Devices, methods and systems for irreversible electroporation of tissue

Abstract

Devices, systems, and methods for achieving irreversible electroporation by means of energy monitoring control are described. An exemplary embodiment of the apparatus has: an electrical signal generator adapted to generate and transmit an electrical signal according to a signal scheme to be received; a pair of electrodes connected to the electrical signal generator and adapted to receive the electrical signal and to close an electrical connection via tissue located between the pair of electrodes; an evaluation and control unit connected to the signal generator and adapted to: in a first operating phase, transmit a measurement signal scheme to the signal generator and determine a tissue impedance based on at least one measurement signal transmitted through the tissue; in a second operating phase, adjusting at least one format of a burst signal sequence scheme based on the determined tissue impedance to specify an amount of energy per burst; in a third operating phase, the adjusted burst signal sequence scheme is transmitted to the signal generator.

Description

Technical Field

[0001] The present application relates to an apparatus, method and system for irreversible electroporation of tissue. Background Art

[0002] In recent years, tissue treatment by means of pulsed electric fields has gradually gained importance as a clinical application. On the other hand, for more than forty years, the effects of the short high-voltage pulses used in such treatments and the resulting high electric field strengths in / on tissue have been part of various research projects. This application can be classified as non-thermal surgery and is based on delivering short high-voltage pulses to / into tissue to generate a local high electric field, typically in the range of several hundred volts per centimeter. Pores are thereby created in the cell membranes of the tissue. If, during pore formation at the lipid bilayer of the cell membrane, the electric field exceeds a certain threshold, so-called electroporation can be irreversible and the pores remain permanently open, ultimately leading to apoptosis (programmed cell death).

[0003] Irreversible electroporation (IRE) is mainly a non-thermal surgery that can affect the tissue temperature increase by no more than a few degrees within a few milliseconds. This differentiates IRE from the conventionally used RF ablation (radiofrequency ablation), in which the tissue temperature increases by 20 to 70 °C and the cells are destroyed by heating. In IRE, bipolar pulses, i.e., a combination of positive and negative pulses, are typically used to avoid muscle contractions as much as possible, which usually occur when a DC voltage is applied. For example, these pulses can be applied between two bipolar electrodes of a catheter, or between a catheter electrode and a surface electrode, which is usually attached to the skin on the patient's back.

[0004] In order for the IRE pulses to create the desired pores in the cell membranes of the target tissue, the electric field strength E defined by the pulses at / in the target tissue between a pair of at least two electrodes must exceed the tissue-related threshold E th . For example, the threshold for cardiac cells is about 500 V / cm, while the threshold for bone is 3000 V / cm. These differences in the field strength thresholds allow for the selective application of IRE in different tissues or mixed tissues (adipose tissue, myocardial tissue and nerve tissue). In order to achieve the required field strength, the voltage applied to the pair of electrodes depends both on the nature of the target tissue and on the distance between the electrodes and the size of the electrodes themselves. These parameters also affect the heat energy input during the ablation process and thus the possible temperature peak of the tissue to be treated. The applied voltage can be as high as 2000 V, far higher than the typical 10 - 200 V voltage in the case of thermal RF ablation.

[0005] The bipolar pulsed 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 of 1 to 5 μs and an interval of 1 to 5 μs between the positive pulse and the negative pulse. The bipolar pulses combine to form a pulse sequence, where each sequence can include more than a hundred bipolar pulses, and the interval between pulses ranges from 1 to 10 ms. The pulse sequence in each case forms a burst, where the entire pulse packet for IRE ablation consists of 1 to 20 bursts / burst units, and each of the bursts / burst units has a burst-to-burst interval ranging from 1 to 1000 ms. The total duration of ablation can reach 10 seconds.

[0006] The above parameters of the pulse scheme should be set before ablation to achieve the desired electroporation effect and associated clinical efficacy, while avoiding possible risks such as muscle contraction or thermal damage to the tissue. In addition to the time and number variables of the pulse scheme, the electrical parameters are also crucial.

[0007] So far, in comparative systems, the electrical parameters are set by specifying a target current that flows through the tissue to be treated between at least two electrodes, thereby locally inducing an electric field. The magnitude of the induced electric field depends on the tissue's impedance. However, the tissue impedance also fluctuates depending on the position or size of the electrodes and the patient, and thus ultimately depends on the energy that is emitted into the tissue during the procedure and can locally heat the tissue. Therefore, adjusting the target current in this way does not ensure that local adverse thermal effects such as blister formation or tissue charring at the electrodes will not occur.

