Pulse generation system, irreversible electroporation equipment and related methods

Abstract

This application provides a pulse generation system, an irreversible electroporation device, and a related method. The pulse generation system generates a high-voltage pulse signal by controlling the conduction of a pulse transmission circuit according to a control signal. This high-voltage pulse signal is applied to biological tissue through at least one pair of electrodes, causing irreversible electroporation and cell death within the tissue. Furthermore, the pulse generation system can also generate a low-voltage pulse signal to collect electrical information from the biological tissue. This electrical information is then used to determine the effectiveness of the irreversible electroporation and whether to continue the high-voltage pulse treatment. Thus, a single pulse generation system can generate both high-voltage and low-voltage pulses without requiring additional equipment, making it more convenient to use. Moreover, since it is a single circuit, the control effect is better.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of biological detection, and in particular to a pulse generation system, an irreversible electroporation device and related methods. BACKGROUND

[0002] Irreversible electroporation is a method of applying high-voltage pulse electric field to cells to cause irreversible damage to cell membranes, i.e., irreversible electroporation, which breaks the physiological balance inside and outside the cells and eventually leads to cell death. This can be applied to tumor lesion treatment, where irreversible electroporation is used to cause tumor cells to die, thereby achieving the purpose of clinical treatment.

[0003] However, the pulse generation system in the prior art can only generate high-voltage pulses. Such high-voltage pulses can only cause cells to die, but the effect of cell death cannot be known, and other devices need to be used for detection, which is cumbersome and complex to use and has poor control effect. SUMMARY

[0004] Therefore, the purpose of the present application is to provide a pulse generation system, an irreversible electroporation device and related methods to solve or partially solve the above technical problems.

[0005] To achieve the above purpose, the first aspect of the present application provides a pulse generation system, comprising:

[0006] a pulse generation circuit configured to generate a high-voltage pulse signal and a low-voltage pulse signal, and to apply the high-voltage pulse signal and the low-voltage pulse signal to a biological tissue through at least one pair of electrodes, wherein the high-voltage pulse signal is used to perform irreversible electroporation on the cell membranes of cells in the biological tissue, and the low-voltage pulse signal is used to measure electrical information of the biological tissue to determine the irreversible electroporation effect.

[0007] Based on the same inventive concept, the second aspect of the present application provides an irreversible electroporation device, comprising:

[0008] a control unit, the pulse generation system of the first aspect, and a data acquisition and processing unit;

[0009] the control unit is configured to control the operation of the pulse generation system and the data acquisition and processing unit;

[0010] the pulse generation system is configured to control the pulse generation circuit to generate a high-voltage pulse signal or a low-voltage pulse signal according to the control signal of the control unit, and to apply the high-voltage pulse signal or the low-voltage pulse signal to a biological tissue, and to measure electrical information of the biological tissue through the low-voltage pulse signal;

[0011] The data acquisition and processing unit is configured to acquire the electrical information from the pulse generation system according to the acquisition signal sent by the control unit, and perform data processing on the electrical information to obtain impedance spectrum output.

[0012] Based on the same inventive concept, the third aspect of the present application provides a pulse generation method applied to the pulse generation system of the first aspect, and the pulse generation method comprises:

[0013] Placing the biological tissue between at least one pair of electrodes of the pulse generation circuit;

[0014] Receiving a control signal;

[0015] In response to determining that the control signal is a high-voltage pulse generation signal, controlling the pulse generation circuit to generate a high-voltage pulse signal, and applying the high-voltage pulse signal to the biological tissue through the at least one pair of electrodes, so that the cell membrane of the biological tissue cells is subjected to irreversible electroporation by the high-voltage pulse signal;

[0016] In response to determining that the control signal is a low-voltage pulse generation signal, controlling the pulse generation circuit to generate a low-voltage pulse signal, and applying the low-voltage pulse signal to the biological tissue through the at least one pair of electrodes, and measuring the electrical information of the biological tissue by the low-voltage pulse signal to determine the irreversible electroporation effect.

[0017] Based on the same inventive concept, the fourth aspect of the present application provides an irreversible electroporation method applied to the irreversible electroporation device of the second aspect, and the irreversible electroporation method comprises:

[0018] Generating a control signal by using a control unit, and sending the control signal to the pulse generation system;

[0019] In response to determining that the control signal is a high-voltage pulse generation signal, generating a high-voltage pulse signal by the pulse generation system and applying it to the biological tissue;

[0020] In response to determining that the control signal is a low-voltage pulse generation signal, generating a low-voltage pulse signal by the pulse generation system and applying it to the biological tissue, and sending the electrical information of the biological tissue measured by the low-voltage pulse signal to the data acquisition and processing unit;

[0021] Acquiring the electrical information by using the data acquisition and processing unit, performing operation processing on the electrical information to obtain impedance spectrum, and outputting the impedance spectrum.

[0022] From the above, the pulse generation system, irreversible electroporation device and related methods provided by the present application can generate high-voltage pulse signals by controlling the conduction of the pulse sending circuit according to the control signal through the pulse generation system, and apply the high-voltage pulse signals to the biological tissue through at least one pair of electrodes, so that the biological tissue is subjected to irreversible electroporation, and the cells in the biological tissue are eliminated. In addition, the pulse generation system can also generate low-voltage pulse signals, and the electrical information of the biological tissue is collected through the low-voltage pulse signals, and then the effect of irreversible electroporation is judged through the electrical information to determine whether to continue to perform irreversible electroporation treatment on the biological tissue through the high-voltage pulse signals. In this way, the generation of high-voltage pulses and low-voltage pulses can be completed through one pulse generation system, without the need to increase other devices, making the use more convenient, and since it is completed by one circuit, the control effect is better. BRIEF DESCRIPTION OF DRAWINGS

[0023] In order to more clearly illustrate the technical solutions in the present application or related art, the drawings needed to be used in the embodiments or related art description will be briefly introduced. Obviously, the drawings in the following description are only embodiments of the present application, and other drawings can be obtained by those skilled in the art without creative labor.

[0024] Figure 1-1 The structure schematic diagram of the pulse generation system of the embodiment of the present application;

[0025] Figure 1-2 The structure schematic diagram of the pulse generation system of the embodiment of the present application;

[0026] Figure 1-3 The structure schematic diagram of the pulse generation system of the embodiment of the present application;

[0027] Figure 1-4 The circuit structure schematic diagram of the pulse generation system provided with four groups of hierarchical circuits of the embodiment of the present application;

[0028] Figure 2 The structure schematic diagram of the irreversible electroporation device of the embodiment of the present application;

[0029] Figure 3-1a The circuit structure schematic diagram of the charging process of the embodiment of the present application;

[0030] Figure 3-1b The circuit structure schematic diagram of the generation of positive high-voltage pulse signals of the embodiment of the present application;

[0031] Figure 3-1c The circuit structure schematic diagram of the generation of negative high-voltage pulse signals of the embodiment of the present application;

[0032] Figure 3-2a Circuit structure schematic diagram for generating positive low-voltage pulse signal of the embodiment of the present application;

[0033] Figure 3-2b Circuit structure schematic diagram for generating negative low-voltage pulse signal of the embodiment of the present application;

[0034] Figure 3-3a Schematic diagram of single positive high-voltage pulse signal;

[0035] Figure 3-3b Schematic diagram of positive high-voltage pulse train;

[0036] Figure 3-3c Schematic diagram of single bipolar high-voltage pulse signal;

[0037] Figure 3-3d Schematic diagram of bipolar high-voltage pulse train;

[0038] Figure 3-4a Schematic diagram of bipolar high-voltage pulse train followed by two bipolar low-voltage pulse trains;

[0039] Figure 3-4b Schematic diagram of bipolar high-voltage pulse train followed by two bipolar low-voltage pulse trains with adjusted amplitude;

[0040] Figure 3-4c Schematic diagram of bipolar high-voltage pulse train followed by positive and negative polarity low-voltage pulse trains;

[0041] Figure 3-4d Schematic diagram of bipolar high-voltage pulse train followed by positive polarity low-voltage pulse train with gradually increasing pulse width;

[0042] Figure 3-5a Schematic diagram of low-voltage pulse voltage waveform under different biological tissue load impedances;

[0043] Figure 3-5b Schematic diagram of low-voltage pulse spectrum;

[0044] Figure 3-5c Schematic diagram of response current values of different biological tissue loads after low-voltage pulse stimulation;

[0045] Figure 3-5d Schematic diagram of response current spectrum of biological tissue load;

[0046] Figure 3-5e Schematic diagram of extracting impedance modulus from impedance spectrum;

[0047] Figure 3-5f Schematic diagram of extracting impedance angular spectrum from impedance spectrum;

[0048] Figure 3-6aFig. 2 is a schematic diagram of the impedance spectrum after adjusting the high frequency of the impedance spectrum band;

[0049] Figure 3-6b Fig. 3 is a schematic diagram of the impedance angle spectrum after adjusting the impedance spectrum band;

[0050] Figure 4 Fig. 4 is a flowchart of the pulse generation method of the embodiment of the present application;

[0051] Figure 5 Fig. 5 is a flowchart of the irreversible electroporation method of the embodiment of the present application. DETAILED DESCRIPTION

[0052] In order to make the objects, technical solutions and advantages of the present application clearer, the present application will be further described in detail below with reference to the embodiments and the accompanying drawings.

