WO2018010659A1 - 不可逆电穿孔设备及其操作方法 - Google Patents

不可逆电穿孔设备及其操作方法 Download PDF

Info

Publication number
WO2018010659A1
WO2018010659A1 PCT/CN2017/092591 CN2017092591W WO2018010659A1 WO 2018010659 A1 WO2018010659 A1 WO 2018010659A1 CN 2017092591 W CN2017092591 W CN 2017092591W WO 2018010659 A1 WO2018010659 A1 WO 2018010659A1
Authority
WO
WIPO (PCT)
Prior art keywords
pulse
bipolar
pulses
biological tissue
irreversible electroporation
Prior art date
Application number
PCT/CN2017/092591
Other languages
English (en)
French (fr)
Inventor
姚陈果
孙颖浩
王海峰
董守龙
Original Assignee
上海睿刀医疗科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=58006917&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2018010659(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by 上海睿刀医疗科技有限公司 filed Critical 上海睿刀医疗科技有限公司
Priority to CN201780007234.0A priority Critical patent/CN109661210B/zh
Publication of WO2018010659A1 publication Critical patent/WO2018010659A1/zh

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/04—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating
    • A61B18/12—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating by passing a current through the tissue to be heated, e.g. high-frequency current
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/04—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating
    • A61B18/12—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating by passing a current through the tissue to be heated, e.g. high-frequency current
    • A61B18/14—Probes or electrodes therefor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00571—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for achieving a particular surgical effect
    • A61B2018/00613—Irreversible electroporation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00636—Sensing and controlling the application of energy
    • A61B2018/00696—Controlled or regulated parameters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/04—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating
    • A61B18/12—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating by passing a current through the tissue to be heated, e.g. high-frequency current
    • A61B18/1206—Generators therefor
    • A61B2018/1246—Generators therefor characterised by the output polarity
    • A61B2018/126—Generators therefor characterised by the output polarity bipolar

Definitions

  • the present application relates to irreversible electroporation devices, and more particularly to devices for producing irreversible perforations on cells of biological tissue to ablate biological tissue and biological tissue ablation methods.
  • Cancer is a major disease that threatens human health.
  • the traditional treatment of tumors and the newly developed thermal ablation physical therapy characterized by minimally invasive ablation have limited limitations due to factors such as indications, contraindications, side effects of treatment, and thermal effects.
  • electric field pulses have attracted the attention of researchers due to their non-thermal, minimally invasive biomedical effects, and irreversible electroporation for the treatment of tumors is fast, controllable, visual, and
  • the advantages and characteristics of selective and non-thermal mechanisms have attracted widespread attention from researchers in the field of bioelectrics at home and abroad, and have gradually been applied to the clinical treatment of tumors.
  • irreversible electroporation technology has been applied to the treatment of clinical tumors, and has achieved very good curative effect. It has good treatment for various cancers such as pancreatic cancer, liver cancer, kidney cancer, prostate cancer, cervical cancer and other cancers. effect.
  • AngioDynamics of the United States invested in the production of the commercial irreversible electroporation tumor treatment instrument NanoKnife, and obtained the US FDA clinical trial license in 2009.
  • the pulse output is a unipolar pulse
  • unipolar pulses may cause muscle contraction when applied to human tissues, increase patient suffering and increase the difficulty of treatment, and the unipolar pulsed electric field does not. Uniform, there is a blind zone, so the ablation effect is not very good.
  • the present application proposes a bipolar composite steep pulse tumor treatment device which can reduce muscle contraction, make the pulse electric field more uniform, and further improve the therapeutic effect.
  • One aspect of the present application relates to an irreversible electroporation apparatus comprising: a pulse forming device configured to generate a bipolar pulse; and an electrode configured to receive a bipolar pulse from the pulse forming device and adapted to Bipolar Sex pulses are applied to biological tissue.
  • the pulse width of the bipolar pulse and the electric field intensity generated in the biological tissue are set to be sufficient to cause irreversible electroporation on the cell membrane of the biological tissue.
  • Another aspect of the present application relates to a biological tissue ablation method comprising the steps of determining a bipolar pulse to be applied according to a biological tissue to be ablated, a pulse width of the bipolar pulse and an electric field generated in the biological tissue
  • the intensity is set to be sufficient to produce irreversible electroporation on the cell membrane of the biological tissue; a bipolar pulse having the set parameters is generated; the generated bipolar pulse is applied to the biological tissue to be ablated.
  • Yet another aspect of the present application provides a method of operating an irreversible electroporation apparatus, comprising: generating a bipolar pulse by a pulse forming device; and applying a bipolar pulse to the biological tissue through the electrode, the electrode from the The pulse forming device receives the bipolar pulse, wherein the total pulse width of the bipolar pulse and the electric field strength generated in the biological tissue are set to be sufficient to cause irreversible electroporation on the cell membrane of the biological tissue.
  • a further aspect of the present application provides a tumor treatment apparatus comprising: a power supply unit for supplying power to the apparatus; a pulse forming unit including a full bridge inverter circuit, the pulse forming unit outputting a pulse current signal; and a measuring unit a parameter configured to measure a pulse generated by the pulse forming unit and supplied to the control unit; the control unit controls the pulse forming unit according to the parameter and the user input parameter provided by the measuring unit, by changing the pulse forming unit
  • the on-time, the breaking frequency, and the number of breaking times of the switching device in the full-bridge inverter circuit change the polarity, pulse width, pulse interval, frequency, and number of pulses of the output pulse.
