Device, method and system for irreversible electroporation of tissue

Abstract

To provide a device, method and system for irreversible electroporation of tissue.SOLUTION: The present invention describes devices, systems and methods which effect irreversible electroporation by means of energy-monitored control. An exemplary embodiment of the device has an electrical signal generator, an electrode pair, and an evaluation and control unit connected to the signal generator.SELECTED DRAWING: Figure 3

Description

Technical Field

[0001] Apparatuses, methods, and systems for irreversible electroporation of tissue are presented herein. The features and characteristics of the apparatus, system, and method are specified in the claims, but the specification and drawings also disclose the apparatus, system, and method and their various aspects and related characteristics.

Background Art

[0002] Treatment of tissue by pulsed electric fields has been gradually increasing in importance as a clinical application in recent years. On the other hand, the effects of the short high-voltage pulses used in such treatments and the resulting high electric field strengths in / on the tissue have been part of various research projects for over 40 years. Such applications can be classified as non-thermal treatments and typically are based on the delivery of short high pulses to / within the tissue to generate locally high electric fields that can be in the region of several hundred volts per centimeter. Thereby, pores are generated within the cell membranes of the tissue. When this electric field exceeds a certain threshold during pore formation in the lipid bilayer of the cell membrane, the so-called electroporation method can be irreversible, and the pores remain permanently open, which ultimately leads to apoptosis (programmed cell death) of the cells.

[0003] Irreversible electroporation (IRE) is a mainly non-thermal treatment that results in an increase in tissue temperature of less than several degrees per millisecond. This distinguishes IRE from RF ablation (radio frequency / radio wave ablation), which has been conventionally used and in which the tissue temperature rises by 20°C to 70°C and cells are destroyed by heating. In IRE, in order to avoid muscle contractions that typically occur in the case of the application of a DC voltage as much as possible, usually bipolar pulses, i.e., a combination of a positive pulse and a negative pulse, are used. The pulses can be applied, for example, between two bipolar electrodes of a catheter or between a catheter electrode and a body surface electrode that is typically attached to the skin on the patient's back.

[0004] For the IRE pulse to create the desired pores within the cell membrane of the target tissue, the electric field strength E defined by the pulse, in and / or at the target tissue between a pair of at least two electrodes, must exceed the tissue-dependent threshold E th not be exceeded. For example, the threshold for cardiac cells is about 500 V / cm, while for bone it is 3000 V / cm. These differences in the threshold of the electric field strength enable the selective application of IRE in different tissues or mixed tissues (adipose tissue, myocardial tissue, and nerve tissue). To achieve the required electric field strength, the voltage to be applied to the electrode pair depends on both the nature of the target tissue and the distance between the electrodes and the size of the electrodes themselves. These parameters also affect the thermal energy input during ablation and, thus, the temperature peaks that can occur in the tissue to be treated. The applied voltage can reach up to 2000 V, which is considerably higher than the voltages of 10 V to 200 V that are typical in the case of thermal RF ablation.

[0005] The bipolar pulse field ablation pulse (bipolar PFA pulse) for IRE includes a positive pulse and a negative pulse, which are applied between two electrodes with a pulse width from 1 μs to 5 μs and an interval between the positive pulse and the negative pulse from 1 μs to 5 μs. The bipolar pulses are combined to form a pulse sequence, and each sequence can include more than 100 bipolar pulses with an inter-pulse interval from 1 ms to 10 ms. The pulse sequence in each case forms a burst, and the entire pulse packet of the IRE ablation consists of one to twenty bursts / burst units, each having a burst-to-burst interval from 1 ms to 1000 ms. The total duration of the ablation can be up to 10 seconds.

[0006] The described parameters of the pulse protocol should be set prior to ablation such that the desired electroporation effect and associated clinical efficacy are achieved while simultaneously avoiding possible risks such as muscle contraction or thermal damage to the tissue. In addition to the temporal and quantitative variables of the pulse protocol, the electrical parameters are also of great importance here.