[0053] It should be noted that, unless otherwise defined, the technical terms or scientific terms used in the embodiments of the present application should be understood as the common meanings understood by those skilled in the art to which the embodiments of the present application belong. The terms "first", "second" and similar terms used in the embodiments of the present application do not represent any order, number or importance, but are only used to distinguish different components. The terms "include" or "contain" and similar terms mean that the elements or objects before the terms cover the elements or objects listed after the terms and their equivalents, and do not exclude other elements or objects. The terms "connect" or "connected" and similar terms are not limited to physical or mechanical connections, but can include electrical connections, whether direct or indirect. The terms "upper", "lower", "left", "right" and the like are only used to represent relative positional relationships, and when the absolute positions of the described objects change, the relative positional relationships may also change accordingly.

[0054] Based on the description of the above background technology, the high-voltage pulse source is the core link of the irreversible electroporation tumor ablation technology, and at present, most high-voltage pulse sources are based on the Marx high-voltage forming circuit of the solid-state switch. With the continuous promotion of the clinical application of irreversible electroporation tumor ablation, clinicians find that it is difficult to meet the current treatment needs by checking the ablation effect through nuclear magnetic resonance imaging or CT scanning 24 hours or even longer after the operation. It is particularly necessary to evaluate the curative effect in real time during the irreversible electroporation tumor ablation process to determine the optimal treatment stopping time point. It is expected to become a breakthrough in real-time evaluation of curative effect by using the real-time changes of the impedance spectrum of biological tissues during irreversible electroporation to reflect the ablation effect. However, how to realize the rapid and accurate measurement of the impedance of biological tissues during pulse action without affecting the stable output of high-voltage pulses and as low as possible to reduce the complexity and production cost of the equipment is a key core problem that needs to be considered.

[0055] The main problems in the related art for evaluating the irreversible electroporation ablation effect based on the change of the biological tissue impedance spectrum are:

[0056] 1. The tissue impedance spectrum is measured by adding a sweep frequency module. This method uses the sweep frequency method to measure impedance information. It takes a relatively long time to obtain low-frequency signals, and it is challenging to obtain a flexible frequency band range of tissue impedance spectrum within the high-voltage pulse action interval (about 1s). At the same time, the additional sweep frequency module requires that the module can cooperate with the high-voltage pulse generation module to apply high-voltage treatment pulses and sweep signals to the biological load in an orderly manner, increasing the system complexity and introducing instability factors.

[0057] 2. The tissue impedance spectrum is calculated by adding a low-voltage pulse forming circuit according to the measured time-domain pulse voltage and current through Fourier transform. This method realizes the rapid measurement of the tissue impedance spectrum within the pulse action interval. However, it still introduces an additional low-voltage module, increases the system complexity, causes related instability factors, and increases the production cost.

[0058] Based on the above description, the pulse generation system 1 proposed by the embodiments of the present disclosure includes: Figure 1-1 as shown, comprising:

[0059] The pulse generation circuit 11 is configured to generate a high-voltage pulse signal and a low-voltage pulse signal, and apply the high-voltage pulse signal and the low-voltage pulse signal to the biological tissue through at least one pair of electrodes, wherein the cell membrane of the biological tissue cells is subjected to irreversible electroporation by the high-voltage pulse signal, and the electrical information of the biological tissue is measured by the low-voltage pulse signal to determine the irreversible electroporation effect. In the embodiments Figure 1-1 , the at least one pair of electrodes at least includes a first electrode 12 and a second electrode 13.

[0060] In specific implementation, the current direction from the upper side of the biological tissue to the lower side is defined as a positive polarity pulse, and vice versa. The biological tissue involved in the present application is tumor tissue with lesions. The first electrode 12 and the second electrode 13 are placed on the biological tissue, and the high-voltage pulse signal is applied to the biological tissue by the pulse generation circuit 11 to produce irreversible electroporation on the cell membrane of the biological tissue, break the physiological balance inside and outside the cell, and cause the cell to die. The corresponding high-voltage pulse signal includes any one of the positive high-voltage pulse signal, the negative high-voltage pulse signal, and the bipolar high-voltage pulse signal. And the pulse width, the maximum voltage value, and the application time of the high-voltage pulse signal can be adjusted according to the lesion condition of the biological tissue.

[0061] The pulse generating circuit 11 can adjust the pulse waveform spectrum distribution by applying a low-voltage pulse signal with continuously changing pulse width using the pulse generating circuit 11 according to the impedance spectrum band requirement of the biological tissue. When the low-voltage pulse signal is applied to the biological tissue, the corresponding voltage signal and current signal are detected, so that the corresponding impedance spectrum can be obtained according to the voltage signal and current signal, and then the effect of irreversible electroporation is determined according to the impedance spectrum.

[0062] The low-voltage pulse signal can continuously detect the impedance spectrum change of the biological tissue in the interval time of the high-voltage pulse signal. And the low-voltage pulse signal is applied multiple times in the interval time of the high-voltage pulse signal, so as to realize the purpose of real-time detection of the impedance spectrum of the biological tissue.

[0063] In specific implementation, a pair of electrodes (i.e. the first electrode 12 and the second electrode 13) can be arranged in the pulse generating circuit 11, or multiple pairs of electrodes can be arranged. The number of pairs is set according to the size of the biological tissue and the pathological condition of the biological tissue.

[0064] Through the above technical solution, the pulse generating system 1 is used to generate a high-voltage pulse signal by controlling the conduction of the pulse sending circuit according to the control signal, and the high-voltage pulse signal is applied to the biological tissue through the first electrode 12 and the second electrode 13, so that the biological tissue is subjected to irreversible electroporation, and the cells in the biological tissue are killed. Moreover, the pulse generating system 1 can also generate a low-voltage pulse signal, and the electrical information of the biological tissue is collected through the low-voltage pulse signal, and then the effect of irreversible electroporation is judged through the electrical information, to determine whether to continue to perform irreversible electroporation on the biological tissue through the high-voltage pulse signal. In this way, the generation of high-voltage pulses and low-voltage pulses can be completed by one pulse generating system 1, without the need to increase other devices, so that the use is more convenient, and since it is completed by one circuit, the control effect is better.

[0065] In some embodiments, as shown in Figure 1-2 The pulse generating circuit 11 includes a first pulse generating circuit 111 and a second pulse generating circuit 112, the first electrode 12 is arranged at the output end of the first pulse generating circuit 111, and the second electrode 13 is arranged at the output end of the second pulse generating circuit 112.

[0066] The first pulse generating circuit 111 generates a positive high-voltage pulse signal according to the control signal, and applies the positive high-voltage pulse signal to the biological tissue through the first electrode 12, while controlling the second electrode 13 of the second pulse generating circuit 112 to be connected to the ground end.

[0067] And / or,

[0068] The second pulse generating circuit 112 generates a negative high-voltage pulse signal according to the control signal, and applies the negative high-voltage pulse signal to the biological tissue through the second electrode 13, while controlling the first electrode 12 of the first pulse generating circuit 111 to connect to the ground terminal.

[0069] In practice, a positive high-voltage pulse signal is generated using a first pulse generating circuit 111, and a negative high-voltage pulse signal is generated using a second pulse generating circuit 112. These signals are then applied according to the specific irreversible electroporation requirements of the biological tissue. A positive high-voltage pulse train can be generated by intermittent application of the positive high-voltage pulse signal; a negative high-voltage pulse train can be generated by intermittent application of the negative high-voltage pulse signal; and a bipolar high-voltage pulse train can be generated by alternating intermittent application of both positive and negative high-voltage pulse signals.

[0070] The frequency and duration of various high-voltage pulse trains can be set according to actual needs, or adjusted in real time.