  • the bipolar pulse according to an embodiment of the present application can effectively increase the uniformity of the ablation electric field, and the pulse width of the bipolar pulse and the electric field intensity generated in the biological tissue are sufficient to generate irreversible electroporation on the cell membrane of the biological tissue. And the zero-level pulse interval between the pulses can further develop the perforation on the cell membrane, thereby reducing the ablation blind zone, improving the treatment efficiency and reducing the repeated treatment.
  • FIG. 1 is a schematic block diagram of an irreversible electroporation device in accordance with a first embodiment of the present application.
  • FIGS. 2A and 2B are schematic views of bipolar pulses formed by a non-reversible electroporation device according to a first embodiment of the present application.
  • FIG. 3 is a schematic block diagram of the configuration of the pulse generating unit 12 according to the first embodiment of the present application.
  • FIG. 4 is a waveform diagram of a bipolar pulse in accordance with an alternate embodiment of the present application.
  • FIG. 5 is a schematic block diagram of an irreversible electroporation device in accordance with another alternative embodiment of the present application.
  • FIG. 6 is a schematic block diagram of a bipolar composite steep pulse tumor treatment device in accordance with a second embodiment of the present application.
  • FIG. 7 is a schematic structural view of a bipolar composite steep pulse tumor treatment apparatus according to a second embodiment of the present application.
  • Fig. 8 shows an example of a full bridge inverter circuit in a main circuit in a composite steep pulse tumor treatment apparatus according to the present application.
  • Figure 9 shows an example of a control unit in a compound steep pulse tumor treatment device in accordance with the present application.
  • Figure 10 shows an example of a multiple output switching unit of a compound steep pulse tumor treatment device in accordance with the present application.
  • Figure 11 shows an example of a fiber optic isolation unit of a composite steep pulse tumor treatment device in accordance with the present application.
  • Figure 12 is a schematic diagram showing exemplary waveforms of the output of the bipolar composite steep pulse tumor treatment device of the present application.
  • Figure 13 shows an example of an actual output voltage current waveform diagram of the bipolar composite steep pulse tumor treatment device of the present application.
  • FIG. 14 is a schematic flow chart of a biological tissue ablation method in accordance with a third embodiment of the present application.
  • Figure 15 is a flow chart showing the operation of the bipolar composite steep pulse tumor treatment apparatus according to the fifth embodiment of the present application.
  • Figure 16 is a schematic diagram showing the results of ablation experiments on cells of rabbit liver tissue, wherein Fig. 16A is an enlarged view of the result of applying a conventional unipolar pulse, and Fig. 16B is a bipolar pulse applied according to an embodiment of the present application. A magnified view of the results.
  • Figure 17 is a schematic diagram showing the results of ablation experiments on cells of rabbit liver tissue, wherein Figure 17A is an enlarged view of the result of applying a bipolar pulse having a pulse width of 1 ⁇ s, and Figure 17B is a bipolar pulse applying a pulse width of 5 ⁇ s. A magnified view of the results.
  • FIG. 1 is a schematic block diagram of an irreversible electroporation device in accordance with a first embodiment of the present application.
  • the irreversible electroporation device 1 includes a pulse forming device 10 and an electrode 20.
  • the pulse forming device 10 is for generating a pulse required for the irreversible electroporation device 1 according to the present embodiment
  • the electrode 20 is for receiving the generated pulse from the pulse forming device 10 and applying the generated pulse to the cells of the biological tissue. , such as tumor cells.
  • the pulse forming apparatus 10 includes a power source 11, a pulse generating unit 12, a control unit 13, a user interface 14, and the like.
  • a power source 11 is used to power the irreversible electroporation device 1 and the various units therein.
  • the pulse generating unit 12 is used to generate pulses required for the irreversible electroporation device 1 according to the present embodiment.
  • the control unit 13 is used to control and monitor the operation of the various units of the irreversible electroporation device 1.
  • User interface 14 is used to provide user input, monitor irreversible electroporation processes, display irreversible electroporation results, and the like.
  • Control unit 13 may be implemented at least in part in digital electronic circuitry, analog electronic circuitry, or computer hardware, firmware, software, or combinations thereof.
  • the control unit 13 can be implemented as a specific purpose logic circuit such as an FPGA (Field Programmable Gate Array) or an ASIC (Application Specific Integrated Circuit).
  • the control unit 13 can be implemented as a computer program product, ie a computer program tangibly embedding an information carrier, such as a machine readable storage device or a generated signal, by a data processing device, such as a programmable processor, a computer or a multi-computer Perform or control operations.
  • the computer program can be written in any programming language, including editing or compiling languages, and can be arranged in any form, including as a stand-alone program or as a module, component, sub-routine or other unit suitable for use in a computing environment.
  • the computer program can be arranged to be executed on one or a plurality of computers distributed at a plurality of locations and on a plurality of computers and interconnected by a communication network.
  • the control unit 13 may further include a memory or the like for storing user settings, various parameters, monitoring results, and the like.
  • the user interface 14 is used to input commands and display states, information, and the like, and may include various input/output devices.