[0007] To date, the electrical parameters have been set in comparative systems by the specification of a target current that passes between at least two electrodes through the tissue to be treated and thus locally induces an electric field. The size of this induced electric field depends on the electrical impedance of the tissue. However, tissue impedance also varies depending on, among other things, the position or size of the electrodes and, depending on the patient, and thus ultimately also on the energy that can be transmitted to the tissue by the treatment and locally heat the tissue. Therefore, adjusting the target current in this way does not guarantee that no locally undesirable thermal effects will occur, such as the formation of water swelling at the electrodes or carbonization of the tissue.

[0008] A further important factor for controlling the PFA pulse is the dependence of the electrical tissue impedance on the applied electric field strength E, as this directly affects the conductivity of the tissue and thus also the local energy input. Therefore, if the measurement of the electrical tissue impedance is performed at an electric field strength different from that of the actual IRE ablation, consequently, the actual energy input into the tissue during ablation will also be different.

[0009] Some comparative systems use active regulation during ablation to adjust the energy input, but it is not guaranteed, for example during the adjustment at the start of ablation, that no thermal damage has yet occurred.

[0010] International Publication No. WO 2022 / 164750 discloses a voltage control pulse sequence for an IRE system. The disclosed system has an ablation catheter with a catheter electrode. The catheter electrode generates an electric field within a target tissue. An additional controller is configured to receive a first pulse voltage of a first pulse sequence and determine a charging voltage based on the first pulse voltage. An additional generator is configured to supply a second pulse sequence of a controlled pulse voltage.

[0011] U.S. Patent Application Publication No. 2021 / 0228260 discloses a system and method for customizable waveforms and control for pulsed electric field ablation. The method includes, in particular, configuring a first output treatment parameter set using a selected treatment profile, generating one or more first treatment outputs using the output treatment parameter set, detecting one or more first feedback parameters, comparing the one or more first feedback parameters to an expected feedback parameter to generate one or more first comparison results, wherein the expected feedback parameter is associated with the selected treatment profile, and configuring a second output treatment parameter set using the first comparison results.

[0012] European Patent Application Publication No. 3964153 discloses a method for irreversible electroporation based on impedance. This method includes measuring tissue impedance and calculating an impedance threshold. The impedance threshold, which is specific to each selected protocol, is calculated based on protocol parameters or read from a predetermined reference, for example, an empirical reference or a pre-calculated reference stored in a look-up table. To achieve the optimal energy for the ablation process, the protocol, more specifically, the pulse duration and / or the number of pulses and / or the number of bursts, is adjusted based on the measured tissue impedance. The value of the voltage peak typically is not reduced when the protocol is adjusted.

[0013] U.S. Patent Application Publication No. 2011238056 discloses a system and method for impedance-mediated control of power supply for electrosurgery. This system and method disclose a series of pulses with an initial pulse, the profile of which corresponds to a preset radio frequency start value. Starting from the radio frequency start value, the radio frequency level increases at a ramp ratio up to a preset radio frequency value.

[0014] Furthermore, European Patent Application Publication No. 3232967, U.S. Patent Application Publication No. 2022 / 0313346, U.S. Patent Application Publication No. 2007 / 0078453, International Publication No. 2022 / 173875, International Publication No. 2022 / 258034, International Publication No. 2020 / 097276 are known.

Prior Art Documents

Patent Documents

[0015]

Patent Document 1

Patent Document 2

Patent Document 3

[0016] Considering the above prior art, the problem is further to control the supply of energy to the tissue to be treated before the IRE treatment. In particular, in order to avoid unwanted thermal effects during adjustment, for example, implementing a control loop during energy supply should be unnecessary. [Means for Solving the Problems]

[0017] To solve this problem, the device according to claim 1, the method according to claim 7, and the system according to claims 5 and 6 are proposed.

