

[0033] IRE Ablation System and IRE Pulse

[0034] Figure 1 FIG2 is a schematic diagram of a multi-channel IRE system 20 for use in an IRE ablation procedure according to an exemplary embodiment of the present invention. In the following description, an IRE ablation procedure will also be referred to as "IRE ablation" or "IRE procedure." In the exemplary embodiment shown, a physician 22 is performing a multi-channel IRE ablation procedure using the IRE system 20. The physician 22 is performing the procedure on a subject 24 using an ablation catheter 26 having a distal end 28 including a plurality of ablation electrodes 30 arranged along the length of the catheter 26.

[0035] The IRE system 20 includes a processor 32 and an IRE module 34, wherein the IRE module includes an IRE generator 36 and an IRE controller 38. As will be described in further detail below, the IRE generator 36 generates a train of electrical pulses that are directed to the selected electrodes 30 to perform the IRE procedure. The waveform (timing and amplitude) of the electrical pulse train is controlled by the IRE controller 38. As will be described in further detail below, the processor 32 handles the input and output interface between the IRE system 20 and the physician 22.

[0036] The processor 32 and the IRE controller 38 typically each comprise a programmable processor programmed in software and / or firmware to perform the functions described herein. Alternatively or in addition, each may comprise hardwired and / or programmable hardware logic circuitry that performs at least some of these functions. Although the processor 32 and the IRE controller 38 are shown in the figures as separate, single functional blocks for simplicity, in practice, some of these functions may be combined in a single processing and control unit having suitable interfaces for receiving and outputting the signals shown in the figures and described herein. In some exemplary embodiments, the IRE controller 38 resides within the IRE module 34 because high-speed control signals are transmitted from the IRE controller to the IRE generator 36. However, if signals can be transmitted from the processor 32 to the IRE generator 36 at sufficiently high speeds, the IRE controller 38 may reside within the processor.

[0037] The processor 32 and the IRE module 34 are typically located within a console 40. The console 40 includes input devices 42, such as a keyboard and a mouse. A display screen 44 is disposed adjacent to (or integral with) the console 40. The display screen 44 may optionally include a touch screen, thereby providing another input device.

[0038] The IRE system 20 may additionally include one or more of the following modules connected to appropriate interfaces and devices in the system 20 (typically located within the console 40):

[0039] • Electrocardiogram (ECG) module 46 is coupled to ECG electrodes 50 attached to subject 24 via cables 48. ECG module 46 is configured to measure the electrical activity of a heart 52 of subject 24.

[0040] A temperature module 54 is coupled to an optional temperature sensor, such as a thermocouple 56 located proximate each electrode 30 on the distal end 28 of the catheter 26 , and is configured to measure the temperature of adjacent tissue 58 .

[0041] Tracking module 60 is coupled to one or more electromagnetic position sensors (not shown) in distal end portion 28. In the presence of an external magnetic field generated by one or more magnetic field generators 62, the electromagnetic position sensors output signals that vary with the position of the sensors. Based on these signals, tracking module 60 can determine the position of electrode 30 in heart 52.

[0042] The modules 46, 54 and 60 described above generally include analog and digital components and are configured to receive analog signals and transmit digital signals. Each module may additionally include hardwired and / or programmable hardware logic circuitry that performs at least some of the functions of the module.

[0043] 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 signals 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.

[0044] External electrodes 65 or “return patches” may additionally be coupled externally between subject 24 (typically on the skin of the subject's torso) and IRE generator 36 .

[0045] Before and / or during an IRE procedure, the processor 32 receives setup parameters 66 for the procedure from the physician 22 (or from another user). The physician 22 uses one or more suitable input devices 42 to set the parameters of the IRE pulse train, as described below with reference to FIG. Figures 2 to 4B and as illustrated in Table 1. The physician 22 further selects pairs of ablation electrodes 30 for activation (for receiving the IRE pulse train) and the order in which to activate them.