[0008] Another important factor in controlling PFA pulses is the relationship between tissue impedance and the applied electric field strength E, as this directly affects the tissue's conductivity and thus the local energy input. Therefore, if the measurement of tissue impedance is performed at an electric field strength different from the actual IRE ablation, 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 for example, it cannot be ensured that thermal damage has not occurred during the regulation at the beginning of ablation.

[0010] WO2022 / 164750A1 discloses a voltage-controlled pulse sequence for an IRE system. One disclosed system has an ablation catheter with catheter electrodes. The catheter electrodes generate an electric field in the target tissue. An additional controller is configured to receive the first pulse voltage of a first pulse sequence and determine a charge voltage based on the first pulse voltage. An additional generator is configured to provide a second pulse sequence at the controlled pulse voltage.

[0011] US2021 / 0228260A1 discloses a system and method for customizable waveform and control for pulsed electric field ablation. The method specifically discloses the following steps: configuring a first set of output treatment parameters using a selected treatment protocol; generating one or more first treatment outputs using the set of output treatment parameters; sensing one or more first feedback parameters; comparing the first feedback parameters with expected feedback parameters to generate one or more first comparison results, where the expected feedback parameters are associated with the selected treatment protocol; and configuring a second set of output treatment parameters using the first comparison results.

[0012] EP3964153A1 discloses an impedance-based irreversible electroporation method. The method includes measuring tissue impedance and calculating an impedance threshold. The impedance threshold inherent in each selected protocol is calculated based on protocol parameters or read from a predetermined reference value, such as an empirical reference value stored in a look-up table or a pre-calculated reference value. To optimize the energy for the ablation process (more specifically, the pulse duration and / or the number of pulses and / or the number of bursts), the protocol can be adjusted based on the measured tissue impedance. When adjusting the protocol, the peak voltage generally does not decrease.

[0013] US2011238056A1 discloses a system and method for impedance-mediated control of electrosurgical power delivery. The system and method disclose a series of pulses with an initial pulse whose profile corresponds to a preset radio frequency start value. Starting from the radio frequency start value, the radio frequency level increases at a ramp rate to a preset radio frequency value.

[0014] There are also other known documents EP3232967A1, US2022 / 0313346A1, US2007 / 0078453A1, WO2022 / 173875A1, WO2022 / 258034A1, WO2020 / 097276A1.

[0015] According to the above prior art, the problem also lies in how to control the energy delivery to the tissue to be treated before IRE surgery. In particular, it is not necessary to implement a control loop during energy delivery to avoid any adverse thermal effects, for example, during adjustment. Summary of the Invention

[0016] To solve this problem, we propose devices, methods, and systems according to various aspects of the present application. The features and characteristics of the devices, systems, and methods are defined in the present application; however, the specification and the drawings also disclose the features of the devices, systems, and methods and their various aspects and relationships.

[0017] According to a first aspect, a device for tissue type-selective irreversible electroporation for an organization is proposed. The device has an electrical signal generator. The electrical signal generator can generate and transmit electrical signals according to a signal protocol to be received. The device has a pair of electrodes, for example exactly one single electrode pair. The electrode pair is (electrically) connected to the electrical signal generator. The electrode pair is adapted to receive electrical signals. The electrode pair can close an electrical connection via the tissue located between the electrode pair. The device has an evaluation and control unit. The evaluation and control unit is (electrically) connected to the signal generator. In particular, in a first operating phase, the evaluation and control unit can transmit a measurement signal protocol to the signal generator. In particular, in a first operating phase, the evaluation and control unit is adapted to receive at least one measurement signal emitted by the tissue. In particular, in a first operating phase, the evaluation and control unit determines the tissue impedance, for example exactly one single tissue impedance, based on at least one received measurement signal. In particular, in a second operating phase, the evaluation and control unit can adjust at least one format of a burst signal sequence scheme (selected from a large number of formats) (predefined by the user) based on the determined tissue impedance in order to specify / define the amount of energy per burst (in joules) (for the signal generator).

[0018] The advantage of this is that fluctuations in the amount of energy per burst caused by tissue impedance and / or electrode geometry can be compensated for before actual ablation (applying a burst signal sequence to the tissue).