[0018] According to a first aspect, an apparatus for the tissue type selective irreversible electroporation of tissue is proposed. The apparatus has an electrical signal generator. The electrical signal generator is configured to generate and transmit an electrical signal according to a signal protocol to be received. The apparatus has an electrode pair, specifically exactly one electrode pair. The electrode pair is (electrically) connected to the electrical signal generator. The electrode pair is configured to receive the electrical signal. The electrode pair is configured to close an electrical connection through the tissue between the electrode pair. The apparatus has an evaluation and control unit. The evaluation and control unit is (electrically) connected to the signal generator. The evaluation and control unit is configured to transmit a measurement signal protocol to the signal generator, especially in a first operating stage. The evaluation and control unit is configured to receive at least one measurement signal transmitted by the tissue, especially in a first operating stage. The evaluation and control unit is configured to identify a tissue impedance, specifically exactly one tissue impedance, based on at least one received measurement signal, especially in a first operating stage. The evaluation and control unit is configured to adjust at least one format of a burst signal sequence protocol (from, for example, a number of formats) (preset by the user) based on the identified tissue impedance in order to specify / stipulate the amount of energy per burst (in joules) for the (signal generator) (by the adjusted burst signal sequence protocol) in a second operating stage.

[0019] This has the advantage that variations in the amount of energy per burst caused by the tissue impedance and / or the electrode shape are compensated for before the actual ablation (application of the burst signal sequence to the tissue).

[0020] The transmitted measurement signal can have a measurement signal level equal to the burst signal sequence level, especially a second voltage level, especially a first voltage level.

[0021] This has the advantage that the tissue impedance is explicitly measured at an equivalent applied voltage at which subsequent ablation should also be performed. Since the impedance depends on the applied voltage, in this way it is ensured that the impedance actually present during subsequent ablation is confirmed and the format can be adjusted based thereon.

[0022] The electrode pair can have exactly a single electrode pair or can be configured as exactly a single electrode pair. The tissue impedance can have exactly a single tissue impedance or can be configured as exactly a single tissue impedance.

[0023] The signal generator can be configured as a voltage source, in particular as a high-voltage signal generator. The signal generator can be configured to supply high-voltage direct current (DC) pulse field ablation (PFA) pulses.

[0024] The evaluation and control unit can be configured to measure the current and voltage, at least once / at least twice / multiple times, in particular in a first operating phase, and therefrom identify at least one / at least two / multiple (average) tissue impedances.

[0025] The evaluation and control unit can be configured to adjust, in particular in a second operating phase, at least one combination of (at least two) of (the multiple formats of) the burst signal sequence protocol based on the identified tissue impedance in order to specify / define the amount of energy per burst. The specified / defined amount of energy per burst can exceed the threshold of the electric field strength induced in / within the tissue required to achieve irreversible electroporation.

[0026] In other words, the evaluation and control unit can monitor / control the temporal and / or electrical parameters of the electrical signal (by the protocol).

[0027] The evaluation and control unit can be arranged within the signal generator.

[0028] The evaluation and control unit is configured to transmit an adjusted burst signal sequence protocol to the signal generator, particularly in the third operating phase.

[0029] The specified / stipulated amount of energy per burst can, particularly in the third operating phase, induce an electric field strength within / in the myocardial tissue. The specified / stipulated amount of energy per burst can be made greater than the electric field strength required to form pores, particularly irreversibly, within the tissue.

[0030] The format of the burst signal sequence protocol can specify the characteristics of the burst signal sequence to be generated by the signal generator and / or the amount of energy per burst.

[0031] The format can have a first number of bursts within the burst signal sequence, at least one first time interval between at least two consecutive bursts of the burst signal sequence, a second number of bipolar pulses within a burst, at least one second time interval between at least two consecutive bipolar pulses within a burst, a third time interval between the positive and negative pulses of at least one bipolar pulse, the pulse width of the positive and / or negative pulses of at least one bipolar pulse, and the value of the pulse deflection of the positive and / or negative pulses of at least one bipolar pulse.