[0071] In some embodiments, such as Figure 1-2 As shown, a first variable resistor R is connected in series at the output terminal of the first pulse generating circuit 111. d1 The output terminal of the second pulse generator is connected in series with a second variable resistor R. d2 ;

[0072] The first variable resistor R in the first pulse generating circuit 111 d1 When energized, the first variable resistor R is connected. d1 The positive high voltage pulse signal is divided to obtain a positive low voltage pulse signal. The positive low voltage pulse signal is applied to the biological tissue through the first electrode 12, while the second electrode 13 of the second pulse generation circuit 112 is connected to the ground terminal.

[0073] And / or,

[0074] The second variable resistor R in the second pulse generating circuit 112 d2 When energized, the second variable resistor R is connected. d2 The negative high-voltage pulse signal is divided to obtain a negative low-voltage pulse signal. The negative low-voltage pulse signal is applied to the biological tissue through the second electrode 13, while the first electrode 12 of the second pulse generation circuit 112 is connected to the ground terminal.

[0075] In a specific implementation, in order to enable the two pulse generating circuits 11 to generate low-voltage pulse signals, a corresponding variable resistor is used for voltage division. The voltage of the corresponding low-voltage pulse signal can be realized by adjusting the resistance value of the variable resistor. The greater the resistance value of the variable resistor, the more the voltage division, and the smaller the voltage of the low-voltage pulse signal.

[0076] Likewise, a positive polarity low-voltage pulse train can be generated by intermittent application of the positive low-voltage pulse signal; a negative polarity low-voltage pulse train can be generated by intermittent application of the negative low-voltage pulse signal, and a bipolar low-voltage pulse train can be generated by intermittent application of the positive low-voltage pulse signal and the negative low-voltage pulse signal. The frequency and duration of various low-voltage pulse trains can be set according to actual needs, or can be adjusted in real time.

[0077] In some embodiments, as shown in Figure 1-2 The first pulse generating circuit 111 includes:

[0078] A first resistor connected to a power supply; a first capacitor having one end connected to the first resistor and the other end connected to a ground terminal; a switch Q1 and a switch Q2 connected in series, the switch Q1 and the switch Q2 connected in parallel with the first capacitor, and the switch Q1 and the switch Q2 connected to the first electrode 12 through a wire; the first variable resistor R d1 having one end connected to the first resistor and the other end connected to the first electrode 12;

[0079] and,

[0080] The second pulse generating circuit 112 includes:

[0081] A second resistor connected to a power supply; a second capacitor having one end connected to the second resistor and the other end connected to a ground terminal; a switch Q11 and a switch Q12 connected in series, the switch Q11 and the switch Q12 connected in parallel with the second capacitor, and the switch Q11 and the switch Q12 connected to the second electrode 13 through a wire; the second variable resistor R d2 having one end connected to the second resistor and the other end connected to the second electrode 13.

[0082] In a specific implementation, the first pulse generating circuit 111 and the second pulse generating circuit 112 generate a high-voltage pulse train by alternately performing a charging process and a high-voltage pulse generation process, and generate a low-voltage pulse train by alternately performing a charging process and a low-voltage pulse generation process.

[0083] Charging process: the switches Q1, Q2, Q11 and Q12 are all disconnected, and the first capacitor and the second capacitor are charged by the power supply.

[0084] The positive high-voltage pulse signal generation process: turn on switch Q1 and switch Q11, turn off switch Q2 and switch Q12, the first capacitor applies positive high voltage to the biological tissue through the first electrode 12, and flows back to the ground through the second electrode 13.

[0085] The negative high-voltage pulse signal generation process: turn on switch Q2 and switch Q12, turn off switch Q1 and switch Q11, the second capacitor applies negative high voltage to the biological tissue through the second electrode 13, and flows back to the ground through the first electrode 12.

[0086] The positive low-voltage pulse signal generation process: turn off switch Q1, switch Q2 and switch Q11, turn on switch Q12, the first variable resistor R d1 is turned on, so that the first variable resistor R d1 divides the positive high-voltage pulse signal, generates a positive low-voltage pulse signal, applies the positive low-voltage pulse signal to the biological tissue through the first electrode 12, and flows back to the ground through the second electrode 13.

[0087] The negative low-voltage pulse signal generation process: turn off switch Q11, switch Q12 and switch Q1, turn on switch Q2, the second variable resistor R d2 is turned on, so that the second variable resistor R d2 divides the negative high-voltage pulse signal, generates a negative low-voltage pulse signal, applies the negative low-voltage pulse signal to the biological tissue through the second electrode 13, and flows back to the ground through the first electrode 12.

[0088] Through the above scheme, the generation process of high-voltage pulse signals and low-voltage pulse signals can be completed, and the corresponding pulse trains can be generated according to the description of each pulse train.

[0089] In some embodiments, at least one hierarchical circuit 113 is also connected in parallel in the first pulse generation circuit 111 or the second pulse generation circuit 112, and the hierarchical circuit 113 is connected with the first electrode 12 or the second electrode 13.

[0090] The hierarchical circuit 113 is configured to expand the voltage value of the positive high-voltage pulse signal or expand the voltage value of the negative high-voltage pulse signal.

[0091] In specific implementation, since the high voltage of the high-voltage pulse signal may not meet the requirement of irreversible electroporation on the biological tissue, it is necessary to increase the voltage value, and the voltage value is increased by using the grading circuit 113. One grading circuit 113 in the embodiment can increase the voltage value by N (for example, N = 1) times, and the number of specific grading circuits 113 can be set according to the voltage value required for irreversible electroporation on the biological tissue. For example, if the voltage value needs to be increased by 4 times, four groups of voltage dividing circuits with N = 1 are connected in parallel. When the low-voltage pulse signal is generated, the first variable resistor R d1 and the second variable resistor R d2 are increased in resistance value, so as to ensure that the voltage value of the low-voltage pulse signal remains unchanged.

[0092] In some embodiments, as shown in Figure 1-3 , the grading circuit 113 comprises:

[0093] a grading diode D1, one end of which is connected with the first resistor or the second resistor;

[0094] a grading capacitor C2, one end of which is connected with the grading diode, and the other end of which is connected with the middle of the switch Q1 and the switch Q2, or the other end of which is connected with the middle of the switch Q11 and the switch Q12;

[0095] a first grading switch Q3 and a second grading switch Q4, the first grading switch Q3 and the second grading switch Q4 being connected in series and connected in parallel with the grading capacitor C2;

[0096] wherein the next grading circuit 113 is connected in parallel across the first grading switch Q3; or the first variable resistor R d1 / the second variable resistor R d2 is connected with the grading diode D1, and is connected with the first electrode 12 / the second electrode 13 through a wire in the middle of the first grading switch Q3 and the second grading switch Q4.

[0097] In specific implementation, it is determined that the switch Q1 and the first grading switch of the grading circuit 113 in the first pulse generating circuit 111 are both first main switches; it is determined that the switch Q2 and the second grading switch of the grading circuit 113 in the first pulse generating circuit 111 are both first charging switches;

[0098] it is determined that the switch Q11 and the first grading switch Q3 of the grading circuit 113 in the second pulse generating circuit 112 are both second main switches; and it is determined that the switch Q12 and the second grading switch Q4 of the grading circuit 113 in the second pulse generating circuit 112 are both second charging switches.

[0099] Charging process: control the first main switch and the first charging switch in the last stage of the first pulse generating circuit 111 to be closed, and charge all the capacitors in the first pulse generating circuit 111; and control the second main switch and the second charging switch in the last stage of the second pulse generating circuit 112 to be closed, and charge all the capacitors in the second pulse generating circuit 112.

[0100] Positive high-voltage pulse signal generation process: control the first main switch in the first pulse generating circuit 111 to be closed and the first charging switch to be opened, and control the second main switch in the second pulse generating circuit 112 to be opened and the second charging switch to be closed, to generate a positive high-voltage pulse signal.

[0101] Negative high-voltage pulse signal generation process: control the first main switch in the first pulse generating circuit 111 to be opened and the first charging switch to be closed, and control the second main switch in the second pulse generating circuit 112 to be closed and the second charging switch to be opened, to generate a negative high-voltage pulse signal.