[0046] In establishing an IRE ablation, the physician 22 may also select a synchronization pattern for the bursts of IRE pulses relative to the cycle of the heart 52. A first option, referred to as "synchronous mode," is to synchronize the IRE pulse bursts so that they occur during the refractory state of the heart 52 when the heart is recharging and will not respond to external electrical pulses. The burst is timed to occur after the QRS complex of the heart 52 with a delay of approximately 50% of the cardiac cycle time so that the burst occurs during the T wave of the heart 52, before the P wave. To implement the synchronous mode, the IRE controller 38 times one or more bursts of IRE pulses based on the ECG signal 414 from the ECG module 46 as follows Figure 5 shown.

[0047] A second synchronization option is asynchronous mode, in which bursts of IRE pulses are initiated independently of the timing of the heart 52. This option is possible because the IRE burst (typically 200 ms in length, with a maximum length of 500 ms) is interpreted by the heart as a short pulse to which the heart does not react. This type of asynchronous operation is useful in simplifying and streamlining the IRE procedure.

[0048] In response to receiving the setup parameters 66, the processor 32 transmits these parameters to the IRE controller 38, which commands the IRE generator 36 to generate an IRE signal according to the settings requested by the physician 22. Additionally, the processor 32 may display the setup parameters 66 on the display screen 44.

[0049] In some exemplary embodiments, processor 32 displays on display 44 an associated image 68 of the subject's anatomy, annotated to show, for example, the current position and orientation of distal tip 28, based on signals received from tracking module 60. Alternatively or additionally, processor 32 may display on display screen 44 the temperature of tissue 58 at each electrode 30 and the electrical activity of heart 52 based on signals received from temperature module 54 and ECG module 46.

[0050] To begin the procedure, physician 22 inserts catheter 26 into subject 24 and then uses control handle 70 to navigate the catheter to an appropriate location within or outside heart 52. Physician 22 then brings distal end 28 into contact with tissue 58 of heart 52 (such as myocardial or epicardial tissue). Next, IRE generator 36 generates a plurality of IRE signals, as described below with reference to FIG. Figure 3 The IRE signal is carried through the catheter 26 on different respective channels to the pairs of ablation electrodes 30 such that current 72 generated by the IRE pulse flows between each pair of electrodes (bipolar ablation) and performs the requested irreversible electroporation on the tissue 58 .

[0051] Figure 2 is a schematic illustration of a bipolar IRE pulse 100 according to an exemplary embodiment of the present invention.

[0052] Curve 102 shows the variation of the voltage V of a bipolar IRE pulse 100 over time t during an IRE ablation procedure. The present exemplary embodiment relates to an IRE generator 36 configured as a voltage source. Therefore, the IRE signal is described herein in terms of its voltage. As will be described below, the IRE generator 36 may alternatively be configured as a current source, in which case the IRE pulse will be described in terms of its current. The bipolar IRE pulse includes a positive pulse 104 and a negative pulse 106, where the terms "positive" and "negative" refer to the arbitrarily selected polarity of the two electrodes 30 between which the bipolar pulse is applied. The amplitude of the positive pulse 104 is labeled V+, and the time width of the pulse is labeled t+. Similarly, the amplitude of the negative pulse 106 is labeled V-, and the time width of the pulse is labeled t-. The time width between the positive pulse 104 and the negative pulse 106 is labeled t 间隔 Typical values ​​for the parameters of the bipolar pulse 100 are given in Table 1 below.

[0053] Figure 3 is a schematic diagram of a burst 200 of bipolar pulses according to an embodiment of the present invention.

[0054] During an IRE procedure, an IRE signal is delivered to electrode 30 as one or more bursts 200 shown by curve 202. Burst 200 includes N TPulse trains 204, each of which includes N P The length of the pulse train 204 is t T The period of the bipolar pulse 100 within the pulse train 204 is denoted as t PP , and the time interval between consecutive strings is marked as Δ T , during which time interval no signal is applied. Typical values ​​of the parameters of the burst 200 are given in Table 1 below.

[0055] Figures 4A to 4B FIG. 3 is a diagram illustrating IRE signals 302 and 304 with a combined RF signal according to an exemplary embodiment of the present invention. Figures 4A to 4B In the exemplary embodiment shown, RF ablation is combined with IRE ablation to obtain the benefits of both ablation modalities.

