Device, method and system for irreversible electroporation of tissue

Abstract

The present invention describes a device, systems, and a method for implementing irreversible electroporation using energy-controlled control. One embodiment of the device comprises an electrical signal generator, a pair of electrodes, and an evaluation and control unit connected to the signal generator.

Description

Herein, an apparatus, method and system for irreversible electroporation of tissue are presented. Features and characteristics of the apparatus, system and method are defined in the claims; however, the description and figures also disclose characteristics of the apparatus, system and method, as well as various aspects and relationships thereof.Tissue treatments using pulsed electric fields have become increasingly important as clinical application in recent years. The effects of the short high-voltage pulses used in this case and the high electric field strengths arising on / in tissue, on the other hand, have been part of various research advances for over four decades. Such an application may be classified as a non-thermal method and is based on the delivery of short high pulses to / in tissue to generate a locally high electric field, which may typically be in the range of several hundreds of volts per centimeter. This creates pores in the cell membranes of the tissue. If this electric field exceeds a certain threshold value during the formation of pores at the lipid bilayers of the cell membrane, the so-called electroporation can be irreversible and the pores remain permanently open, which ultimately leads to apoptosis (programmed cell death) of the cell.Irreversible electroporation (IRE) is a predominantly non-thermal method that causes an increase in tissue temperature by at most several degrees for several milliseconds. Thus, IRE is different from the conventionally used RF ablation (radio frequency / radio frequency ablation), in which the tissue temperature rises by 20 to 70° C. and the cells are destroyed by heating. In IRE, bipolar pulses are typically used, i.e. combinations of positive and negative pulses, in order to avoid muscle contraction, which typically results from the application of direct voltages, as far as possible. The pulses may be applied, for example, between two bipolar electrodes of a catheter, or between a catheter electrode and a body surface electrode, which is typically bonded to the skin of the patient's back.In order for the IRE pulses to produce the desired pores in the cell membranes of the target tissue, the electric field strength E at / in the target tissue defined by the pulses must exceed a tissue-dependent threshold value E th between a pair of at least two electrodes. For example, the threshold value for heart cells is about 500 V / cm, while for bone it is 3000 V / cm. These differences in the threshold values of the field strengths allow 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 to be applied to a pair of electrodes depends both on the type of target tissue and on the distance between the electrodes and on the electrode size itself. Similarly, these parameters also influence the thermal energy input during ablation and thus the temperature peaks that can occur on the tissue to be treated. The applied voltages can reach up to 2000 V, which is substantially higher than the typical voltages of 10-200 V in thermal RF ablation.The bipolar pulsed field ablation pulse (the bipolar PFA pulse) for IRE includes positive and negative pulses applied between two electrodes having a pulse width of 1 to 5 μs and a distance between the positive and negative pulses of 1 to 5 μs. The bipolar pulses are assembled into pulse sequences, wherein each sequence can comprise over a hundred bipolar pulses with a pulse-to-pulse interval of 1 to 10 ms. The pulse sequences form a burst in each case, wherein the entire pulse packet of the IRE ablation is composed of 1 to 20 bursts / burst units, each of which has a burst-to-burst interval of 1 to 1000 ms. The total duration of an ablation can be up to 10 s.The parameters of the pulse protocol set forth should be adjusted in advance of ablation in such a way that the desired electroporation effect and a associated clinical effectiveness are achieved and at the same time possible risks such as muscle contraction or thermal damage to the tissue are avoided. In addition to the time and quantitative variables of the pulse protocol, the electrical parameters are also of decisive importance in this case.Up to now, the setting of the electrical parameters in comparison systems is effected by presetting a target current which flows between at least two electrodes through the tissue to be treated and thus locally induces an electric field. The magnitude of this induced electric field is dependent on the electrical impedance of the tissue. However, this tissue impedance likewise fluctuates depending on the position or size of the electrodes and depending on the patient and thus ultimately also the energy which is transmitted through the procedure into the tissue and can locally heat it. Thus, this regulation of the target current does not ensure that locally undesirable thermal effects can occur, such as, for example, the formation of bubbles at the electrodes or the carbonizing of the tissue.A further decisive factor for controlling the PFA pulses is the dependence of the electrical tissue impedance on the applied electrical field strength E, since this directly influences the conductivity of the tissue and thus also the local energy input. If the measurement of the electrical tissue impedance is accordingly carried out at a different electrical field strength than the actual IRE ablation, the actual energy input into the tissue during the ablation thus also differs.Comparison systems here use, for compensation, in part an active control during ablation in order to regulate the energy input, but it is not ensured here that, for example, thermal damage has not already been produced at the beginning of ablation during the