[0102] Positive low-voltage pulse signal generation process: control the first main switch in the first pulse generating circuit 111 to be opened, the first charging switch in the last stage of the first pulse generating circuit 111 to be opened, and the other first charging switches in the first pulse generating circuit 111 to be closed; and control the second main switch in the second pulse generating circuit 112 to be opened, and the second charging switches in the second pulse generating circuit 112 to be closed, so that the first variable resistor R d1 is connected in series, and the positive high-voltage pulse signal is divided by the first variable resistor R d1 to obtain a positive low-voltage pulse signal.

[0103] Negative low-voltage pulse signal generation process: control the first main switch in the first pulse generating circuit 111 to be opened, and the first charging switch in the first pulse generating circuit 111 to be closed; and control the second main switch in the second pulse generating circuit 112 to be opened, the second charging switch in the last stage of the second pulse generating circuit 112 to be opened, and the other second charging switches in the second pulse generating circuit 112 to be closed, so that the second variable resistor R d2 is connected in series, and the negative high-voltage pulse signal is divided by the second variable resistor R d2 to obtain a negative low-voltage pulse signal.

[0104] In some embodiments, the pulse generating circuit 11 is used to generate the low-voltage pulse signal in the interval of the high-voltage pulse signal.

[0105] In some embodiments, based on the description of the above embodiments, the high-voltage pulse signal comprises at least one of the following:

[0106] a positive high-voltage pulse signal or a positive high-voltage pulse train formed by repeatedly superimposing the positive high-voltage pulse signal, a negative high-voltage pulse signal or a negative high-voltage pulse train formed by repeatedly superimposing the negative high-voltage pulse signal, a bipolar high-voltage pulse signal formed by alternately arranging the positive high-voltage pulse signal and the negative high-voltage pulse signal or a bipolar high-voltage pulse train formed by repeatedly superimposing the bipolar high-voltage pulse signal;

[0107] The low-voltage pulse signal comprises at least one of the following:

[0108] a positive low-voltage pulse signal or a positive low-voltage pulse train formed by repeatedly superimposing the positive low-voltage pulse signal, a negative low-voltage pulse signal or a negative low-voltage pulse train formed by repeatedly superimposing the negative low-voltage pulse signal, a bipolar low-voltage pulse signal formed by alternately arranging the positive low-voltage pulse signal and the negative low-voltage pulse signal or a bipolar low-voltage pulse train formed by repeatedly superimposing the bipolar low-voltage pulse signal.

[0109] The width of the high-voltage pulse signal and the low-voltage pulse signal in the above embodiments is controlled according to the on-off time of the corresponding switch.

[0110] Through the description of the above embodiments, the hierarchical circuit 113 (such as Figure 1-4 As shown in the first pulse generating circuit 111 and the second pulse generating circuit 112, four groups of hierarchical circuits are arranged, and then the high-voltage value of the high-voltage pulse signal is increased through the hierarchical circuit 113, and the control of the voltage division can also be realized by adjusting the two variable resistors, so that the two pulse generating circuits 11 can generate corresponding low-voltage pulse signals, thereby meeting the condition that one pulse generating system 1 can generate high-voltage pulse signals and low-voltage pulse signals, without adding an additional low-voltage stimulation module, simplifying the system complexity and reducing the production cost; At the same time, it can realize the rapid measurement of biological tissue electric information, determine the corresponding impedance spectrum according to the electric information, and then dynamically track the change of biological tissue impedance information.

[0111] Based on the same inventive concept, the application also provides an irreversible electroporation device 2, as shown in Figure 2 Comprise:

[0112] A control unit 21, a pulse generating system 22 in the above embodiments and a data acquisition and processing unit 23, the control unit 21 is connected with the pulse generating system 22 and the data acquisition and processing unit 23 respectively, and the pulse generating system 22 is also connected with the data acquisition and processing unit 23;

[0113] The control unit 21 is configured to control the operation of the pulse generation system 22 and the data acquisition and processing unit 23.

[0114] The pulse generation system 22 is configured to control the pulse generation circuit to generate high-voltage pulse signals or low-voltage pulse signals according to the control signal of the control unit 21, and apply the signals to biological tissue, and send the electrical information of the biological tissue measured by the low-voltage pulse signal to the data acquisition and processing unit 23.

[0115] The data acquisition and processing unit 23 is configured to receive the electrical information and perform data processing on the electrical information to obtain impedance spectrum output.

[0116] In specific implementation, the control process is as follows: the control unit 21 generates a control signal, and sends the control signal to the pulse generation system 22.

[0117] (1) If the control signal is a high-voltage pulse generation signal, the pulse generation system 22 generates a high-voltage pulse signal applied to biological tissue. The specific generation process of the high-voltage pulse signal is the same as described in the above embodiment, which will not be repeated here.

[0118] (2) If the control signal is a low-voltage pulse generation signal, the pulse generation system 22 generates a low-voltage pulse signal applied to biological tissue and sends the electrical information of the biological tissue measured by the low-voltage pulse signal to the data acquisition and processing unit 23, wherein the electrical information includes voltage information and current information. The specific generation process of the low-voltage pulse signal is the same as described in the above embodiment, which will not be repeated here.

[0119] Then, the data acquisition and processing unit 23 is used to perform fast Fourier transform on the voltage information to obtain a voltage spectrum, and perform fast Fourier transform on the current information to obtain a current spectrum.

[0120] Voltage spectrum: U(ω) = FFT(u(t)), where u(t) is the voltage information. Current spectrum: I(ω) = FFT(i(t)), where i(t) is the current information.

[0121] The data acquisition and processing unit 23 is used to perform operation processing on the voltage spectrum and the current spectrum to obtain impedance spectrum Z(ω) = (U(ω)) / (I(ω)), and output the impedance spectrum Z(ω), for example, to a user interface.

[0122] The following describes an embodiment of an irreversible electroporation device corresponding to the addition of 4 groups of sub-circuits:

[0123] The following embodiments are described in the context of the corresponding circuit part in the figure, the black marked connection and components represent on in the corresponding embodiment scenario, the gray marked connection and components represent off in the corresponding embodiment scenario.

[0124] The topology of the two pulse generating circuits (Marx) in the present application is to facilitate the generation of high-voltage square wave pulses of different polarities. Figure 3-1a The charging mode is shown. Figure 3-1b The generation circuit of positive polarity square wave pulse (i.e. positive high-voltage pulse signal) is shown. The definition of current direction from the upper side of the biological load (i.e. biological tissue) to the lower side is positive polarity pulse, and vice versa is negative polarity pulse.

[0125] From Figure 3-1b It can be seen that when switch Q 1,3,5,7,9 is on, Q 2,4,6,8,10 is off, the capacitors C1-C5 are connected in series to discharge the biological load, and the voltage is NU0, N is the number of stages corresponding to the Max generator (i.e. the first / second pulse generating circuit) (this embodiment has 4 groups of sub-circuit, so the number of stages N is 5); at the same time, switch Q 11,13,15,17,19 is off, Q 12,14,16,18,20 is on, therefore, the lower end of the biological tissue load is connected to the ground through switch Q 12,14,16,18,20 , thus generating a pulse with amplitude NU0 on the load, N is the number of stages corresponding to the Max generator. The principle of generating negative polarity high-voltage pulse (i.e. negative high-voltage pulse signal) is similar to that of generating positive polarity high-voltage pulse, as shown in Figure 3-1c The negative polarity discharge mode is shown. Switch Q 1,3,5,7,9 is off, Q 2,4,6,8,10 is on, thus the upper side of the biological load is directly connected to the ground, while switch Q 11,13,15,17,19 is on, Q 12,14,16,18,20 is off, the capacitors C6-C10 are connected in series to discharge the biological load, thus generating a pulse with amplitude NU0 on the biological load. The timing sequence of the switch on for generating positive and negative polarity high-voltage pulses is the same as that of the related art Marx generator. The gray color in each figure represents the off state of the circuit.

[0126] The significant difference between the present application and the Marx generator in the related art is that the pulse generator of the present application can simultaneously generate low-voltage pulse signals for measuring the impedance spectrum of biological tissue to evaluate the treatment effect of high-voltage pulses on biological tissue. Unlike other impedance spectrum measurement methods, the present application does not need to add any external low-voltage module, but directly extracts low-voltage pulse signals from the pulse generating circuit, simplifying the system complexity and reducing the production cost. The discharge principle diagram of the low-voltage pulse signal generation in the present application is shown in Figure 4 .