[0032] The evaluation and control unit can be configured to adjust at least one format (out of a number of formats) of the burst signal sequence protocol (predetermined by the user) based on a specified tissue impedance to specify / stipulate the amount of energy per burst according to the first time interval, particularly in the second operating phase.

[0033] The first number of bursts within a burst signal sequence can be within a value range of 1 to 100 burst units.

[0034] At least a first time interval between two consecutive bursts of a burst signal sequence can be within a value range of 1 ms to 1000 ms.

[0035] The second number of bipolar pulses within a burst can be within a value range of 1 to 300 bipolar pulse units.

[0036] At least one second time interval between at least two consecutive bipolar pulses within a burst can be within a value range of 1 ms to 10 ms. The third time interval between a positive pulse and a negative pulse can be within a value range of 1 μs to 5 μs.

[0037] The pulse width of the positive and / or negative pulse can be within a value range of 1 μs to 10 μs. The pulse width of the positive pulse can be different from that of the negative pulse.

[0038] The value of the pulse deflection of the positive pulse can be within a value range of 200 V to 2000 V. The value of the pulse deflection of the negative pulse can be within a value range of -200 V to -2000 V.

[0039] According to a second aspect, a system for irreversible electroporation of tissue is proposed. This system has an apparatus according to the first aspect and a monopolar catheter. The catheter has a distal end. The electrode pair is configured as a first electrode and a body surface electrode. The first electrode is disposed at the distal end of the catheter, and the body surface electrode is disposed on the patient's body surface. The first electrode can be disposed within the catheter and protrude from the catheter at the distal end. The catheter can have a shaft to which the first electrode is disposed / attached at its end.

[0040] According to a third aspect, a system for irreversible electroporation of tissue is proposed. This system has an apparatus according to the first aspect and a bipolar catheter for tissue type selective irreversible electroporation of tissue. The catheter has a distal end. The electrode pair is configured as an electrode pair disposed at the distal end of the bipolar catheter. The electrode pair is disposed within the bipolar catheter and may protrude from the bipolar catheter at the distal end.

[0041] The apparatus for tissue type selective irreversible electroporation of tissue provides the advantage that it can be combined with one of various catheter systems. Since variations in electrode size and the electrode spacing between the positive and negative electrodes are reflected in the measured tissue impedance, both a monopolar multi-electrode catheter system and a bipolar multi-electrode catheter system can be used with the same energy activation, and thus equivalent maximum energy can be guaranteed during ablation regardless of the catheter selection.

[0042] According to a fifth aspect, a method for irreversible electroporation of tissue is proposed. The method includes providing an electrical signal generator. The signal generator is configured to generate and transmit an electrical signal according to a signal protocol to be received. The method includes providing an electrode pair connected to the electrical signal generator. The electrode pair is configured to receive the electrical signal and close an electrical connection through the tissue between the electrode pair. The method includes providing an evaluation and control unit connected to the signal generator. The method includes, in a first operating stage, transmitting a measurement signal protocol to the signal generator by the evaluation and control unit. The method includes, in the first operating stage, transmitting at least one measurement signal through the tissue by the signal generator and the electrode pair. The method includes, in the first operating stage, identifying the tissue impedance based on the measurement signal transmitted through the tissue (and received by the electrode pair / evaluation and control unit). The method includes, in a second operating stage, adjusting at least one format of a burst signal sequence protocol by the evaluation and control unit based on the tissue impedance to specify the amount of energy per burst. The method includes, in a third operating stage, transmitting the adjusted burst signal sequence protocol to the signal generator by the evaluation and control unit.

[0043] Further features, characteristics, advantages and possible modifications will become apparent to those skilled in the art from the following description with reference to the accompanying drawings.