adjustment.WO 2022 / 164750 A1 discloses voltage-controlled pulse sequences for IRE systems. A disclosed system includes an ablation catheter with catheter electrode. The catheter electrode generates an electric field in the 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 output a second pulse train with controlled pulse voltage.US 2021 / 0228260 A1 discloses a system and a method for an adjustable waveform and control for ablation with pulsed electric fields. The method discloses, among other things, the steps of: configuring a first output therapy parameter set using a selected therapy profile; generating one or more first therapy outputs using the first output therapy parameter set; detecting one or more first feedback parameters; comparing the first feedback parameters with an expected feedback parameter to generate one or more first comparison results, wherein the expected feedback parameter is associated with the selected therapy profile; and configuring a second output therapy parameter set using the first comparison results.EP 3 964 153 A1 discloses a method for impedance-based irreversible electroporation. The method includes measuring a tissue impedance and calculating an impedance threshold. The impedance threshold inherent in each selected protocol is calculated from protocol parameters or read from a predetermined reference, such as an empirical reference or precomputed references stored in a look-up table. In order to achieve the optimal energy for the ablation process, the protocol is adapted on the basis of the measured tissue impedance, more precisely the pulse duration and / or the number of pulses and / or the number of bursts. The magnitudes of the voltage peaks are typically not reduced when the protocol is adjusted.US 2011 238 056 A1 discloses a system and a method for impedance-switched control of the power supply for electrosurgery. The system and method disclose a pulse series with an initial pulse whose profile corresponds to a preset radio frequency starting value. Beginning with the radio frequency starting value, a radio frequency level rises at a ramp rate up to a preset radio frequency value.Furthermore, the documents EP 3 232 967 A1, US 2022 / 0313346 A1, US 2007 / 0078453 A1, WO 2022 / 173875 A1, WO 2022 / 258034 A1, WO 2020 / 097276 A1 are known.In view of the above state of the art, there is also the problem of controlling the release of energy into the tissue to be treated in advance of an IRE procedure. In particular, it should not be necessary to implement a control loop during the energy output in order to avoid any undesired thermal effects, for example during the adjustment.To solve this problem, an apparatus according to claim 1, a method according to claim 7 and systems according to claims 4, 5 and 6 are proposed.According to a first aspect, a device for tissue-type selective irreversible electroporation of a tissue is proposed. The device 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 device has a pair of electrodes, for example exactly a single pair of electrodes. The pair of electrodes is (electrically) connected to the electrical signal generator. The pair of electrodes is configured to receive the electrical signal. The pair of electrodes is configured to close an electrical connection across the tissue located between the pair of electrodes. The device 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, in particular in a first operating phase. The evaluation and control unit is configured to receive at least one measurement signal transmitted through the tissue, in particular in a first operating phase. The evaluation and control unit is configured to determine a tissue impedance, for example exactly one tissue impedance, on the basis of the at least one received measurement signal, in particular in a first operating phase. The evaluation and control unit is configured to adapt, in particular in a second operating phase, on the basis of the determined tissue impedance, at least one format (e.g. of a plurality of formats) of a burst signal sequence protocol (predefined by a user) in order to specify / define (by means of the adapted burst signal sequence protocol) an energy amount per burst (in Joules) (to the signal generator).This has the advantage that fluctuations in the energy amount per burst, which arise as a result of tissue impedance and / or electrode geometry, are compensated for in advance of the actual ablation (application of a burst signal sequence to the tissue).The transmitted measurement signal can have a measurement signal level, in particular a first voltage level, which equals a burst signal sequence level, in particular a second voltage level.This has the advantage that the tissue impedance is measured explicitly with the same applied voltage with which ablation is also to be carried out subsequently. Since the impedance is dependent on the applied voltage, it is ensured in this way that the actually present impedance is determined during the later ablation and the formats can be adapted on this basis.The electrode pair can have exactly one single electrode pair or be formed as exactly one single electrode pair. The tissue impedance can have exactly one tissue impedance or can be designed as exactly one tissue impedance.The signal generator can be designed as a voltage source, in particular as a high-voltage signal generator. The signal generator may be configured to emit high-voltage direct current (DC) pulsed field ablation (PFA) pulses.The evaluation and control unit can be configured to measure an electrical current and an electrical voltage at least once / at least twice / multiple times, in particular in a first operating phase, and to determine therefrom at least one / at least two / a plurality (of) (average(s)) of tissue impedance(s).The evaluation and control unit can be configured to adapt, in particular in a second operating phase, on the basis of the determined tissue impedance, at least one combination of (at least two) formats (of a plurality of formats) of a burst signal sequence