[0127] The circuit for generating the positive low-voltage measurement pulse (i.e., the positive low-voltage pulse signal) is as follows: Figure 3-2a As shown, switch Q 1,3,5,7,9 and Q 11,13,15,17,19 Off, Q 2,4,6,8 and Q 12,14,16,18,20 When the circuit is turned on, all capacitors are in a parallel charging state. The only difference is that Q is now... 10 When switched off, the charging voltage U0 of the upper Marx circuit (i.e., the first pulse generation circuit) can pass through the voltage divider resistor R. d1 biological tissue load Z L and switch Q 12,14,16,18,20 A discharge circuit is formed, generating a voltage amplitude of U0Z on the biological tissue load. L / (Z L +R d1 The low-voltage positive polarity pulse, Z L This represents the resistance value of the biological tissue load.

[0128] Among them, the amplitude of the positive polarity low-voltage pulse (i.e., the low-voltage value of the positive polarity low-voltage pulse signal) can be obtained through R. d1 The width of the positive low-voltage pulse signal can be adjusted by adjusting switch Q. 20 On / off time control.

[0129] The generation principle of negative polarity low-voltage measurement pulses is similar to that of positive polarity low-voltage measurement pulses, such as... Figure 3-2b As shown, switch Q 1,3,5,7,9 Q 11,13,15,17,19 Off, Q 2,4,6,8,10 Q 12,14,16,18 On, Q 20 With the circuit off, all capacitors are in a parallel charging state. The charging voltage U0 of the Marx circuit below (i.e., the second pulse generation circuit) can be divided by the voltage divider resistor R. d2 biological tissue load Z L and switch Q 2,4,6,8,10 A discharge circuit is formed, generating a voltage amplitude of U0Z on the load. L / (Z L +R d2 The negative polarity low-voltage pulse (i.e., the negative polarity low-voltage pulse signal) is generated. The amplitude of the negative polarity low-voltage pulse can be determined by R. d2 The width of the negative low-voltage pulse signal can be adjusted by adjusting switch Q. 10 On / off time control.

[0130] Impedance spectroscopy calculation of biological tissues:

[0131] In the process of applying high and low voltage pulse signals, the data acquisition and processing unit acquires the voltage (u(t)) and response current (i(t)) data applied to the biological tissue in the pulse generating system in real time; the acquired high / low voltage and current data are subjected to fast Fourier transform, as follows:

[0132] U(ω) = FFT(u(t)) (1)

[0133] I(ω) = FFT(i(t)) (2)

[0134] In formula (1) (2), FFT is fast Fourier transform, the time domain waveform measured is shown in Figure 3-5a , 3-5c The calculated voltage / current spectrum is shown in Figure 3-5b , 3-5d

[0135] According to the calculated voltage / current spectrum, the load impedance spectrum can be calculated:

[0136] Z(ω) = (U(ω)) / (I(ω)) (3);

[0137] The impedance modulus and impedance angle spectrum are extracted respectively, and the results shown in Figure 3-5e , Figure 3-5f

[0138] The simulation circuit of the pulse generating system of the present application is shown in Figure 1-4 By controlling the switch driving signals, different forms of high voltage pulse signals can be generated, as shown in FIG. 3-3. In the simulation, the charging voltage is 1kV, the pulse width is 100μs, and the output high voltage amplitude is 5kV. Figure 3-3a It is a single unipolar pulse, which is a commonly used pulse form of irreversible electroporation. Figure 3-3b It is a unipolar high frequency pulse train, the width of a single pulse in the pulse train is 5μs, the pulse interval time is 5μs, and the total high level time of all pulses in the pulse train is still 100μs, which is a commonly used pulse form of high frequency unipolar irreversible electroporation at present. Figure 3-3c It is a single bipolar pulse, the positive and negative pulse widths are both 50μs, the pulse interval is 5μs, Figure 3-3d It is a bipolar pulse train, the positive and negative pulse widths in the train are both 5μs, the pulse interval is also 5μs, and the total high level time of the positive and negative pulses in the train is 100μs, which is a commonly used pulse form of high frequency irreversible electroporation at present. As can be seen, the pulse generating system proposed by the present application can generate different forms of high voltage pulses. Here, only four representative waveforms are taken as examples, and in fact, all the pulse parameters above can be independently adjusted to generate a variety of pulse forms, such as pulse trains with gradually increasing or gradually decreasing pulse widths, bipolar pulses with asymmetric positive and negative pulses, etc.​​

[0139] The innovation of this application lies in that it can not only generate various commonly used high-voltage pulse waveforms as shown in Figure 3-3, but also generate low-voltage measurement pulses during the high-voltage pulse operation based on the same topology for real-time monitoring of the status of the object being processed.

[0140] Taking bipolar pulse trains as an example, this illustrates the coordination methods between different types of low-voltage measurement pulses and high-voltage pulses. Similar results can be obtained for other types of high-voltage pulses. Figure 3-4a A high-voltage pulse is followed by two bipolar low-voltage pulse trains. The specific parameters of the pulse trains (high-level time, pulse width, pulse time interval) and the number of pulse trains are flexibly adjustable; the amplitude of the low-voltage pulse trains can be controlled by a variable resistor (R). d1 Or R d2 Adjustments can be made, such as... Figure 3-4b As shown, compared to Figure 3-4a The amplitude of the low-voltage pulse train has been significantly improved. A unipolar pulse train can also be used as the low-voltage measurement pulse after the high-voltage pulse train, such as... Figure 3-4c As shown. Figure 3-4c The pulses are followed by a positive pulse train and a negative pulse train, respectively, mainly to illustrate the flexible and adjustable low-voltage pulse parameters. Figure 3-4d The demonstration shows a positive polarity low-voltage pulse train with gradually increasing pulse width. Using this type of pulse train can effectively increase the bandwidth of the impedance spectrum.

[0141] To verify whether the high-voltage pulse generator proposed in this application can capture the dynamic changes in the impedance spectrum of biological tissues during high-voltage pulse treatment, the simulation simulated the continuous increase in the degree of electroporation of tissue cells by gradually reducing the equivalent resistance Rm of the cell membrane. The load was stimulated with low-voltage pulses and the voltage and current data were recorded. The load impedance spectrum was obtained by Fourier transform, and the results are shown in Figure 3-5. Figure 3-5a The low-voltage pulse waveforms under different load impedances show that as the load impedance gradually decreases, the amplitude of the low-voltage voltage across the load also gradually decreases. This is because the voltage divider resistor value remains unchanged during the test; the decrease in load impedance leads to a decrease in the voltage it receives. However, what we need to obtain is the impedance spectrum of the object being processed, which is an essential property of the object and does not change with external stimuli. Figure 3-5b The low-voltage test pulse spectrum shows that the spectral distribution is basically the same, with only some differences in amplitude. Figure 3-5c The figures show the response current values ​​under different loads after low-voltage pulse stimulation. It can be seen that as the equivalent circuit of the cell membrane in the biological load gradually decreases, the response current gradually increases. Figure 3-5d The response current spectrum under biological loads is similar to the voltage spectrum, meaning that the frequency band of the response current under different biological loads is basically the same, with only the amplitude differing.

[0142] From the frequency spectrum distribution, it can be seen that the voltage and current spectrum content of high frequency above 106Hz is low, close to 0, so the impedance spectrum error calculated by using this frequency band is large. Therefore, the measurement frequency band selected when calculating the impedance spectrum by using the measurement pulse is 5kHz-1MHz. It can be seen from the impedance modulus and phase angle spectrum that the noise signal has begun to appear at high frequency, but the overall impedance change trend is still clear. In the simulation, the gradually reduced cell membrane equivalent resistance is used to simulate the continuous progress of electroporation. It can be seen from the calculation result that, with the continuous progress of electroporation, the impedance spectrum modulus of biological tissue at low frequency gradually decreases, which is consistent with the experimental results recorded in the related art. This is mainly because the generation of electroporation makes the cell space ion flow more free and the conductivity better, that is, it is manifested as the decrease of the impedance modulus. However, as the frequency continuously increases, the high-frequency signal can penetrate the cell membrane capacitor, and the cell membrane equivalent resistance is short-circuited, so the impedance modulus at high frequency is not much affected by different cell membrane equivalent resistances. At this time, the tissue space mainly exhibits resistance characteristics, and the impedance angle develops from the negative impedance angle reflecting the capacitive characteristics to the 0 impedance angle reflecting the resistance characteristics.

[0143] Due to the frequency band limitation, the impedance information at high frequency cannot be observed here. By adjusting the low-voltage measurement pulse parameters, the impedance spectrum frequency band can be adjusted to obtain more high-frequency information, as shown in Figures 3-6, which can more clearly show the impedance spectrum at high frequency ( Figure 3-6a ) and the impedance angle spectrum ( Figure 3-6b ). It can be seen that the impedance spectrum measurement function of the pulse generation system proposed in the present application can flexibly adjust the parameters of the low-voltage pulse signal according to actual needs, so as to obtain the required impedance spectrum information.