Brief Description of the Drawings

[0044]

Figure 1

Figure 2

Figure 3

Embodiments of the Invention

[0045] Figure 1 shows a schematic diagram of bipolar pulse 100 generated by a signal generator when an evaluation and control unit transmits a burst signal sequence protocol to the signal generator. In this case, the signal generator is configured as a voltage source and is not shown in Figure 1. In this example, the format that determines the characteristics of bipolar pulse 100 is pre-specified by the user. In the illustrated example, the value kV+ of the pulse deflection of positive pulse 101 and the value kV- of the pulse deflection of negative pulse 104 are ±500 kV. The third time interval 103 between positive pulse 101 and negative pulse 104 is 2.5 μs. The pulse width 102 of positive pulse 101 is different from the pulse width 105 of negative pulse 104. The difference in pulse widths is not shown in Figure 1.

[0046] When tissue impedance is measured in the first operating stage, a protocol according to the format described above is transmitted by the evaluation and control unit to the signal generator, and the signal generator then implements the transmitted measurement signal protocol and transmits the measurement signal through the tissue. In this example, the illustrated bipolar pulse 100 is generated and transmitted as the measurement signal. Based on the bipolar pulse 100 transmitted through the tissue, the evaluation and control unit identifies the tissue impedance. The tissue impedance is used by the evaluation and control unit as a basis for adjusting the above format.

[0047] In this case, the tissue is myocardial tissue, and from the tissue impedance, the minimum electric field strength that must be induced in the myocardial tissue for irreversible electroporation to be performed in the myocardial tissue is derived.

[0048] In this case, the third time interval 103 between positive pulse 101 and negative pulse 104 is reduced by the evaluation and control unit. Alternatively, the pulse widths 102, 105 can each be increased by different amounts. In other words, the pulse widths 102, 105, the third time interval 103, and the values kV+, kV- of the pulse deflections can each be configured independently of the others.

[0049] When the format is adjusted by the evaluation and control unit, the burst signal sequence protocol is transmitted to a signal generator configured as a voltage source in the third stage of operation by the evaluation and control unit, and the signal generator then transmits a burst signal sequence for irreversible electroporation through the tissue.

[0050] Figure 2 schematically shows this burst signal sequence. Two bursts are seen, one of which is labeled with reference numeral 110. Each burst has two bipolar pulses 100. Each bipolar pulse 100 occurring in the burst signal sequence has the characteristics that the adjusted format from the description of the foregoing figure is newly defined / adjusted based on the measured tissue impedance. The first number of bursts, here two bursts as an example, the second time interval 111, and the first time interval 112 between two consecutive bursts 110 are specified by the user before the first stage of operation. The burst signal sequence seen extends over a duration 113 corresponding to the duration of the irreversible electroporation.

[0051] Figure 3 schematically shows the steps included in method 200 for irreversible electroporation. This method will hereinafter be referred to as an irreversible electroporation treatment or, for short, an IRE treatment. The IRE treatment starts at step 201. Then, in step 202, a user, for example, a physician, predefines values for individual formats. In other words, the physician assigns values to each format. This can be done by manually entering corresponding data in the evaluation and control unit. The values of the formats and thus the characteristics of the signal sequence to be generated are predefined here. In a third step, the tissue impedance is measured. For this purpose, the evaluation and control unit sends a measurement signal protocol to the signal generator. The measurement signal protocol indicates to the signal generator the values for which the format necessary to generate bipolar pulses should be implemented. Then, the measurement pulses are sent through the tissue by the signal generator and received again. Based on this received measurement pulse, the tissue impedance is measured, from which the electric field strength that has to be induced in the tissue in order to perform IRE can be derived.

[0052] For the iterative adjustment of the format of the burst signal sequence protocol following the tissue impedance measurement, in step 204, the first number of bursts and the second number of bipolar pulses are adjusted to the format predefined by the user. Then, in 205, calculations are performed to determine the energy per burst that does not exceed the maximum allowable energy for subsequent ablation but ensures the ablation itself. In other words, at least one format, or a combination of formats, is configured such that, for example, carbonization or steam formation in the tissue or adjacent tissue is avoided in subsequent ablation, but the IRE is performed. When this iterative adjustment is completed, the evaluation and control unit sends the adjusted burst signal sequence protocol to the signal generator, which then, after approval by the user, for example, a physician, performs the ablation in 206. At the completion of the ablation, in 207, the IRE treatment is completed.