[0019] The emitted measurement signal can have a measurement signal level, in particular a first voltage level, which is equal to the burst signal sequence level, in particular a second voltage level.

[0020] The advantage of this is that the tissue impedance is clearly measured at the same applied voltage, and subsequent ablation is also carried out at the same applied voltage. Since the impedance depends on the applied voltage, it is thus possible to ensure that the impedance actually present in subsequent ablation is determined in this way and the format is adjusted on this basis.

[0021] The electrode pair can have exactly one single electrode pair or can be configured to be exactly one single electrode pair. The tissue impedance can be via exactly one single tissue impedance or can be configured to be exactly one single tissue impedance.

[0022] The signal generator can be configured as a voltage source, in particular a high-voltage signal generator. The signal generator can be adapted to provide high-voltage direct current (DC) pulsed field ablation (PFA) pulses.

[0023] In particular, in a first operating phase, the evaluation and control unit can be adapted to measure the current and voltage at least once / at least twice / multiple times and thereby determine at least one / at least two / a large number of (average) tissue impedances.

[0024] In particular, in the second operation phase, the evaluation and control unit can be adapted to adjust a combination of at least one (at least two) of (a large number of formats) of the burst signal sequence scheme based on the determined tissue impedance to specify / define the amount of energy per burst. The amount of energy per burst specified / defined can exceed the threshold of the electric field strength induced in the tissue / at the tissue required to achieve irreversible electroporation.

[0025] In other words, the evaluation and control unit can monitor / control the time and / or electrical parameters of the electrical signal (by means of the scheme).

[0026] The evaluation and control unit can be arranged in the signal generator.

[0027] In particular, in the third operation phase, the evaluation and control unit is adapted to transmit the adjusted burst signal sequence scheme to the signal generator.

[0028] In particular, in the third operation phase, the amount of energy per burst specified / defined can induce an electric field strength in the tissue (especially in the myocardium) / at the tissue. The amount of energy per burst specified / defined can be greater than the electric field strength required to form pores (especially irreversible pores) in the tissue.

[0029] The format of the burst signal sequence scheme can specify the properties of the burst signal sequence to be generated by the signal generator and / or the amount of energy per burst.

[0030] The format can have: the number of first bursts in the burst signal sequence, at least one first time interval between at least two consecutive bursts in the burst signal sequence, the number of second 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 pulse deflection value of the positive and / or negative pulses of at least one bipolar pulse.

[0031] In particular, in the second operation phase, the evaluation and control unit can be adapted to adjust at least one format of (among a large number of formats) the burst signal sequence scheme (predetermined by the user) based on the determined tissue impedance in order to specify / define the amount of energy per burst according to the first time interval.

[0032] The number of first bursts in the burst signal sequence can be in the numerical range of 1 to 100 burst units.

[0033] At least the first time interval between two consecutive bursts of the burst signal sequence can be in the numerical range of 1 ms to 1000 ms.

[0034] The second quantity of the burst of bipolar pulses can be in the numerical range of 1 to 300 bipolar pulse units.

[0035] At least a second time interval between at least two consecutive bipolar pulses in the burst can be in the numerical range of 1 to 10 ms. A third time interval between the positive and negative pulses can be in the numerical range of 1 to 5 μs.

[0036] The pulse width of the positive and / or negative pulses can be in the numerical range between 1 and 10 μs. The pulse width of the positive pulse can be different from that of the negative pulse.

[0037] The pulse deflection value of the positive pulse can be in the numerical range of 200 to 2000 V. The pulse deflection value of the negative pulse can be in the numerical range of -200 to -2000 V.

[0038] According to a second aspect, a system for irreversible electroporation of tissue is provided. The system has a device 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 body surface of the patient. The first electrode can be disposed in the catheter and protrude from the distal end of the catheter. The catheter can have a shaft, and the first electrode is disposed / attached at the end of the shaft.

[0039] According to a third aspect, a system for irreversible electroporation of tissue is provided. The system has a device for tissue type-selective irreversible electroporation of tissue according to the first aspect and a bipolar catheter. 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 can be disposed in the bipolar catheter and protrude from the distal end of the bipolar catheter.

[0040] The advantage of this device for tissue type-selective irreversible electroporation of tissue is that it can be combined with one of various catheter systems. The device can use monopolar and bipolar multi-electrode catheter systems activated with the same energy, because changes in electrode size and the electrode spacing between the positive and negative poles are reflected in the measured tissue impedance, so the same maximum energy can be ensured during ablation regardless of which catheter is selected.