protocol in order to preset / define an energy amount per burst. The predetermined / defined amount of energy per burst may exceed a threshold value of an electric field strength induced in / to the tissue, which is necessary to achieve irreversible electroporation.In other words, the evaluation and control unit can control / control temporal and / or electrical parameters of the electrical signal (by means of a protocol).The evaluation and control unit can be arranged in the signal generator.The evaluation and control unit is configured to transmit the adapted burst signal sequence protocol to the signal generator, in particular in a third operating phase.The predefined / defined energy amount per burst can induce an electric field strength in / to the, in particular myocardial, tissue, in particular in the third operating phase. The predetermined / defined energy amount per burst can be greater than an electric field strength required for tissue packaging, in particular irreversible tissue packaging.The formats of the burst burst burst signal sequence protocol can specify properties and / or the amount of energy per burst of a burst signal sequence to be generated by the signal generator.The format / s can / can have: a first number of bursts within the burst signal sequence, at least one first time interval between at least two successive 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 successive bipolar pulses within a burst, a third time interval between a positive and negative pulse of at least one bipolar pulse, a pulse width of a positive and / or a negative pulse of at least one bipolar pulse, a value of a pulse deflection of a positive and / or a negative pulse of at least one bipolar pulse.The evaluation and control unit can be configured to adapt, in particular in a second operating phase, on the basis of the one specific tissue impedance, at least one (of a plurality of) format(s) of a burst signal sequence protocol (predefined by a user) in order to preset / define an energy amount per burst as a function of the first time interval.A first number of bursts within the burst signal sequence may be in a range of 1 to 100 burst units.At least a first time interval between two successive bursts of the burst signal sequence can lie in a value range from 1 ms to 1000 ms.A second number of bipolar pulses may lie within a burst in a range of 1 to 300 bipolar pulse units.At least a second time interval between at least two successive bipolar pulses within a burst can lie in a value range of 1 to 10 ms. A third time interval between a positive and a negative pulse can lie in a value range between 1 and 5 μs.A pulse width of a positive and / or a negative pulse can lie in a value range between 1 and 10 μs. A pulse width of a positive pulse may be different from a pulse width of a negative pulse.A value of a pulse deflection of a positive pulse may be in a range of values from 200 to 2000 V. A value of a pulse deflection of a negative pulse may be in a range of values from -200 to -2000 V.According to a second aspect, a system for irreversible electroporation of a tissue is proposed. The system comprises a device according to the first aspect and a monopolar catheter. The catheter has a distal end. The pair of electrodes is formed 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 at a body surface of a patient. The first electrode may be disposed in a catheter and project from the catheter at the distal end. The catheter may comprise a shaft at the end of which the first electrode is arranged / attached.According to a third aspect, a system for irreversible electroporation of a tissue is proposed. The system comprises a device according to the first aspect for tissue-type selective irreversible electroporation of a tissue and a bipolar catheter. The catheter has a distal end. The pair of electrodes is formed as one such pair of electrodes disposed at the distal end of the bipolar catheter. The pair of electrodes may be disposed in the bipolar catheter and project out of the catheter at the distal end.The device for tissue-type selective irreversible electroporation of a tissue offers the advantage of being able to be combined with a catheter system that differs from each other. The device can use both unipolar and bipolar multi-electrode catheter systems with the same energy control, since variations in the electrode size and in the electrode distance between positive and negative pole are reflected in the measured tissue impedance and thus the same maximum energy can be ensured during ablation independently of the choice of catheter.According to a fifth aspect, a method for irreversible electroporation of a tissue is proposed. The method comprises 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 a pair of electrodes connected to the electrical signal generator. The pair of electrodes is configured to receive the electrical signal and to close an electrical connection across the tissue located between the pair of electrodes. The method comprises providing an evaluation and control unit connected to the signal generator. The method comprises transmitting, in a first operating phase, a measurement signal protocol to the signal generator by means of the evaluation and control unit. The method comprises transmitting, in the first operating phase, at least one measurement signal by means of the signal generator and the electrode pair through the tissue. The method comprises determining, in the first operating phase, a tissue impedance based on the measurement signal transmitted by the tissue (and received by the electrode pair / the evaluation and control unit). The method comprises adapting, in a second operating phase, by means of the evaluation and control unit, at least one format of a burst signal sequence protocol on the basis of the tissue impedance in order to specify an amount of energy per burst. The method comprises transmitting, in a third operating phase, by means of the evaluation and control unit, the adapted burst sequence protocol to the signal generator.Further