[0056] exist Figure 4A , curve 306 depicts the voltage V as it follows two bipolar pulses 310 and 312 (similar to Figure 2 The time t of the RF signal 308 between the bipolar pulses 100) is changed. The amplitude of the RF signal 308 is marked as V RF , and its frequency is marked as f RF , and the spacing between bipolar pulses 310 and 312 is marked as Δ RF . Usually, the frequency f RF Between 350kHz and 500kHz, and the amplitude V RF Between 10V and 200V, but higher or lower frequencies and amplitudes may alternatively be used.

[0057] exist Figure 4B , curve 314 shows the voltage V as a function of time t of the RF signal 316 between a positive IRE pulse 318 and a negative IRE pulse 320. The IRE pulses 318 and 320 are similar to Figure 2 In this exemplary embodiment, the interval t between the positive pulse 318 and the negative pulse 320 is 间隔 has been stretched as shown in Table 1.

[0058] Typical values ​​of the amplitude and frequency of RF signals 308 and 316 are given in Table 1. Figure 4A or Figure 4B As shown, when the RF signal is inserted into the IRE signal, the combination of these two signals is repeated until the end of the ablation procedure.

[0059] Table 1: Typical values ​​of IRE signal parameters

[0060]

[0061] IRE module

[0062] Figure 5 FIG. 3 is a block diagram schematically illustrating details of the IRE module 34 and its connection with other modules in the system 20 according to an exemplary embodiment of the present invention.

[0063] refer to Figure 1 The IRE module 34 includes an IRE generator 36 and an IRE controller 38. The IRE module 34 Figure 5 402. Within the box 402, the IRE generator 36 is depicted by the inner dashed box 404. The IRE generator 36 includes a pulse generation component 406 and a pulse routing and metering component 408. Figures 6 to 9 It will be described in further detail in .

[0064] The IRE generator 36 can be configured as a voltage source or a current source. Typical voltages of IRE pulses range from 200 V to 2000 V, the ohmic load of the pulses ranges from 75 Ω to 200 Ω, and thus the current ranges from 1 A to 26 A. In this exemplary embodiment, the IRE generator 36 is configured as a voltage source. Configuring the IRE generator 36 as a current source will be readily apparent to those skilled in the art after reading this specification.

[0065] The IRE controller 38 communicates with the processor 32 via a bidirectional signal 410, wherein the processor transmits commands reflecting the setting parameters 66 to the IRE controller. The IRE controller 38 also receives digital voltage and current signals 412 from the pulse routing and metering component 408. The controller utilizes these signals, among other things, in calculating the energy flow dissipated in the tissue 58. Additionally, the IRE controller 38 receives a digital ECG signal 414 from the ECG module 46 and a digital temperature signal 416 from the temperature module 54, and transmits these signals to the processor 32 via the bidirectional signal 410.

[0066] The IRE controller 38 transmits a digital command signal 418 derived from the setup parameters 66 and the calculated energy dissipation to the pulse generation component 406. The command signal 418 causes the IRE generator 36 to generate a pulse such as Figures 3 to 5 The IRE pulse shown in FIG, and the IRE controller 38 adjusts the characteristics of the IRE pulse based on the calculated energy dissipation and the required dissipated energy. (More details of the control process are shown in FIG. Figure 10 These IRE pulses are sent as analog pulse signals 420 to the pulse routing and metering component 408. The pulse routing and metering component 408 is coupled to the electrode 30 via output channel 422 and to the return patch 65 via connection 424. Figure 5 Ten output channels 422 are shown, labeled CH1 through CH10. In the following description, a particular electrode is referred to by the name of the particular channel to which it is coupled; for example, electrode CH5 refers to the electrode coupled to CH5 of channel 422. Although Figure 5 Ten channels 422 are referred to, but IRE generator 36 may alternatively include a different number of channels, such as 8, 16, or 20 channels, or any other suitable number of channels.

[0067] Figure 6 According to an exemplary embodiment of the present invention Figure 5 Schematic diagram of the circuit of the pulse routing and metering component 408. For the sake of clarity, the circuits involved in measuring current and voltage have been omitted. These circuits will be described below. Figure 7 Output channel 422 and connection 424 are described in detail in Figure 6 Used in Figure 5 The same labels are shown.

[0068] The pulse routing and metering assembly 408 includes modules 502, one for each output channel 422. Figure 7 A pair 504 of adjacent modules 502 is shown in detail.