  • the input device can use a touch screen, a keypad, or a full keyboard, and includes various input interfaces, disk drives, and the like.
  • Output devices include various visual, audible, tactile output devices such as displays, LED lights, vibrators, and the like.
  • the pulse generated by the pulse generating unit 12 according to the present embodiment will be described below.
  • a strong pulse When a strong pulse is applied to the cell membrane of a biological tissue, a large enough transmembrane potential distribution is established on the cell membrane under the action of a strong electric field generated by a strong pulse, thereby generating a nanometer on the phospholipid bilayer of the cell membrane.
  • electroporation has less damage to the cell membrane
  • the electrical pulse when the electrical pulse is stopped, the pores are closed and the cells can survive, such a condition being referred to as reversible electroporation (RE).
  • RE reversible electroporation
  • IRE Inreversible Electroporation
  • the inventors of the present application have recognized that a cell membrane of a cell of a biological tissue has a resting transmembrane potential of about -90 mV, and therefore, when a single-polar electric pulse is applied to a cell of a biological tissue, due to a resting transmembrane potential of the cell membrane There is a possibility that the transmembrane potential distribution established on the cell membrane by a single polarity electrical pulse may be non-uniform.
  • Such unevenness may result in the transmembrane potential of the rest of the cell membrane still failing to reach the irreversible electroporation threshold when the transmembrane potential of part of the cell membrane of the cell exceeds the irreversible electroporation threshold, such that the transmembrane potential fails to reach
  • the cell membrane region of the irreversible electroporation threshold does not form irreversible electroporation.
  • the electroporation process is random, that is, even if the transmembrane potential of a certain region of the cell membrane reaches the irreversible electroporation threshold, the region of the cell membrane does not necessarily undergo complete irreversible electroporation.
  • the region of the cell membrane whose transmembrane potential exceeds the irreversible electroporation threshold becomes uneven, which greatly reduces the probability of irreversible electroporation of the cell membrane of a single cell, resulting in An ablation dead zone may exist when irreversible electroporation is performed by applying a pulse of a single polarity.
  • the resting potential of the cell membrane has a greater influence on the overall irreversible electroporation efficiency of the cells.
  • the inventors of the present application have made the above considerations, and have proposed an irreversible electrical pulse ablation device of the present application, wherein a bipolar pulse is used, the total pulse width of the bipolar pulse and the bipolar pulse in the biological tissue
  • the electric field strength generated in the medium is set to be sufficient to cause irreversible electroporation on the cell membrane of the biological tissue.
  • the total pulse width refers to the sum of the high-level time of the positive polarity pulse and the negative polarity pulse
  • the electric field intensity generated by the bipolar pulse in the biological tissue refers to the application of the positive polarity pulse and the negative polarity pulse through the electrode.
  • the electric field strength generated in biological tissues refers to the application of the positive polarity pulse and the negative polarity pulse through the electrode.
  • the intensity of the electric field generated in the biological tissue by the bipolar pulse can be determined according to the magnitude of the applied pulse, the configuration of the electrode for applying the pulse, the distance between the electrodes, and the electrical conductivity of the biological tissue, the dielectric constant, and the like.
  • the total pulse width of a bipolar pulse and the electric field strength generated by the bipolar pulse in biological tissue is sufficient to cause irreversible electroporation on the cell membrane of a biological tissue
  • the electric field is applied during application.
  • Intensity and total pulse When the voltage pulse of the width is pulsed, irreversible electroporation can be produced on the cell membrane of the biological tissue, so that the cell eventually dies.
  • the problem of uneven distribution of the transmembrane potential exceeding the irreversible electroporation threshold due to the presence of the cell membrane resting potential is avoided when the single polarity electric field pulse is applied.
  • the single polarity electric field pulse is applied.
  • the total pulse width of the bipolar pulse sufficient to produce irreversible electroporation on the cell membrane and the electric field strength produced by the bipolar pulse in the biological tissue may differ.
  • a bipolar pulse sufficient to generate irreversible electroporation on the cell membrane of a biological tissue produces an electric field intensity in the biological tissue of, for example, 1.5 kV/cm.
  • the total pulse width is, for example, 50 ⁇ s or more.
  • the applied electric field strength of the bipolar pulse in the biological tissue can be, for example, below 3 kV/cm, the total pulse.
  • the width can be, for example, below 150 ⁇ s.
  • cells can be equivalent to a series model of capacitance and resistance composed of membrane capacitance and ion conductance.
  • the inventors of the present application applied the characteristics of the first-order circuit step response to the bio-dielectric cell model, and found that when the electric pulse is applied to the cells of the biological tissue, the charging time constant is 4 to 5 times. After the charging duration, the cells can reach a stable state of charge, thereby producing a strong irreversible electroporation effect on the cell membrane to achieve a better tissue ablation effect.
  • the pulse widths of the individual positive and negative polarity pulses are at least 4 to 5 times the charge time constant of the cells of the biological tissue.
  • the pulse widths of the single positive polarity and negative polarity pulses are at least about 5 ⁇ s.
  • the pulse width of the single positive polarity and negative polarity pulses can be, for example, below about 50 ⁇ s. .
  • the total pulse width of the bipolar pulse that is, the sum of the pulse widths of the positive polarity and the negative polarity pulse
  • the pulse width is equivalent.
  • the pulse width of a single pulse is typical.