features, characteristics, advantages and possible modifications will become apparent to a person skilled in the art from the following descriptions, in which reference is made to the attached drawings. FIG. 1 shows a schematic illustration of a bipolar pulse. FIG. 2 shows a schematic illustration of a pulse protocol implemented by way of example, and FIG. 3 schematically shows method steps for irreversible electroporation of a tissue.FIG. 1 shows a schematic illustration of a bipolar pulse 100 which is generated by the signal generator when the evaluation and control unit sends a burst signal sequence protocol to the signal generator. The signal generator is designed as a voltage source in the present case and is not shown in FIG. 1. In the present example, the formats that determine characteristics of bipolar pulse 100 have been predefined by a user. The values of the pulse deflection kV+, kV- of the positive 101 and negative 104 pulses are ±500 kV in the example shown. The third time interval 103 between the positive 101 and negative 104 pulses 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 the pulse widths is not shown in FIG. 1.If the measurement of the tissue impedance is to take place in a first operating phase, a protocol according to the formats explained above is sent from the evaluation and control unit to the signal generator, which thereupon converts the sent measurement signal protocol and sends a measurement signal through the tissue. In the present example, the bipolar pulse 100 shown is generated and transmitted as a measurement signal. The evaluation and control unit determines a tissue impedance on the basis of the bipolar pulse 100 transmitted through the tissue. The tissue impedance serves the evaluation and control unit as a basis for adapting the above formats.In the present case, the tissue is a myocardial tissue and it is derived from the tissue impedance which electric field strength has to be at least induced in the myocardial tissue in order for irreversible electroporation to occur in the myocardial tissue.In the present case, the third time interval 103 between the positive 101 and negative 104 pulses is reduced by the evaluation and control unit. Alternatively, the pulse widths 102, 105 could each be increased by a different amount. In other words, the pulse widths 102, 105, the third time interval 103 and the values of the pulse deflection kV+, kV- can each be configured independently of one another.If the formats have been adapted by the evaluation and control unit, a burst signal sequence protocol is sent by the evaluation and control unit in a third phase of operation to the signal generator designed as a voltage source, which then sends a burst signal sequence for irreversible electroporation through the tissue.Fig. 2 schematically shows this burst signal sequence. Two bursts can be seen, one of which is provided with the reference symbol 110. Each burst comprises two bipolar pulses 100. Each bipolar pulse 100 occurring in the burst signal sequence has the properties that newly defined / adjusted the adjusted format from the preceding description of the figures on the basis of the measured tissue impedance. The first number of bursts, here exemplarily two bursts, the second time interval 111 and the first time interval 112 between two consecutive bursts 110 have been determined by a user before a first operating phase. The burst signal sequence to be detected extends over a duration 113 which corresponds to the duration of the irreversible electroporation.Figure 3 schematically shows the steps involved in the irreversible electroporation method 200. The method is referred to below as the irreversible electroporation procedure or IRE procedure for short. The IRE procedure starts with step 201. Subsequently, a user, for example a doctor, pre-defines the values of the individual formats in step 202. In other words, the physician assigns a value to each format. This can be done by manually inputting the corresponding data at the evaluation and control unit. The values of the formats and thus the property of a signal sequence to be generated are now predefined. In a third step, the measurement of the tissue impedance takes place. 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 with which values the formats necessary for generating a bipolar pulse are to be converted. A measurement pulse is then transmitted through the tissue by the signal generator and received again. On the basis of this received measurement pulse, a tissue impedance is measured, from which it can be derived which electric field strength must be induced in the tissue in order for an IRE to be established.For an iterative adaptation of the formats of a burst signal sequence protocol following the tissue impedance measurement, a first number of bursts and a second number of bipolar pulses are adapted in step 204 in the formats previously defined by the user. A calculation is then carried out 205 to determine the energy per burst, which does not exceed the maximum permissible energy for the ablation which will follow, but ensures the ablation itself. In other words, an adaptation of at least one format or a combination of formats follows, so that, for example, carbonizing or water vapor formation in the tissue or adjacent tissue during later ablation is avoided, but the IRE is established. Once this iterative adaptation has been completed, the evaluation and control unit sends the adapted burst signal sequence protocol to the signal generator, which then, after being enabled by a user, for example. Physician performing ablation 206. Upon completion of ablation, the IRE procedure is completed 207.References included in the specificationThis list of documents cited by the applicant has been produced in an automated manner and is only included for the better information of the reader. The list is not part of the German patent application or utility model application. The DPMA does not take any adhesion for any faults or omissions.Patent Literature citedWO 2022 / 164750 A1