[0144] In summary, the effects of the above embodiments include: (1) Compared with the traditional irreversible electroporation ablation device, the present application only adds a variable voltage dividing resistor at the output end of the pulse generation circuit. By changing the control signal of the last stage switch, a low-voltage pulse signal for real-time measurement of tissue impedance spectrum is obtained on the biological load during the high-voltage pulse application interval. The amplitude of the low-voltage pulse signal can be adjusted by changing the variable resistance value, and the pulse polarity, pulse width, repetition number, etc. of the measurement pulse can be adjusted by the switch driving signal. During the pulse treatment process, the data acquisition and processing unit can collect and analyze the high and low voltage and current signals in real time, calculate the tissue impedance information, and transmit it to the user interface to display the real-time changes of the tissue state.

[0145] (2) The irreversible electroporation device of the present application has the function of real-time measurement of tissue impedance spectrum during pulse action. Compared with the existing real-time impedance measurement method, the present application does not need to add an additional low-voltage stimulation module, simplifying the system complexity and reducing the production cost; at the same time, it can realize the rapid measurement of impedance information and dynamically track the change of tissue impedance information.

[0146] (3) The Marx generator proposed in the present application is based on the traditional Marx circuit topology, does not require an additional low-voltage module, does not affect the system complexity, and does not increase the production cost.

[0147] (4) The present application uses the impulse response method to calculate the impedance spectrum during the high-voltage pulse action, has the characteristics of fast test speed, and can realize multiple tracking measurements of the impedance spectrum of biological tissues during the high-voltage pulse action (~1s), thereby laying an important hardware foundation for real-time evaluation of the irreversible electroporation ablation effect.

[0148] (5) The parameters of the low-voltage pulse signal of the present application are flexible and adjustable, so that the impedance measurement requirements in different situations, such as different frequency spectrum ranges and frequency resolution, can be met.

[0149] (6) The pulse generation circuit of the present application can be simply modified based on the existing pulse source based on the Marx circuit topology to realize the real-time impedance spectrum measurement function, and is easy to upgrade and popularize the existing products.

[0150] Based on the same inventive concept, the present application proposes a pulse generation method applied to the pulse generation system described in the above embodiments, as shown in Figure 4 , comprising:

[0151] Step 401, placing the biological tissue between at least one pair of electrodes of the pulse generation circuit.

[0152] Step 402, receiving a control signal.

[0153] Step 403, in response to determining that the control signal is a high-voltage pulse generation signal, controlling the pulse generation circuit to generate a high-voltage pulse signal, and applying the high-voltage pulse signal to the biological tissue through the at least one pair of electrodes, so that the cell membrane of the biological tissue cells is subjected to irreversible electroporation by the high-voltage pulse signal.

[0154] Step 404, in response to determining that the control signal is a low-voltage pulse generation signal, controlling the pulse generation circuit to generate a low-voltage pulse signal, and applying the low-voltage pulse signal to the biological tissue through the at least one pair of electrodes, and measuring the electrical information of the biological tissue by the low-voltage pulse signal to determine the irreversible electroporation effect.

[0155] The steps 403 and 404 in the above are selected and executed respectively according to the actual control signal requirements.

[0156] In some embodiments, before steps 403 and 404, comprising:

[0157] Charging process: all of the control switch Q1, switch Q2, switch Q11 and switch Q12 are disconnected, the first capacitor and the second capacitor are charged by the power supply;

[0158] Step 403 includes:

[0159] Step 403A, positive high-voltage pulse signal generation process: switch on switch Q1 and switch Q11, switch off switch Q2 and switch Q12, the first capacitor applies positive high-voltage electricity on the biological tissue by the first electrode, and flows back to the ground end through the second electrode.

[0160] And / or,

[0161] Step 403B, negative high-voltage pulse signal generation process: switch on switch Q2 and switch Q12, switch off switch Q1 and switch Q11, the second capacitor applies negative high-voltage electricity on the biological tissue by the second electrode, and flows back to the ground end through the first electrode.

[0162] In some embodiments, step 404 includes:

[0163] Step 404A, positive low-voltage pulse signal generation process: switch off switch Q1, switch Q2 and switch Q11, switch on switch Q12, the first variable resistor R d1 is turned on, so that the first variable resistor R d1 divides the positive high-voltage pulse signal to generate a positive low-voltage pulse signal, and the positive low-voltage pulse signal is applied on the biological tissue by the first electrode and flows back to the ground end through the second electrode.

[0164] And / or,

[0165] Step 404B, negative low-voltage pulse signal generation process: switch off switch Q11, switch Q12 and switch Q1, switch on switch Q2, the second variable resistor R d2 is turned on, so that the second variable resistor R d2 divides the negative high-voltage pulse signal to generate a negative low-voltage pulse signal, and the negative low-voltage pulse signal is applied on the biological tissue by the second electrode and flows back to the ground end through the first electrode.

[0166] In some embodiments, a hierarchical circuit is arranged in both the first pulse generation circuit and the second pulse generation circuit.

[0167] determining that the switch Q1 and the first-stage switch of the cascade circuit in the first pulse generating circuit are both first main switches; determining that the switch Q2 and the second-stage switch of the cascade circuit in the first pulse generating circuit are both first charging switches; determining that the switch Q11 and the first-stage switch of the cascade circuit in the second pulse generating circuit are both second main switches; and determining that the switch Q12 and the second-stage switch of the cascade circuit in the second pulse generating circuit are both second charging switches.

[0168] Before steps 403 and 404, comprising:

[0169] a charging process: controlling the first main switch and the first charging switch in the last-stage cascade circuit of the first pulse generating circuit to be off, charging all capacitors in the first pulse generating circuit; and controlling the second main switch and the second charging switch in the last-stage cascade circuit of the second pulse generating circuit to be off, charging all capacitors in the second pulse generating circuit.

[0170] Step 403 comprises:

[0171] Step 403A', a positive high-voltage pulse signal generating process: controlling the first main switch in the first pulse generating circuit to turn on the first charging switch to turn off, and controlling the second main switch in the second pulse generating circuit to turn off the second charging switch to turn on, to generate a positive high-voltage pulse signal.

[0172] and / or,

[0173] Step 403B', a negative high-voltage pulse signal generating process: controlling the first main switch in the first pulse generating circuit to turn off the first charging switch to turn on, and controlling the second main switch in the second pulse generating circuit to turn on the second charging switch to turn off, to generate a negative high-voltage pulse signal.

[0174] In some embodiments, step 404 comprises:

[0175] Step 404A', a positive low-voltage pulse signal generating process: controlling the first main switch in the first pulse generating circuit to turn off, the first charging switch of the last-stage cascade circuit of the first pulse generating circuit to turn off, and other first charging switches of the first pulse generating circuit to turn on; and simultaneously controlling the second main switch in the second pulse generating circuit to turn off, and the second charging switch in the second pulse generating circuit to turn on, so that the first variable resistor R d1 is turned on, and the first variable resistor R d1 divides the positive high-voltage pulse signal to obtain a positive low-voltage pulse signal.

[0176] And / or,

[0177] Step 404B', Negative Low-Voltage Pulse Signal Generation Process: The first main switch in the first pulse generation circuit is turned off, and the first charging switch of the first pulse generation circuit is turned on; simultaneously, the second main switch in the second pulse generation circuit is turned off, the second charging switch of the last stage circuit of the second pulse generation circuit is turned off, and the other second charging switches of the second pulse generation circuit are turned on, causing the second variable resistor R... d2 When the power is turned on, the second variable resistor R is used. d2 The negative high-voltage pulse signal is divided to obtain the negative low-voltage pulse signal.

[0178] The circuit structure used in the above process corresponds to the pulse generation system in the above embodiment, and will not be described again here.

[0179] The above scheme can generate positive high voltage pulse signals, negative high voltage pulse signals, positive low voltage pulse signals and negative low voltage pulse signals. The adjustment of the width and amplitude of the generated pulse signals is the same as the control of the pulse generation system in the above embodiment, and will not be repeated here.

[0180] Based on the same inventive concept, this application proposes an irreversible electroporation method, which is applied to the irreversible electroporation device described in the above embodiments.