[0069] Each module 502 includes a switching device, labeled FO for the i-th module. i 、SO i 、N i and BP i Switching device FO i They are all fast switching devices used to switch IRE ablation from one channel to another, and the switching device SO i 、N i and BP i It is a slower relay used to set the pulse routing and metering assembly 408 for a given IRE ablation mode. It is used to quickly switch the device FO i The typical switching time is less than 0.3μs, while the slow relay SO i 、N i and BP i A switching time of only 3 ms is required.The examples given below demonstrate the use of switching devices and relays.

[0070] Example 1 demonstrates IRE ablation using switches and relays between electrode pairs according to an odd-even scheme (CH1-CH2, CH3-CH4, CH5-CH6, CH7-CH8, and CH9-CH10). (Here, bipolar pulses are applied between each electrode and the first adjacent volume.) The settings for the switches and relays are shown in Table 2 below.

[0071] Table 2: Switching device and relay settings of Example 1

[0072]

[0073] Example 2 demonstrates IRE ablation using switches and relays between electrode pairs according to an even-odd scheme (CH2-CH3, CH4-CH5, CH6-CH7, and CH8-CH9), where bipolar pulses are applied between each electrode and its second-adjacent electrode. For a circular catheter 26 in which the first and last electrodes are placed side by side, the pair CH10-CH1 can be added to the even-odd pairs. The settings for the switches and relays are shown in Table 3 below.

[0074] Table 3: Switching device and relay settings for Example 2

[0075]

[0076] Combining the embodiment 1 and the embodiment 2, the rapid IRE ablation between all pairs of electrodes 30 can be achieved by the following method: first ablation is performed using the even-odd scheme of the embodiment 1, and then each rapid switching device FO i Switch to the opposite state (from on to off, from off to on), and then use the odd-even scheme of embodiment 2 to ablate. Since there is no need to switch the slow relay SO i 、N i and BP i state, so switch to FO i The switching device is carried out at a speed.

[0077] Example 3 demonstrates IRE ablation between non-adjacent electrodes 30 (CH1-CH3, CH4-CH6, and CH7-CH9 in this example). This type of configuration can be used to induce deeper lesions in tissue 58. The settings of the switching devices and relays are shown in Table 4 below.

[0078] Table 4: Switching device and relay settings for Example 3

[0079]

[0080] Likewise, by reconfiguring the switching device FO i to quickly select other electrode pairs.

[0081] Example 4 shows an alternative way to perform ablation between channels CH1 and CH3. In this example, the ablation circuit is closed using BP line 506. The settings of the switching devices and relays are shown in Table 5 below.

[0082] Table 5: Switching device and relay settings for Example 4

[0083]

[0084] In Example 4, the pulse routing and electrical paths in the metering assembly 408 couple the transformer secondary coils 508 and 510 in series. Since the distance between electrodes CH1 and CH3 is twice the distance between adjacent electrodes (e.g., CH1 and CH2), the voltage between CH1 and CH3 must be twice the voltage between adjacent electrodes in order to have the same electric field strength between the corresponding electrodes. This is achieved by driving the primary coils of these two secondary coils in opposite phases. The slow switching device SO i All remain in the on state to prepare for the next ablation between another pair of electrodes (for example, between CH2 and CH4).

[0085] As shown in the above embodiments, the use of relays and fast switching devices to implement the pulse routing and metering assembly 408 enables flexible and rapid distribution of IRE pulses to the electrodes 30 and flexible reconfiguration of the applied IRE pulse amplitude.

[0086] Figure 7 FIG. 4 is a circuit diagram of two adjacent modules 601 and 602 of a pulse routing and metering assembly 408 according to an exemplary embodiment of the present invention.

[0087] Module 601 and module 602 Figure 6 504, as shown by the dashed boxes with the same label (504). Module 601 and module 602 are fed by pulse generating circuit 603 and pulse generating circuit 604, respectively, with reference to Figure 5 , these pulse generating circuits include parts of the pulse generating assembly 406. Similar to Figure 6 Module 502 of pair 504, module 601 and module 602 in turn feed channel CH1 and channel CH2 respectively. Figure 7 6 and 602 are shown in order to illustrate the connection 605 between the modules. Since both modules are identical (and identical to the other modules in the pulse routing and metering assembly 408), only module 601 will be described in detail below.