[0041] According to a fifth aspect, a method for performing irreversible electroporation on tissue is proposed. The method includes providing an electrical signal generator. The signal generator is adapted to generate and transmit electrical signals according to a signal scheme to be received. The method includes providing an electrode pair connected to the electrical signal generator. The electrode pair is adapted to receive the electrical signal and close the electrical connection via the tissue located 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 phase, transmitting a measurement signal scheme to the signal generator by means of the evaluation and control unit. The method includes, in the first operating phase, transmitting at least one measurement signal through the tissue by means of the signal generator and the electrode pair. The method includes, in the first operating phase, determining 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 phase, adjusting at least one format of the burst signal sequence scheme based on the tissue impedance by means of the evaluation and control unit to specify the amount of energy per burst. The method includes, in a third operating phase, transmitting the adjusted burst signal sequence scheme to the signal generator by means of the evaluation and control unit. Description of the Drawings

[0042] From the following description, those skilled in the art will clearly understand further features, performance, advantages and possible modifications, with reference to the accompanying drawings.

[0043] Figure 1 A schematic diagram of a bipolar pulse is shown.

[0044] Figure 2 A schematic diagram showing an example of implementing a pulse scheme is shown, and

[0045] Figure 3 The method steps for irreversible electroporation of tissue are schematically shown. Detailed Description of the Invention

[0046] Figure 1 A schematic diagram of a bipolar pulse 100 is shown. When the evaluation and control unit transmits a burst signal sequence scheme to the signal generator, the bipolar pulse 100 is generated by the signal generator. In this example, the signal generator is configured as a voltage source and is not shown in Figure 1 In this example, the format determining the nature of the bipolar pulse 100 has been predefined by the user. In the shown example, the pulse deflection kV+ and kV- values of the positive pulse 101 and the negative pulse 104 are ±500 kV. The third time interval 103 between the positive pulse 101 and the negative pulse 104 is 2.5 μs. The pulse width 102 of the positive pulse 101 is different from the pulse width 105 of the negative pulse 104. The difference in pulse width is not shown in Figure 1 here.

[0047] If tissue impedance is measured during the first operating phase, a protocol in the above format will be sent by the evaluation and control unit to the signal generator, which will then implement the sent measurement signal protocol and send the measurement signal through the tissue. In this example, the bipolar pulse 100 shown is generated and sent as the measurement signal. Based on the bipolar pulse 100 sent through the tissue, the evaluation and control unit determines the tissue impedance. The tissue impedance is used by the evaluation and control unit as the basis for the above format adjustment.

[0048] In this example, the tissue is myocardial tissue, and the minimum electric field strength that must be induced in the myocardial tissue can be derived from the tissue impedance in order to perform irreversible electroporation in the myocardial tissue.

[0049] In this example, the third time interval 103 between the positive pulse 101 and the negative pulse 104 is shortened by the evaluation and control unit. Alternatively, the pulse widths 102 and 105 can also be increased by different amounts respectively. In other words, the pulse widths 102, 105, the third time interval 103, and the pulse deflection values kV+ and kV- can each be configured independently of the others.

[0050] If the format has been adjusted by the evaluation and control unit, then during the third operating phase, a burst signal sequence protocol is sent by the evaluation and control unit to the signal generator configured as a voltage source, which will subsequently send a burst signal sequence for irreversible electroporation through the tissue.

[0051] Figure 2 Such a burst signal sequence is schematically shown. Two bursts can be seen, one with the reference sign 110. Each burst has two bipolar pulses 100. Each bipolar pulse 100 that appears in the burst signal sequence has the following property, the adjusted format in the above description has just been defined / adjusted based on the measured tissue impedance. Before the first operating phase, the user has specified the first burst number (here two bursts are taken as an example), the second time interval 111, and the first time interval 112 between two consecutive bursts 110. It can be seen that the burst signal sequence extends over a duration 113, which corresponds to the duration of irreversible electroporation.