  • the value is 100 ⁇ s, and with reference to this parameter, the sum of the pulse widths of the positive polarity and negative polarity pulses in the embodiment of the present application may be 100 ⁇ s.
  • the bipolar pulse according to an embodiment of the present application may be repeatedly applied a plurality of times.
  • the bipolar pulse may be applied periodically, for example, every 1 second and repeatedly applied, for example, 90 cycles.
  • any number of bipolar pulses can be generated aperiodically, as appropriate.
  • FIG. 2 is a schematic diagram of a bipolar pulse formed by the irreversible electroporation device 1 according to the first embodiment of the present application.
  • Fig. 2A shows a case in which positive and negative polarity pulses are alternately applied, and as shown in Fig. 2A, there are zero-level pulse intervals between positive and negative alternating pulses.
  • the polarity of the pulse applied to the electrode is not limited to a positive-negative alternating change, but may be two positive polarity pulses, two negative polarity pulses alternate, or may be multiple positive polarity pulses, multiple negative electrodes
  • the alternating pulses alternate, and an example in which a plurality of positive polarity pulses and a plurality of negative polarity pulses are alternated is shown in FIG. 2B.
  • Fig. 2B shows a case in which a pulse of a positive polarity is applied first, and a pulse of a negative polarity is applied, and a pulse interval of zero level is applied between each pulse.
  • the electric field generated around the electrode is also alternating due to the alternating positive polarity pulse and several negative polarity pulses of the pulse on the electrode. Varying, this avoids the problem that the unipolar electrical pulse establishes a heterogeneous distribution of transmembrane potential on the cell membrane and there is a blind zone. Positive and negative due to a zero-level pulse interval between every two pulses After the ions are driven by the electric field, during the zero-interval pulse interval, the positive and negative ions can continue to move due to the zero electric field.
  • the accumulation of motion allows the electroporation on the cells to develop; the same polarity after the pulse interval
  • the pulse which allows the positive and negative ions that have not stopped to continue to accelerate, continue to move in the same direction, and the electroporation on the cell is further developed; after the end of the pulse interval after several pulses of the same polarity, the opposite pole is applied. In this way, the punching efficiency can be improved.
  • the pulse width and the number of alternating positive and negative polarity pulses and the length of the pulse interval can be set according to actual needs.
  • the generated electric field can be sufficiently applied to the cell membrane to cause it to occur. Irreversible electroporation increases treatment efficiency and reduces the number of times patients need to repeat treatment.
  • the total pulse width is the sum of positive and negative pulse widths, that is, the product of the positive and negative polarity pulse widths and the positive and negative polarity pulse numbers. And the total pulse width can be set to 100 ⁇ s.
  • the bipolar pulses employed are bipolar square wave pulses for purposes of illustration and explanation.
  • the parameters of the bipolar pulse can be appropriately set according to the specific conditions of different biological tissues and the like.
  • the sum of the pulse widths of the positive polarity and the negative polarity pulse in the embodiment of the present application does not necessarily refer to the parameters of the conventional unipolar pulse irreversible electroporation device, but may Set it appropriately according to the specific situation.
  • the total pulse width may be set to respective values in the range of 50 ⁇ s to 150 ⁇ s, for example, 50 ⁇ s, 60 ⁇ s, 70 ⁇ s, 80 ⁇ s, 90 ⁇ s, 100 ⁇ s, 110 ⁇ s, 120 ⁇ s, 130 ⁇ s, 140 ⁇ s, and 150 ⁇ s, and the like.
  • the arrangement of the positive polarity and negative polarity pulses applied in the embodiments of the present application is not limited to the two arrangements shown in FIGS. 2A and 2B, but may be Set it appropriately according to the specific situation.
  • the positive polarity and negative polarity pulses need not be applied alternately, but may be applied in any order or the like.
  • the ratio of the number of positive polarity and negative polarity pulses in the embodiment of the present application is not necessarily a 1:1 relationship, but may be appropriately set according to a specific case as long as The pulse applied to the biological tissue includes both a positive polarity pulse and a negative polarity pulse.
  • the ratio of the number of positive polarity and negative polarity pulses may be any value in the range of 1:2 to 2:1, for example, 1:2, 2:3, 4:5, 1:1, 5: 4, 3:2, 2:1, etc.
  • a pulse width and a field intensity generated in the biological tissue may be applied to the biological tissue to cause a plurality of bipolar pulses of irreversible electroporation of the cell membrane of the biological tissue, and the generated electric field may be sufficient. Acting on the cell membrane to cause irreversible electroporation, so that the electric field is more evenly distributed for each cell of the biological tissue, thereby reducing the ablation blind zone.
  • FIG. 3 is a schematic diagram of the configuration of the pulse generation unit 12 according to the present embodiment.
  • the pulse generating unit 12 includes an energy storage element 121 and a switching circuit 122.
  • the energy storage element 121 stores the energy supplied by the power source 11 and releases the energy to the electrode 20 through the switch circuit 122.
  • the switch circuit 122 is configured to perform a corresponding switching action in the form of a pulse in accordance with a pulse width, a pulse interval, and a number of pulses set by the user, thereby generating a desired pulse waveform.
  • switch circuit 122 is a full bridge circuit, and by controlling the state, sequence, frequency, and number of times of the opening and closing of the switches in the full bridge circuit, the required positive polarity pulse and negative polarity pulse can be formed.