Claims

1. 1. An apparatus for tissue-type selective irreversible electroporation of tissue, comprising: an electrical signal generator configured to generate and transmit electrical signals according to the signal protocol to be received; - an electrode pair connected to the electrical signal generator and configured to receive the electrical signal and close an electrical connection through tissue between the electrode pair; an evaluation and control unit connected to said signal generator, said evaluation and control unit comprising: - in a first operational phase, transmitting a measurement signal protocol to the signal generator and determining tissue impedance based on at least one measurement signal transmitted through the tissue; - during a second operational phase, adjusting at least one format of a burst signal sequence protocol based on said determined tissue impedance to specify an amount of energy per burst; - in a third operation phase, transmitting the adjusted burst signal sequence protocol to the signal generator; an evaluation and control unit configured to An apparatus having the above configuration.

2. 2. The device of claim 1, wherein the specified amount of energy per burst induces an electric field strength in the tissue that is greater than an electric field strength required to irreversibly form pores in the tissue, particularly during the third phase of operation.

3. The burst signal sequence protocol format is: specifying characteristics of a burst signal sequence to be generated by said signal generator and said amount of energy per burst; a first number of bursts in said sequence of burst signals; at least one first time interval between at least two successive bursts of said burst signal sequence; a second number of bipolar pulses in the burst; and at least one second time interval between at least two successive bipolar pulses within a burst; a third time interval between the positive and negative pulses of the at least one bipolar pulse; the pulse width of the positive and / or negative pulse of at least one bipolar pulse, the value of the pulse deflection of the positive and / or negative pulse of at least one bipolar pulse, 3. The apparatus according to claim 1 or 2, comprising:

4. 4. Apparatus according to claim 1, wherein the transmitted measurement signal has a measurement signal level equal to a burst signal sequence level.

5. A system for irreversible electroporation of tissue, comprising a device according to any one of claims 1 to 4 and a monopolar catheter, comprising: The system, wherein the catheter has a distal end and an electrode pair is configured as a first electrode and a body surface electrode, the first electrode being positioned at the distal end of the catheter and the body surface electrode being positioned on a patient's body surface.

6. A system for irreversible electroporation of tissue, comprising a device according to any one of claims 1 to 4 and a bipolar catheter, comprising: The catheter has a distal end and an electrode pair is disposed at the distal end.

7. 1. A method for irreversible electroporation of tissue, comprising: - providing an electrical signal generator configured to generate and transmit electrical signals according to the signal protocol to be received; - providing an electrode pair connected to the electrical signal generator, the electrode pair being configured to receive the electrical signal and to close an electrical connection through the tissue between the electrode pair; - providing an evaluation and control unit connected to said signal generator; - in a first operating phase, transmitting a measurement signal protocol by said evaluation and control unit to said signal generator; - transmitting, during said first operating phase, at least one measurement signal through said tissue by means of said signal generator and said electrode pair; - determining tissue impedance based on the measurement signal transmitted through the tissue during the first operational phase; - during a second operational phase, adjusting by said evaluation and control unit the format of at least one of the burst signal sequence protocols based on said tissue impedance in order to specify an amount of energy per burst; - in a third operating phase, transmitting the adjusted burst signal sequence protocol by the evaluation and control unit to the signal generator; A method comprising:

8. The burst signal sequence protocol format is: specifying characteristics of a burst signal sequence to be generated by said signal generator and said amount of energy per burst; a first number of bursts in said sequence of burst signals; at least one first time interval between at least two successive bursts of said burst signal sequence; a second number of bipolar pulses in the burst; and at least one second time interval between at least two successive bipolar pulses within a burst; a third time interval between the positive and negative pulses of the at least one bipolar pulse; the pulse width of the positive and / or negative pulse of at least one bipolar pulse, the value of the pulse deflection of the positive and / or negative pulse of at least one bipolar pulse, 8. The method of claim 7, comprising:

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