[0088] More details of the pulse generating circuits 603 and 604 are given below. Figures 8 and 9 The pulse generating assembly 406 includes a pulse generating circuit similar to the circuits 603 and 604 of each channel of the IRE generator 36. The pulse generating assembly 406 also includes a Figure 8 The high voltage power supply 607 is described in detail in FIG.

[0089] The pulse generating circuit 603 is coupled to the module 601 through the transformer 606. The fast switching device FO1 and the slow relays SO1, N1 and BP1 are similar to Figure 6 Mark. Low-pass filter 608 converts the pulse train transmitted by pulse generating circuit 603 via transformer 606 and switching device FO1 into a sinusoidal signal, thereby allowing CH1 to be used for RF ablation. (Similarly, each channel of IRE generator 36 can be used independently for RF ablation.) The engagement of filter 608 is controlled by relay 610. Pulse generating circuit 603 transmits the pulse at frequency f through low-pass filter 608. RF Transmit a series of bipolar pulses to generate a given frequency f RF and amplitude V RF The low-pass filter converts the pulse train into an RF signal with a frequency of f RF Sine signal. Adjust the amplitude of the bipolar pulse train so that the amplitude of the sine signal is V RF .

[0090] The voltage V1 and current I1 coupled to CH1 are Figure 7 Shown in FIG is the voltage between channel CH1 and channel CH2, and the current flowing to CH1 and returning from CH2.

[0091] V1 and I1 are measured by a metering module 612, which includes an operational amplifier 614 for measuring voltage and a differential amplifier 616 for measuring current across a current sensing resistor 618. The voltage V1 is measured from a voltage divider 620 including resistors R1, R2, and R3, and an analog multiplexer 622. The analog multiplexer 622 is coupled in resistors R1 or R2 so that the voltage divider 620 has a voltage division ratio of R1 / R3 or R2 / R3. The metering module 612 also includes an analog-to-digital converter (ADC) 624 for converting the measured analog voltage V1 and current I1 into digital signals DV1 and DI1. These digital signals are sent to the IRE controller 38 as signals 412 ( Figure 5 ).like Figure 10 As further described in detail in FIG, the IRE controller 38 uses the digital signals DV1 and DI1, as well as corresponding digital signals from other modules, to calculate the energy dissipated in the tissue 58. The digital isolator 626 protects the subject 24 ( Figure 1 ) are protected from harmful voltages and currents.

[0092] Switching device FO1, relays SO1, BP1, N1 and 610 and analog multiplexer 622 are driven by IRE controller 38. For simplicity, Figure 7 The corresponding control lines are not shown.

[0093] Figure 8 FIG. 6 is a circuit diagram of a pulse generating circuit 603 , a transformer 606 , and a high-voltage power supply 607 according to an exemplary embodiment of the present invention.

[0094] Pulse generating circuit 603 ( Figure 7 ) includes two switching devices 702 and 704, the internal details of which are described below. Figure 9 . Switching device 702 includes a command input 706, a source 708, and a drain 710. Switching device 704 includes a command input 712, a source 714, and a drain 716. Switching devices 702 and 704 together form one half of an H-bridge (as known in the art), also referred to as a "half-bridge."

[0095] The high voltage power supply 607 provides a positive voltage V+ and a negative voltage V- to respective output terminals 720 and 722, adjustable within a respective positive and negative range of ±(10-2000) V in response to a signal received from the IRE controller 38 at a high voltage command input 724. The high voltage power supply 607 also provides a ground connection 723. A single high voltage power supply 607 is coupled to all of the pulse generating circuits of the pulse generating assembly 406. Alternatively, each pulse generating circuit may be coupled to a separate high voltage power supply.