  • the switch circuit 122 in accordance with embodiments of the present application can also operate to generate unipolar electrical pulses.
  • the cell membrane is induced to undergo irreversible electroporation, thereby causing cell death, and at the same time, it is fast (the treatment application pulse time is only tens of seconds, the whole process is also Only a few minutes), controllable (the treatment parameters can be obtained by 3D modeling electric field calculation, the treatment range is accurate and safe), visible (the treatment process can be completed under ultrasound/CT/MRI guidance, and the effect can be obtained by ultrasound/CT/ MRI assessment), selective (does not damage the bile duct, blood vessels and nerves in the ablation zone) and non-thermal mechanism (no thermal effect, can overcome the advantages of 'thermal damage' and 'heat sink' caused by thermal therapy).
  • the cell membrane can fully complete the irreversible electroporation process, and the pulse electric field is greatly improved in the cell.
  • the uniformity of distribution in the tissue can break through the resting potential of the cell membrane, the capacitive effect, and the uneven distribution of the internal electric field caused by the anisotropy of the biological tissue, thereby realizing effective coverage of the electric field of the target tissue region to achieve the irreversible electroporation dose.
  • the pulse width of the positive polarity and the negative polarity pulse is at least 4 to 5 times the charging time constant of the cells of the biological tissue, it is possible to avoid the problem of excessively reducing the decrease in the ablation effect caused by the pulse width, thereby reducing Small ablation blind spot.
  • the pulse width of the pulse of each polarity can be appropriately reduced, and in some cases, the pulse width of the pulse of each polarity can be set to It is about 4 to 5 times the charging time constant of the cells of the ablated biological tissue, thereby ensuring a reduction in the ablation blind zone while reducing the pain and discomfort to the patient.
  • the pulse width of each polarity pulse formed by the irreversible electroporation device can be defined to be about 5 [mu]s.
  • 4 is a waveform diagram of a bipolar pulse in accordance with this alternative embodiment of the present application.
  • this embodiment of the present application advantageously reduces the pulse width of each polarity pulse as much as possible while ensuring the ablation effect, further reducing the patient's pulse Pain and discomfort.
  • FIG. 5 is a schematic illustration of another alternative embodiment of the irreversible electroporation device 2 of the embodiment shown in FIG.
  • the irreversible electroporation device 2 as shown in FIG. 5 is different from the irreversible electroporation device 1 shown in FIG. 1 in that the pulse forming device 10 may further include a pulse measuring unit 15.
  • the pulse measuring unit 15 is configured to measure the parameters of the pulses generated by the pulse generating unit 12 and supply the obtained parameters to the control unit 13.
  • the parameters of the pulse measured by the pulse measuring unit 15 may include, for example, the amplitude of the pulse, the polarity of the pulse, the pulse width, the pulse interval, the number of pulses, and the number of pulses.
  • the control unit 13 can monitor the parameters to be obtained and can provide the obtained parameters to the user through the user interface 14.
  • control unit 13 can adjust the pulse generation unit 12 as needed, either automatically or under the control of the user, to ensure the accuracy of the output pulse parameters.
  • the application provides a bipolar complex steep pulse tumor treatment device.
  • the device uses a full-bridge inverter technology combined with soft switching technology to generate bipolar composite steep pulses.
  • the pulse circuit Under the precise control of the control unit and control software, the pulse circuit generates the required pulse voltage according to the specified requirements and acts on Human tumor tissue to achieve the purpose of treating tumors.
  • FIG. 6 is a schematic block diagram of a bipolar composite steep pulse tumor treatment apparatus according to a second embodiment of the present application
  • FIG. 7 is a schematic structural view of the apparatus.
  • the tumor treatment apparatus includes: a power supply unit 21, a high frequency composite steep pulse forming unit 22, a measuring unit 23, a control unit 24, an optical fiber isolation unit 25, and a microcomputer.
  • the supporting software program has functions such as data acquisition, over-current protection, and safety warning to ensure the safety of patients and treatment devices.
  • the power supply unit 21 may include, for example, a mains power supply, a main switch, a fuse, a power supply filter device, a high voltage DC power supply (for example, an input of 220V/50 Hz alternating current, a maximum voltage amplitude of 3000V, a maximum current amplitude of 100 mA DC),
  • the isolation transformer for example, voltage to frequency ratio is 1:1
  • the switching power supply module can include a transformer and a rectifying device, for example, changing a 220V/50Hz AC input to a 12V DC output.
  • the choice of filter is mainly to isolate the harmonic interference in the mains power supply, and to prevent the harmonic interference generated by the instrument from being transmitted to the mains power source to pollute the mains power supply.
  • the isolation transformer is an equal-voltage, equal-frequency transformer that is primarily used to isolate the voltage, so that the patient does not need to be suspended from the ground during treatment, making the treatment process easier.
  • the maximum output voltage of the high-voltage DC power supply is greater than or equal to the amplitude of the final output pulse voltage.
  • the maximum output current of the high-voltage DC power supply needs to meet the allowable value of the voltage drop at the highest frequency, maximum pulse width and minimum impedance of the device output.
  • the switching power supply module needs to output the voltage required by the subsequent circuit, and its output current should satisfy the sum of the current consumed by all the devices that are connected to it.