[0181] like Figure 5 As shown, the irreversible electroporation method includes:

[0182] Step 501: Use the control unit to generate a control signal and send the control signal to the pulse generation system.

[0183] Step 502: In response to determining that the control signal is a high-voltage pulse generation signal, a high-voltage pulse signal is generated by the pulse generation system and applied to the biological tissue.

[0184] Step 503: In response to determining that the control signal is a low-voltage pulse generation signal, a low-voltage pulse signal is generated by the pulse generation system and applied to the biological tissue, and the electrical information of the biological tissue is measured by the low-voltage pulse signal, wherein the electrical information includes voltage information and current information.

[0185] Steps 502 and 503 above are selected and executed respectively according to the actual control signal requirements.

[0186] Step 504: The electrical information is acquired using the data acquisition and processing unit, the electrical information is processed to obtain the impedance spectrum, and the impedance spectrum is output.

[0187] In some embodiments, the electrical information comprises: voltage information u(t) and current information i(t), t is time.

[0188] Step 504 comprises:

[0189] Step 5041, using the data acquisition and processing unit to perform fast Fourier transform on the voltage information u(t) to obtain voltage spectrum U(ω), the formula is: U(ω) = FFT(u(t)).

[0190] Step 5042, performing fast Fourier transform on the current information i(t) to obtain current spectrum I(ω), the formula is: I(ω) = FFT(i(t)).

[0191] Step 5043, calculating the impedance spectrum Z(ω) according to the voltage spectrum U(ω) and the current spectrum I(ω) and outputting, the formula is: Z(ω) = (U(ω)) / (I(ω)).

[0192] Based on the above description, the obtained impedance spectrum Z(ω) can be sent to the user interface for the user to view.

[0193] It should be noted that the method of the embodiments of the present application can be executed by a single device, such as a computer or a server, etc. The method of the embodiments of the present application can also be applied to a distributed scenario, and be completed by multiple devices cooperating with each other. In this distributed scenario, one of the multiple devices can only execute one or more steps in the method of the embodiments of the present application, and the multiple devices can interact with each other to complete the method.

[0194] It should be noted that some embodiments of the present application have been described above. Other embodiments are within the scope of the appended claims. In some cases, the actions or steps recited in the claims can be performed in a different order and still achieve desirable results. Additionally, the processes depicted in the figures do not necessarily require the particular order shown, or sequential order to achieve the desired results. In certain implementations, multitasking and parallel processing can be advantageous.

[0195] Those skilled in the art will understand that the discussion of any embodiments is merely exemplary and not intended to suggest that the scope of the application (including the claims) is limited to these examples. In the disclosure of the present application, the technical features of the above embodiments or different embodiments can be combined, the steps can be implemented in any order, and there are many other variations of the aspects of the embodiments of the present application as described above. In order to be brief, they are not provided in detail.

[0196] Additionally, to simplify the description and discussion, and so as not to obscure the embodiments of the application being presented, the well-known functions or constructions of integrated circuit (IC) chips and other components can or can not be shown in the figures and will be omitted as not to unnecessarily obscure the embodiments of the application being presented. Moreover, the devices can be shown in block diagram form in order to avoid obscuring the embodiments of the application, and this also acknowledges the fact that the details in regard to the implementation of the block diagram devices are highly dependent on the platform within which the embodiments of the application are to be implemented (i.e., these details should be well within the purview of one of ordinary skill in the art). Where specific details are set forth in order to describe an illustrative embodiment of the application, it will be apparent to one of ordinary skill in the art that the embodiments of the application can be practiced without, or with variation of, these specific details. Thus, the description is to be considered as illustrative only and not restrictive in nature.

[0197] While the application has been described in connection with specific embodiments thereof, it will be understood that many modifications, substitutions and changes will be apparent to those of ordinary skill in the art. For example, other memory architectures (e.g., dynamic RAM (DRAM)) can use the embodiments discussed.

[0198] It is intended to cover all alternatives, modifications and variations of this application falling within the scope of the appended claims. Accordingly, all such changes are intended to be included within the scope of the application as set forth in the claims.

Claims

1. A pulse generation system, characterized by, The application relates to a pulse generating circuit, comprising: a pulse generating circuit configured to generate a high-voltage pulse signal and a low-voltage pulse signal, and apply the high-voltage pulse signal and the low-voltage pulse signal to a biological tissue through at least one pair of electrodes, wherein the high-voltage pulse signal is used to perform irreversible electroporation on a cell membrane of a cell of the biological tissue, and the low-voltage pulse signal is used to measure electrical information of the biological tissue to determine the irreversible electroporation effect. The pulse generating circuit comprises: a first pulse generating circuit and a second pulse generating circuit, and the at least one pair of electrodes comprises at least a first electrode and a second electrode. The first pulse generating circuit comprises: And / or, A first resistor is connected to a power supply. A first capacitor has one end connected to the first resistor and the other end connected to a ground terminal. Switch Q1 and switch Q2 are connected in series and in parallel with the first capacitor. The switch Q1 and the switch Q2 are connected to the first electrode through a wire between the switch Q1 and the switch Q2. An output terminal of the first pulse generating circuit is connected in series with a first variable resistor R d1 . The first variable resistor R d1 has one end connected to the first resistor and the other end connected to the first electrode. The second pulse generating circuit comprises: The first electrode is arranged at an output end of the first pulse generating circuit, and the second electrode is arranged at an output end of the second pulse generating circuit. A second resistor is connected to the power supply. A second capacitor has one end connected to the second resistor and the other end connected to the ground. Switch Q11 and switch Q12 are connected in series and in parallel with the second capacitor. The second electrode is connected to the middle of the series connection of switch Q11 and switch Q12 through a wire. The output of the second pulse generating circuit is connected in series with a second variable resistor Rd2. One end of the second variable resistor Rd2 is connected to the second resistor and the other end is connected to the second electrode. d2 , the second variable resistor Rd2, one end is connected to the second resistor, the other end is connected to the second electrode; In the generation process of the positive low-voltage pulse signal, the switch Q1, the switch Q2 and the switch Q11 are disconnected, the switch Q12 is connected, the first variable resistor R d1 is connected, and the positive low-voltage pulse signal is generated; and / or, In the generation process of the negative low-voltage pulse signal, the switch Q11, the switch Q12 and the switch Q1 are disconnected, the switch Q2 is connected, the second variable resistor R d2 is connected, and the negative low-voltage pulse signal is generated.

2. The pulse generation system of claim 1, wherein, The first pulse generating circuit generates a positive high-voltage pulse signal according to a control signal, and applies the positive high-voltage pulse signal to the biological tissue through the first electrode while controlling the second electrode of the second pulse generating circuit to be connected to a ground end. And / or, The second pulse generating circuit generates a negative high-voltage pulse signal according to a control signal, and applies the negative high-voltage pulse signal to the biological tissue through the second electrode while controlling the first electrode of the first pulse generating circuit to be connected to the ground end. At least one grading circuit is further arranged in parallel in the first pulse generating circuit or the second pulse generating circuit, and the grading circuit is connected to the first electrode or the second electrode.

3. The pulse generation system of claim 1, wherein, The grading circuit is configured to expand a voltage value of the positive high-voltage pulse signal or a voltage value of the negative high-voltage pulse signal. The grading circuit comprises:

4. The pulse generation system of claim 3, wherein, A grading diode connected to one end of the first resistor or the second resistor; A grading capacitor connected to one end of the grading diode and connected to the middle of the switch Q1 and the switch Q2 at the other end, or connected to the middle of the switch Q11 and the switch Q12 at the other end; A first grading switch and a second grading switch, and the first grading switch and the second grading switch are connected in series and connected in parallel to the grading capacitor. The pulse generating circuit is used to generate the low-voltage pulse signal in the interval time of the high-voltage pulse signal. Wherein, the next stage circuit is connected in parallel across the first stage switch; or, the first variable resistor R d1 The second variable resistor R d2 is connected with the stage diode, and is connected with the first electrode / second electrode through a wire between the first stage switch and the second stage switch.