[0096] The drain 710 of the switching device 702 is coupled to the positive voltage output terminal 720, and the source 708 of the switching device is coupled to the input terminal 726 of the transformer 606. When the command input terminal 706 receives the command signal CMD+, the positive voltage V+ is coupled from the positive voltage output terminal 720 to the transformer input terminal 726 via the switching device 702. The source 714 of the switching device 704 is coupled to the negative voltage output terminal 722, and the drain 716 of the switching device is coupled to the transformer input 726. When the command input terminal 712 receives the command signal CMD-, the negative voltage V- is coupled from the negative voltage output terminal 722 to the transformer input terminal 726 via the switching device 704. Thus, by alternately activating the two command signals CMD+ and CMD-, positive pulses and negative pulses are respectively coupled to the transformer input terminal 726 and then transmitted by the transformer 606 to its output terminal 728. The timing of the pulses (their width and spacing) is controlled by the command signals CMD+ and CMD-, and the amplitude of the pulses is controlled by the high voltage command signal CMD+. HV Control to the high voltage command input 724. Receives all three command signals CMD+, CMD- and CMD from the IRE controller 38 HV , the IRE controller thus controls the pulses fed into the corresponding channels of the pulse routing and metering component 408 .

[0097] In an alternative exemplary embodiment (not shown), a full H-bridge with a unipolar high-voltage power supply is utilized. This configuration can also be used to generate positive and negative pulses from a unipolar source in response to a signal controlling the full H-bridge. This exemplary embodiment has the advantage of using a simpler high-voltage power supply, while the advantages of a half-bridge and dual high-voltage power supply are that they provide a fixed ground potential and independently adjustable positive and negative voltages.

[0098] Figure 9 FIG. 7 is a circuit diagram of a switching device 702 according to an embodiment of the present invention. The switching device 704 is implemented in a similar manner to the switching device 702 .

[0099] The switching function of the switching device 702 is implemented by a field effect transistor (FET) 802 including a gate 804, a source 708, and a drain 710. The command input 706 is coupled to the gate 804, and the source 708 is coupled to the drain 710. Figure 8 Additional components 806 including a Zener diode, a diode, a resistor, and a capacitor act as circuit protectors.

[0100] Figure 10 A flowchart 900 is shown schematically illustrating a method for controlling an IRE procedure according to an exemplary embodiment of the present invention. In flowchart 900, dashed boxes 902 schematically indicate steps of a process occurring within the IRE generator 36, and dashed boxes 904 schematically indicate steps of a process occurring within the IRE controller 38. However, this particular functional division is described herein by way of example only, and the principles of the present method may alternatively be applied to other types of IRE module configurations and other IRE systems, as will be apparent to those skilled in the art after reading this specification.

[0101] The IRE procedure begins in a start step 906. In a setup definition step 908, the physician 22 defines the setup parameters for the procedure via the input device 42. These setup parameters are based on, for example, the desired tissue volume, field strength within the tissue, catheter configuration, and the energy to be delivered to the tissue during the procedure. The processor 32 transmits these setup parameters to the IRE controller 38 in a parameter transmission step 910. In a request energy step 911, the IRE controller 38 extracts or calculates the requested total dissipated energy from the setup parameters. This step defines a target value (e.g., in joules) of energy to be dissipated from the IRE pulse into the tissue at each location where ablation is to occur.

[0102] In a set step 912, the IRE controller 38 sets the IRE ablation parameters for the IRE generator 36 and transmits them to the generator in a modify / transmit step 914. Once the ablation parameters are set in the IRE generator 36, the IRE controller 38 initiates ablation by sending appropriate commands to the IRE generator 36 in an ablation start / continue step 916. In response to the commands, the IRE generator 36 applies an IRE pulse to the electrode 30 in an IRE pulse step 918. Simultaneously, the metering module 612 ( Figure 7 ) In the V / I measurement step 920, the voltage V in each channel i is measured. i and current I i , and transmits its value to the IRE controller 38.

[0103] Based on the received V i and I i The IRE controller 38 continuously calculates the energy dissipated in the tissue 58 in a dissipated energy step 922. The calculation of the dissipated energy is based on the value V received in each time interval sequence. i and I i In a first comparison step 924, the IRE controller 38 checks whether the cumulative dissipated energy at the start of the procedure, calculated from the dissipated energy step 922, has equaled (or possibly exceeded) the requested total dissipated energy recorded in the requested energy step 911. If the result is positive, the IRE ablation is terminated in an end step 926.

[0104] If the requested total dissipated energy has not been reached at step 924, the IRE controller 38 calculates the predicted total dissipated energy in a prediction step 928, assuming ablation continues using the current parameters of the IRE generator 36 (such as bipolar pulse amplitude, pulse width, and number of remaining pulses). In a second comparison step 930, the IRE controller 38 compares the predicted total dissipated energy (from step 928) with the requested total dissipated energy (from step 911). If the two are equal, ablation continues using the current ablation parameters, and ablation proceeds to step 916.