  • the mains power supply is generally 220V, 50Hz AC power supply.
  • the grounding wire of the mains power supply cannot be connected to the isolation transformer, nor can it be connected to the ground of the electrical equipment after the isolation transformer, but directly connected to the bipolar composite steep.
  • the metal housing of the pulse therapy device can reduce electromagnetic interference from the ground wire and make the instrument power supply more stable.
  • the utility power source is first connected to the input of the main switch, and the live line of the alternating current after the main switch is connected to one end of the fuse, and the neutral line of the alternating current and the live line after the fuse are connected to the input end of the filter.
  • the function of the fuse is to quickly cut off the power supply in the event of an overload or short circuit to prevent damage to the equipment. It should be noted that the fuse needs to be selected according to the overall power output of the instrument.
  • the mains power supply after the filter is connected to the input end of the isolation transformer, the input end of the ECG module, the power input end of the liquid crystal display, the input end of the power adapter of the microcomputer, and the power input end of the optical fiber isolation unit through the terminal block.
  • the output end of the isolation transformer is connected to the input end of the high voltage DC power supply and the input end of the switching power supply module, and the output end of the high voltage DC power supply is connected to the full bridge inverter circuit of the high frequency composite steep pulse forming unit 22 through the wire.
  • the switching power supply module converts 220V alternating current into 12V direct current, and the output end thereof passes through the power input end of the driving chip of the pulse generating circuit in the wire and high frequency compound steep pulse forming unit 22, the power input end of the cooling fan, and the power of the control unit.
  • the inputs are connected.
  • the heat dissipation fan is used for dissipating heat generated inside the device to the external space by forced convection, thereby reducing The temperature inside the body.
  • the power supply unit 21 provides safe and stable power for the remaining components of the apparatus of the present application to ensure proper operation of the apparatus.
  • the high frequency composite pulse forming unit 22 is composed of a storage capacitor, a full bridge inverter circuit and its drive circuit, an external load switching circuit, a discharge circuit, and an internal discharge resistor.
  • the energy storage capacitor is connected in parallel to the output end of the high voltage DC power supply in the power supply unit 21, and both ends of the full bridge inverter circuit are connected to the output end of the high voltage DC power supply of the power supply unit 21 through wires, that is, two parallel storage capacitors at the same time. end.
  • Each bridge arm unit of the full-bridge inverter circuit is composed of a single IGBT having a sufficiently high withstand voltage or a plurality of MOSFETs connected in series.
  • the full-bridge inverter circuit is also equipped with a corresponding drive circuit, bypass diode, and averaging circuit (if multiple MOSFETs are connected in series).
  • the cathode of the bypass diode is connected to the C pole of the IGBT or the D pole of the MOSFET through a wire
  • the anode is connected to the E pole of the IGBT or the S pole of the MOSFET through a wire
  • the G pole of the solid state switching device passes through the wire.
  • the input of the driver chip is connected to a corresponding control interface in the control unit.
  • the discharge circuit and the internal discharge resistor are connected in series and connected in parallel at both ends of the storage capacitor, and the control end of the discharge circuit is connected to each other through a wire and a corresponding control interface of the control unit.
  • the control unit turns on the discharge circuit, and the charge on the storage capacitor is discharged through the discharge circuit, thereby achieving the purpose of step-down and shutdown.
  • the control end of the external load switching circuit is connected to the control interface of the control unit via a wire to output a pulse to the outside of the device for treatment of the patient.
  • the energy storage capacitor in the schematic diagram of the device as shown in FIG. 7 can be used, for example, model MMJ5kV-100 ⁇ F (its maximum withstand voltage 5000V, capacitance value 100 ⁇ F) for storing energy, and the composite steep pulse main circuit from the energy storage The capacitor gets the energy.
  • the maximum isolation voltage of the isolation transformer needs to meet at least the maximum output voltage of the instrument, and the power of the isolation transformer needs to be greater than the maximum power consumption of the device.
  • Figure 8 shows an example of a full-bridge inverter circuit in the main circuit of a compound steep-pulse tumor treatment device.
  • the IGBT can be selected from the IXEL40N400 model, and the maximum reverse breakdown voltage is 4000V.
  • the turn-on time is no more than 300ns, and the typical turn-off time is 425ns.
  • the non-inductive resistance in the main circuit of the composite steep pulse can be 300 ⁇
  • the discharge resistance of the main circuit can be a high-power resistor with a resistance of 20 k ⁇ .
  • the vacuum relay in the main circuit can be GL81C235 model, the maximum working voltage is 10kV, the maximum continuous load current is 5A, the maximum contact resistance is 0.05 ⁇ , the maximum working time and maximum release time are 10ms, and the mechanical life is 2000000 times.
  • the resistance of the resistor divider can be selected as: 1206 package, the divider arm resistance is 6M ⁇ and 10k ⁇ respectively. According to the resistor divider principle, the maximum output voltage of the resistor divider can be obtained at the maximum output voltage of the pulse transformer of 3000V. 4.992V, about 5V, can be input to the AD module for measurement.
  • the Pearson coil type of the composite steep pulse forming main pulse generating circuit can be 411, the ratio parameter 0.1V/A, bandwidth 20MHz, can accurately measure the pulse current generated by the main circuit.