[0010] US 2021 / 0228260 A1

[0011] EP 3 964 153 A1

[0012] US 2011 238 056 A1

[0013] EP 3 232 967 A1

[0014] US 2022 / 0313346 A1

[0014] US 2007 / 0078453 A1

[0014] WO 2022 / 173875 A1

[0014] WO 2022 / 258034 A1

[0014] WO 2020 / 097276 A1

[0014]

Claims

A device for tissue-type selective irreversible electroporation of a tissue, comprising: - an electrical signal generator configured to generate and transmit an electrical signal according to a signal protocol to be received; - a pair of electrodes connected to the electrical signal generator configured to receive the electrical signal and to close an electrical connection via tissue lying between the pair of electrodes; an evaluation and control unit connected to the signal generator, configured to: - transmit a measurement signal protocol to the signal generator in a first operating phase and determine a tissue impedance on the basis of at least one measurement signal transmitted through the tissue, - adapt at least one format of a burst signal sequence protocol in a second operating phase on the basis of the determined tissue impedance in order to specify an amount of energy per burst, - transmit the adapted burst signal sequence protocol to the signal generator in a third operating phase.The device according to claim 1, wherein the predetermined amount of energy per burst, in particular in the third operating phase, induces an electric field strength into the tissue that is greater than an electric field strength necessary for an, in particular irreversible, tissue poration.The device according to claim 1 or 2, wherein the formats of the burst signal sequence protocol specify properties and the energy amount per burst of a burst signal sequence to be generated by the signal generator, comprising: - a first number of bursts within the burst signal sequence, - at least one first time interval between at least two successive 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 successive bipolar pulses within a burst, - a third time interval between a positive and negative pulse of at least one bipolar pulse, - a pulse width of a positive and / or a negative pulse of at least one bipolar pulse, - a value of a pulse deflection of a positive and / or a negative pulse of at least one bipolar pulse.The apparatus of any of claims 1 to 3, wherein the transmitted measurement signal has a measurement signal level equal to a burst burst burst burst burst signal burst level.A system for irreversible electroporation of tissue, comprising the device of any one of claims 1 to 4 and a monopolar catheter, wherein the catheter has a distal end and the pair of electrodes is formed 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 at a body surface of a patient.A system for irreversible electroporation of tissue comprising the device of any one of claims 1 to 4 and a bipolar catheter, wherein the catheter has a distal end and the pair of electrodes is disposed at the distal end.A method for irreversible electroporation of a tissue, comprising the steps of: - providing an electrical signal generator configured to generate and transmit an electrical signal according to a signal protocol to be received; - providing a pair of electrodes connected to the electrical signal generator configured to receive the electrical signal and to close an electrical connection via the tissue lying between the pair of electrodes; - providing an evaluation and control unit connected to the signal generator; - in a first operating phase, transmitting a measurement signal protocol to the signal generator by means of the evaluation and control unit; - in the first operating phase, transmitting at least one measurement signal by means of the signal generator and the pair of electrodes through the tissue; in the first operating phase, determining a tissue impedance on the basis of the measurement signal transmitted through the tissue; in a second operating phase, by means of the evaluation and control unit, adapting at least one format of a burst signal sequence protocol on the basis of the tissue impedance in order to specify an amount of energy per burst; in a third operating phase, by means of the evaluation and control unit, transmitting the adapted burst sequence protocol to the signal generator.The method according to claim 7, wherein the formats of the burst burst signal sequence protocol specify properties and the amount of energy per burst of a burst signal sequence to be generated by the signal generator, comprising: - a first number of bursts within the burst signal sequence, - at least one first time interval between at least two successive 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 successive bipolar pulses within a burst, - a third time interval between a positive and negative pulse of at least one bipolar pulse, - a pulse width of a positive and / or a negative pulse of at least one bipolar pulse, and - a value of a pulse deflection of a positive and / or a negative pulse of at least one bipolar pulse.

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