[0105] When the predicted total dissipated energy deviates from the requested total dissipated energy at step 930, the IRE controller 38 modifies the IRE ablation parameters in a modification / transmission step 914, and Figure 10 The cycle continues. Therefore, by the ablation voltage V i and current I iThe measurement of ΔV provides feedback to the IRE controller 38, enabling the controller to adjust the ablation parameters of the IRE generator 36 in order to achieve the requested total dissipated energy for the ablation procedure.

[0106] Alternatively or additionally, when a setup parameter specifies the energy of each pulse or pulse train, the process flow described by flowchart 900 is modified accordingly.

[0107] It will be understood that the above embodiments are cited by way of example only, and that the present invention is not limited to what has been specifically shown and described hereinabove. On the contrary, the scope of the present invention includes combinations and subcombinations of the various features described above, as well as variations and modifications thereof, which will occur to those skilled in the art upon reading the above description and which are not disclosed in the prior art.

Claims

1. A medical device for modulating the delivery of an irreversible electroporation pulse, the medical device comprising: a probe configured for insertion into a patient's body and comprising a plurality of electrodes configured to contact tissue within the body; an electrical signal generator configured to apply a train of bipolar pulses between at least one pair of the plurality of electrodes, each bipolar pulse having a voltage amplitude of at least 200 V and a duration of less than 20 μs between at least one pair of the plurality of electrodes in contact with the tissue, thereby causing irreversible electroporation of the tissue between the at least one pair of electrodes; one or more electrical sensors coupled to an output of the electrical signal generator and configured to measure a voltage and a current flowing between the at least one pair of electrodes in the plurality of electrodes over a series of time intervals; as well as A controller configured to: i) measuring electrical energy dissipated between the at least one pair of electrodes from the bipolar pulse train, which will be transferred to the tissue during the bipolar pulse train, by calculating the sum of the products of the voltage and the current flowing between the at least one pair of electrodes during the series of time intervals, the voltage and the current being measured by the one or more electrical sensors; ii) determining a target value for the dissipated electrical energy to be transferred to the tissue from the bipolar pulse train applied to the tissue in contact with the at least one pair of electrodes based on an IRE setting parameter; iii) enabling the electrical parameters and time parameters of the bipolar pulse train to be transmitted to the electrical signal generator; iv) continuously determining whether a measured amount of dissipated electrical energy to be transferred to said tissue in contact with said at least one pair of electrodes during an IRE equals or exceeds said target value; v) terminating the IRE when the measured dissipated electrical energy transferred to the tissue equals or exceeds the target value; vi) determining a predicted total dissipated electrical energy to be transferred to the tissue based on the electrical parameter and the time parameter when the measured dissipated electrical energy to be transferred to the tissue is less than the target value; vii) comparing the predicted total dissipated electrical energy with the target value; viii) when the predicted total dissipated electrical energy is less than a target value, causing the electrical parameter and the time parameter to be modified; as well as ix) terminating the IRE when the measured dissipated electrical energy to be transferred to the tissue equals the target value.

2. The medical device according to claim 1, wherein The electrical parameter controlled by the controller includes voltage.

3. The medical device according to claim 1, wherein The electrical parameter controlled by the controller includes current.

4. The medical device according to claim 1, wherein The controller is configured to adjust a peak amplitude of the bipolar pulse train applied between the at least one pair of electrodes among the plurality of electrodes so that the dissipated electrical energy meets the target value.

5. The medical device according to claim 1, wherein The controller is configured to control the electrical parameter and the time parameter so that the dissipated electrical energy between each pair of electrodes of at least one pair of electrodes among the plurality of electrodes satisfies the target value.

6. The medical device of claim 5, and wherein the controller is configured to adjust the number of the pulses applied between the at least one pair of electrodes in the plurality of electrodes so that the dissipated electrical energy meets the target value.

7. The medical device of claim 5, and wherein the controller is configured to adjust the duration of the pulse applied between the at least one pair of electrodes in the plurality of electrodes so that the dissipated electrical energy meets the target value.

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