  • the composite steep pulse forms a positive polarity pulse of the main circuit; when the IGBT1 and IGBT4 of the circuit are turned off, the IGBT3 and the IGBT2 are turned off.
  • the compound steep pulse forms the negative pulse of the main circuit output, and the output of the bipolar composite steep pulse can be realized by the alternation of the above two control modes.
  • the pulse generating circuit stops outputting to the outside, and the pulse of the output of the full-bridge inverter circuit is connected in parallel across the non-inductive resistor, and the resistance of the non-inductive resistor is 300 ⁇ .
  • the wire connected to the non-inductive resistor passes through the center of the Pearson coil, so that the Pearson coil can accurately measure the pulse current of the output, and combined with the resistance of the non-inductive resistor, the pulse voltage can be calculated.
  • the non-inductive resistor can also avoid the floating of the pulse output, making the pulse output waveform more ideal.
  • the composite steep circuit forms the discharge circuit of the main circuit and is controlled by the IGBT5 switching device. When receiving the discharge or step-down signal, the IGBT 5 is turned on, so that the charge on the capacitor can be discharged through the discharge loop.
  • the measuring unit 23 includes a resistor divider, a Pearson current sensor and its associated processing circuitry.
  • the resistance of the resistor divider is connected in parallel across the storage capacitor.
  • the voltage division ratio of the resistor divider circuit needs to be within the range that can be tolerated by the subsequent processing circuit.
  • the output of the voltage divider is connected to the input terminal of the analog-to-digital conversion module of the control unit through the coaxial cable.
  • the current sensor uses a Pearson coil.
  • the bandwidth of the Pearson coil needs to satisfy the frequency band range of the pulse voltage of the composite steep pulse device, and the output voltage of the coil needs to be within the voltage measurement range of the control unit.
  • the output of the full-bridge inverter circuit passes through a circular hole in the center of the Pearson coil and is connected in series with a non-inductive resistor of suitable resistance.
  • the output of the current sensor (Pearson coil) is connected via a coaxial cable to the corresponding interface of the control unit.
  • the magnitude of the pulse voltage can be calculated from the current measured by the Pearson coil and the magnitude of the non-inductive resistor in series.
  • the current measurement circuit and the voltage measurement circuit also add necessary processing circuits (protection circuits) for limiting the over-range signal collected by the current sensor and the voltage divider to prevent damage to the subsequent control unit.
  • the control unit of the tumor treatment device may include a field programmable logic gate array (FPGA), an ARM (STM32) and a microcomputer, and associated software programs, codes, help files, and hardware devices.
  • the control unit's microcomputer can be equipped with supporting control software.
  • the operator can set basic parameters such as basic information of the patient, basic information of the tumor, information of the doctor, and information of the treatment through the control software.
  • By running the control software a corresponding control command can be generated based on the input tumor information, the specific frequency of the pulse parameter, the amplitude, the intra-string frequency, the polarity, and the number.
  • the control command can be transmitted to the ARM of the control unit through the serial port, CAN bus or Bluetooth communication mode, and the ARM transmits the data to the FPGA after processing, and the FPGA generates a trigger wave corresponding thereto.
  • the output driving signal of the output end of the driving chip is connected to the control end of the switching device, thereby controlling the switching device to be turned on and off, thereby controlling the high frequency composite steep pulse forming unit and the multiple output
  • the switching unit generates pulses of the specified parameters.
  • FIG 9 shows an example of a control unit 24 in the composite steep pulse tumor treatment device of Figure 6.
  • the control unit 24 includes a communication module 31, an ARM module 32, a DAC module 33, a PWM module 34, an FPGA module 35, an ADC module 36, a power module 37, a level conversion module 38, and an optocoupler module 39.
  • the power module 37 can output voltages of different magnitudes for powering the remaining modules in the tumor treatment device.
  • the ARM module 32 is connected to the communication module 31, the DAC module 33, and the FPGA module 35.
  • the FPGA module 35 is connected to the PWM module 34, the ADC module 36, the ARM module 32, and the level conversion module 38.
  • the communication module 31 is composed of a serial communication module, a CAN bus module and a Bluetooth communication module, so that the required signals can be accurately and quickly transmitted between the control unit 24 and the microcomputer unit 26.
  • the ARM chip 32 is responsible for pre-processing the data received by the communication module 31 from the microcomputer 26.
  • the FPGA module 35 is configured to receive an instruction of the ARM module 32 to generate a corresponding PWM control signal, and the FPGA module 35 measures the voltage signal and the pulse current signal in the circuit through the ADC module 36.
  • the FPGA module 35 is coupled to the level shifting module 38 for controlling the turn-on and turn-off of the solid state switching device and the vacuum relay of the main circuit and the pulse output switching circuit.
  • the level shifting module 38 is for converting the output voltage of the FPGA to a range of signal voltages allowed by the optocoupler module 39 to enable them to communicate with each other.
  • the optocoupler module 39 is used to isolate the weak signal control voltage of the control circuit board from the high voltage of the main circuit and the device such as the switching circuit.
  • the ADC module 36 receives the voltage output from the high frequency composite pulse forming unit and the high frequency steep pulse current signal transmitted from the output terminal of the processing circuit of the measuring unit 23, and is sent to the FPGA module 35 after analog-to-digital conversion, and the FPGA module 35 converts the ADC.
  • the data sent by the module 36 is subjected to calculation processing and then sent to the ARM module 32.