5. The pulse generation system of claim 1, wherein, The high-voltage pulse signal comprises at least one of the following:

6. The pulse generation system of any one of claims 1 to 5, wherein, A positive high-voltage pulse signal, a positive polarity high-voltage pulse train formed by repeatedly superimposing the positive high-voltage pulse signal, a negative high-voltage pulse signal, a negative polarity high-voltage pulse train formed by repeatedly superimposing the negative high-voltage pulse signal, a bipolar high-voltage pulse signal formed by alternately arranging the positive high-voltage pulse signal and the negative high-voltage pulse signal, or a bipolar high-voltage pulse train formed by repeatedly superimposing the bipolar high-voltage pulse signal; The low-voltage pulse signal comprises at least one of the following: ​ The positive low-voltage pulse signal or the positive low-voltage pulse signal repeatedly superimposed to form a positive low-voltage pulse train, the negative low-voltage pulse signal or the negative low-voltage pulse signal repeatedly superimposed to form a negative low-voltage pulse train, the bipolar low-voltage pulse signal formed by the positive low-voltage pulse signal and the negative low-voltage pulse signal alternately or the bipolar low-voltage pulse signal repeatedly superimposed to form a bipolar low-voltage pulse train.

7. An irreversible electroporation apparatus, characterized by, Comprise: A control unit, the pulse generation system of any one of claims 1 to 6, and a data acquisition and processing unit; The control unit is configured to control the operation of the pulse generation system and the data acquisition and processing unit; The pulse generation system is configured to control the pulse generation circuit to generate a high-voltage pulse signal or the low-voltage pulse signal according to the control signal of the control unit, and measure the electrical information of the biological tissue by the low-voltage pulse signal; The data acquisition and processing unit is configured to acquire the electrical information from the pulse generation system according to the acquisition signal from the control unit, and perform data processing on the electrical information to obtain an impedance spectrum output.

8. The irreversible electroporation device of claim 7, wherein, The irreversible electroporation device performs a pulse generation method; The pulse generation method is applied to the pulse generation system, and the pulse generation method comprises: Receiving a control signal; In response to determining that the control signal is a high-voltage pulse generation signal, controlling the pulse generation circuit to generate a high-voltage pulse signal, and applying the high-voltage pulse signal to the biological tissue through the at least one pair of electrodes, so that the cell membrane of the biological tissue cells is subjected to irreversible electroporation by the high-voltage pulse signal; In response to determining that the control signal is a low-voltage pulse generation signal, controlling the pulse generation circuit to generate a low-voltage pulse signal, and applying the low-voltage pulse signal to the biological tissue through the at least one pair of electrodes, and measuring the electrical information of the biological tissue by the low-voltage pulse signal to determine the irreversible electroporation effect.

9. The irreversible electroporation device of claim 8, wherein, Before the control of the pulse generation circuit to generate a high-voltage pulse signal or a low-voltage pulse signal, comprising: Charging process: controlling switches Q1, Q2, Q11 and Q12 to be all disconnected, and charging the first capacitor and the second capacitor by the power supply; The control of the pulse generation circuit to generate a high-voltage pulse signal comprises: Positive high-voltage pulse signal generation process: turning on switches Q1 and Q11, turning off switches Q2 and Q12, and applying positive high-voltage electricity to the biological tissue through the first electrode by the first capacitor, and flowing back to the ground through the second electrode; And / or, Negative high-voltage pulse signal generation process: turning on switches Q2 and Q12, turning off switches Q1 and Q11, and applying negative high-voltage electricity to the biological tissue through the second electrode by the second capacitor, and flowing back to the ground through the first electrode.

10. The irreversible electroporation device of claim 9, wherein, The control of the pulse generation circuit to generate a low-voltage pulse signal comprises: The positive electrode low-voltage pulse signal generation process: turn off switch Q1, switch Q2 and switch Q11, turn on switch Q12, turn on the first variable resistor R d1 Turn on, so that the first variable resistor R d1 The positive electrode high-voltage pulse signal is divided, the positive electrode low-voltage pulse signal is generated, the positive electrode low-voltage pulse signal is applied on the biological tissue by the first electrode, and the second electrode flows back to the ground end; And / or, The negative low-voltage pulse signal generation process: turn off switch Q11, switch Q12 and switch Q1, turn on switch Q2, and turn on the second variable resistor R d2 Turn on, so that the second variable resistor R d2 The voltage divider negative high-voltage pulse signal generates a negative low-voltage pulse signal, and applies the negative low-voltage pulse signal to the biological tissue by the second electrode, and flows back to the ground through the first electrode.

11. The irreversible electroporation device of claim 8, wherein, A hierarchical circuit is arranged in the first pulse generation circuit and the second pulse generation circuit; The first hierarchical switch of the hierarchical circuit in the first pulse generation circuit and the switch Q1 are all first main switches; The switch Q2 and the second stage switch of the stage circuit in the first pulse generating circuit are first charging switches; The switch Q11 and the first stage switch of the stage circuit in the second pulse generating circuit are second main switches; The switch Q12 and the second stage switch of the stage circuit in the second pulse generating circuit are second charging switches; Before the control of the pulse generating circuit to generate a high-voltage pulse signal or a low-voltage pulse signal, the method comprises: a charging process: controlling the first main switch and the first charging switch in the last stage of the first pulse generating circuit to be closed, charging all capacitors in the first pulse generating circuit; and controlling the second main switch and the second charging switch in the last stage of the second pulse generating circuit to be closed, charging all capacitors in the second pulse generating circuit; The control of the pulse generating circuit to generate a high-voltage pulse signal comprises: a positive high-voltage pulse signal generation process: controlling the first main switch in the first pulse generating circuit to turn on the first charging switch to be closed, and controlling the second main switch in the second pulse generating circuit to turn on the second charging switch to be closed, to generate a positive high-voltage pulse signal; and / or, a negative high-voltage pulse signal generation process: controlling the first main switch in the first pulse generating circuit to turn on the first charging switch to be closed, and controlling the second main switch in the second pulse generating circuit to turn on the second charging switch to be closed, to generate a negative high-voltage pulse signal.

12. The irreversible electroporation device of claim 11, wherein, The control of the pulse generating circuit to generate a low-voltage pulse signal comprises: The positive electrode low-voltage pulse signal generation process: control the first main switch in the first pulse generating circuit to be turned off, the first charging switch of the last stage circuit of the first pulse generating circuit to be turned off, and the other first charging switches of the first pulse generating circuit to be turned on; at the same time, control the second main switch in the second pulse generating circuit to be turned off, and the second charging switch in the second pulse generating circuit to be turned on, so that the first variable resistor R d1 When the power is turned on, the first variable resistor R d1 The positive electrode high-voltage pulse signal is divided to obtain a positive electrode low-voltage pulse signal; and / or, The negative low-voltage pulse signal generation process: control the first main switch in the first pulse generating circuit to be off, and the first charging switch of the first pulse generating circuit to be on; at the same time, control the second main switch in the second pulse generating circuit to be off, the second charging switch of the last stage circuit of the second pulse generating circuit to be off, and the other second charging switches of the second pulse generating circuit to be on, so that the second variable resistor R d2 Power on, use the second variable resistor R d2 Divide the negative high-voltage pulse signal to obtain the negative low-voltage pulse signal.

13. The irreversible electroporation apparatus of claim 7, wherein, The irreversible electroporation device performs an irreversible electroporation method; The irreversible electroporation method comprises: generating a control signal by using a control unit, and sending the control signal to the pulse generating system; in response to determining that the control signal is a high-voltage pulse generation signal, generating a high-voltage pulse signal by using the pulse generating system and applying the high-voltage pulse signal to a biological tissue; in response to determining that the control signal is a low-voltage pulse generation signal, generating a low-voltage pulse signal by using the pulse generating system, applying the low-voltage pulse signal to the biological tissue, and measuring electrical information of the biological tissue by using the low-voltage pulse signal; collecting the electrical information by using the data acquisition and processing unit, performing operation processing on the electrical information to obtain an impedance spectrum, and outputting the impedance spectrum.

14. The irreversible electroporation device of claim 13, wherein, The electrical information comprises voltage information u(t) and current information i(t), and t is time; The collection of the electrical information by using the data acquisition and processing unit, the operation processing on the electrical information to obtain an impedance spectrum, and the output of the impedance spectrum comprise: performing fast Fourier transform on the voltage information u(t) by using the data acquisition and processing unit to obtain a voltage spectrum U(ω), and the formula is U(ω)=FFT(u(t)); performing fast Fourier transform on the current information i(t) to obtain a current spectrum I(ω), and the formula is I(ω)=FFT(i(t)); The impedance spectrum Z(ω) is calculated according to the voltage spectrum U(ω) and the current spectrum I(ω) and output, and the formula is: Z(ω)=(U(ω)) / (I(ω)). The impedance spectrum Z(ω) is calculated according to the voltage spectrum U(ω) and the current spectrum I(ω) and output, and the formula is: Z(ω)=(U(ω)) / (I(ω)).

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