[0052] Figure 3Schematically shows the steps included in the irreversible electroporation method 200. This method is hereinafter referred to as irreversible electroporation, abbreviated as IRE. The IRE starts from step 201. Then, in step 202, the user (such as a doctor) predefines the values of each format. In other words, the doctor assigns values to each format. This can be achieved by manually entering the corresponding data in the evaluation and control unit. The values of the format and the nature of the signal sequence to be generated are now predefined. In the third step, the tissue impedance is measured. For this purpose, the evaluation and control unit transmits a measurement signal scheme to the signal generator. The measurement signal scheme indicates to the signal generator the format values required to generate bipolar pulses. The measurement pulses are then transmitted by the signal generator through the tissue and received again. Based on the received measurement pulses, the tissue impedance is measured, and from this, the electric field strength that must be induced in the tissue for IRE is deduced.

[0053] For the iterative adjustment of the format of the burst signal sequence scheme after tissue impedance measurement, in step 204, the first burst number and the second bipolar pulse number are adjusted to the format predefined by the user previously. Then, calculation 205 is performed to determine the energy of each burst, which does not exceed the maximum allowable energy for subsequent ablation but ensures the ablation itself. In other words, at least one format or format combination is adjusted such that charring or the formation of water vapor in the tissue or adjacent tissue is avoided in subsequent ablation, but IRE is performed. If the iterative adjustment is completed, the evaluation and control unit transmits the adjusted burst signal sequence scheme to the signal generator, and then, after approval by the user (such as a doctor), ablation 206 is performed. After the ablation is completed, the IRE is completed 207.

Claims

1. A device for tissue type selective irreversible electroporation of a tissue, comprising: - an electrical signal generator adapted to generate and transmit an electrical signal according to the signal scheme to be received; - an electrode pair connected to the electrical signal generator and adapted to receive the electrical signal and to close an electrical connection via tissue located between the electrode pair; - an evaluation and control unit, which is connected to the signal generator and is suitable for: - in a first operating phase, transmitting a measurement signal scheme to the signal generator and determining the tissue impedance based on at least one measurement signal transmitted through the tissue, - in a second operating phase, adjusting at least one format of a burst signal sequence scheme based on said determined tissue impedance to specify an amount of energy per burst, - In a third operating phase, transmitting the adjusted burst signal sequence scheme to the signal generator.

2. The device according to claim 1, wherein: The amount of energy specified per burst, in particular in said third operating phase, induces in said tissue an electric field strength greater than that required to form (in particular irreversible) pores in said tissue.

3. The device according to claim 1 or 2, wherein: The format of the burst signal sequence scheme specifies the nature of the burst signal sequence generated by the signal generator and the amount of energy of each burst, having: - the first burst number in the burst signal sequence, - at least one first time interval between at least two consecutive bursts in the burst signal sequence, - the number of second 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 a positive pulse and a negative pulse of at least one bipolar pulse, - the pulse width of the positive pulse and / or the negative pulse of at least one bipolar pulse, - a pulse deflection value of a positive pulse and / or a negative pulse of at least one bipolar pulse.

4. The device according to any one of claims 1 to 3, wherein: The transmitted measurement signal has a measurement signal level equal to the burst signal sequence level.

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

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

7. A method for irreversible electroporation of tissue, comprising the following steps: - providing an electrical signal generator adapted to generate and transmit electrical signals according to the signal scheme to be received; - providing an electrode pair connected to the electrical signal generator and adapted to receive the electrical signal and to close an electrical connection via tissue located between the electrode pair; - providing an evaluation and control unit connected to said signal generator; - in a first operating phase, transmitting a measurement signal scheme to the signal generator by means of the evaluation and control unit; - in a first operating phase, transmitting at least one measurement signal through the tissue by means of the signal generator and the electrode pair; - in a first operating phase, determining tissue impedance based on said measurement signal transmitted through said tissue; - in a second operating phase, based on the tissue impedance, adapting by means of the evaluation and control unit at least one format of the burst signal sequence scheme to specify the amount of energy per burst; In a third operating phase, the adapted burst sequence scheme is transmitted to the signal generator by means of the evaluation and control unit.

8. The method of claim 7, wherein: The format of the burst signal sequence scheme specifies the nature of the burst signal sequence to be generated by the signal generator and the amount of energy per burst, having: - the first burst number in the burst signal sequence, - at least one first time interval between at least two consecutive bursts in the burst signal sequence, - the number of second 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 a positive pulse and a negative pulse of at least one bipolar pulse, - the pulse width of the positive pulse and / or the negative pulse of at least one bipolar pulse, - a pulse deflection value of a positive pulse and / or a negative pulse of at least one bipolar pulse.

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