  • the ARM module 32 After receiving the data, the ARM module 32 transmits the data to the microcomputer through the communication module 31 for display and storage.
  • the ARM module 32 receives the instruction of the microcomputer unit through the communication module 31, the ARM module 32 first determines the sent command, generates a control signal corresponding thereto, and sends the control signal to the FPFA module 35 for generation. Different PWM control signals to output different pulse waveforms.
  • the ARM module 32 When receiving the instruction to adjust the output voltage of the high voltage DC power supply and the maximum output current, the ARM module 32 outputs a corresponding signal to the DAC module 33 according to the control command to adjust the output voltage of the DAC module 33, thereby adjusting the output voltage of the high voltage DC power supply.
  • the FPGA module 35 passes through the level conversion module 38 and the optocoupler module 39 and the control end of the switch driving of the full bridge inverter circuit of the high frequency composite steep pulse forming unit, the control end of the discharge circuit, the control end of the internal and external load switching circuit, and the like.
  • the control end of the road output switching unit is connected to realize control of the output waveform.
  • the FPGA module 35 is controlled by an optocoupler module 39 and a multi-output switching unit.
  • ARM module 32 through photoelectric conversion module, optical fiber
  • the data communication is performed with the ECG module and the foot switch in the electro-optical conversion module and the auxiliary control unit 27, so that the operator can control the device by stepping on or off the foot switch, and the ECG module in the auxiliary control unit can also
  • the purpose of reducing muscle contraction is achieved by adjusting the generation time of the pulse.
  • the communication module 31 is connected to the computer host of the microcomputer unit by means of multi-core shielded wire or wireless communication to realize communication between the control unit 24 and the microcomputer unit 26; the output pin of the optocoupler chip of the optocoupler module 39 is used for the lead wire.
  • the control terminal of the driving chip of the solid-state switching device of the composite steep pulse main circuit, the control terminal of the vacuum relay, and the control terminal of the vacuum relay of the multi-output switching circuit are connected.
  • the DAC module 33 controls the output voltage and the maximum output current of the high-voltage DC power supply module by outputting different analog voltage values, thereby achieving the purpose of controlling the pulse voltage outputted by the composite steep-pulse tumor treatment device.
  • the FPGA module can use the Altera Corporation's cyclone III series chip, and the ARM can use the STMICROELECTRONICS STM32F4 series ARM chip, and the optocoupler module can Using the optocoupler chip of BROADCOM LIMITED, the level conversion module can use the level conversion chip of Philips Semiconductor.
  • the serial communication in the communication module can use the RS232 serial port chip of ANALOG DEVICES.
  • the CAN communication in the communication module can use the CAN bus transceiver of ANALOG DEVICES company.
  • the Bluetooth chip in the communication module uses Qualcomm's Bluetooth data transmission chip.
  • FIG. 10 shows an example of a multiple output switching unit of a compound steep pulse tumor treatment device in accordance with the present application.
  • the vacuum relay employed by the multi-output switching unit 28 of the compound steep pulse tumor treatment apparatus can use the same type of relay as the composite pulse forming main circuit.
  • An example in which 12 vacuum relays are employed is shown in FIG. 10, but it should be understood that other quantities are also possible, which is not limited in this application.
  • the 12 vacuum relays are connected in the manner shown in Figure 10 to form six sets of vacuum relay groups. When the vacuum relay is controlled, the relays connected to the normally open contacts cannot be simultaneously turned on.
  • relay 1 and relay 2 cannot be turned on at the same time, if normally open
  • the composite steep pulse will form a short circuit of the main circuit, causing damage to the treatment personnel and the instrument.
  • relay 1 and relay 4 are simultaneously turned on, a composite steep pulse voltage is output between the pulse output interface 1 and the pulse output interface 2, and if the relay 1 and the relay 4 and the relay 6 are simultaneously turned on, the electrode needle 1 and the electrode needle are A composite steep pulse voltage is output between 2 and between the electrode needle 1 and the electrode needle 3.
  • the multi-output switching unit 28 mainly includes components such as a vacuum relay, a triode, a decoupling capacitor, a magnetic bead, and an optocoupler device.
  • the multi-output switching unit 28 outputs the pulse voltage outputted by the full-bridge inverter circuit to different external electrodes through different vacuum relays, thereby achieving the purpose of forming pulse electric field action regions of different forms and shapes.
  • the pulses output by the multi-output switching system can produce different ablation ranges and regions on the tumor tissue, thereby achieving precise ablation of the tumor.
  • Relay 1, relay 2, relay 3, relay 4, relay 5, relay 6, relay 7, relay 8, relay 9, relay 10, relay 11, relay 12 and other components constitute the main circuit of the multi-output switching circuit.
  • relay 1 relay 3, relay 5, relay 7, relay 9, the common end of relay 11 is connected with the high potential end of the composite steep pulse generating main circuit
  • relay 2, relay 4, relay 6, relay 8, relay 10 The common terminal of the relay 12 is connected to the ground potential terminal of the composite steep pulse generating circuit.
  • the control terminals of all relays are connected to the corresponding pins of the control unit through the corresponding triodes and optocouplers. When the control signal is not received, the common end of the relay and the normally closed contact are connected to each other; when the control signal is received, the common end of the relay and its normally open contact are connected to each other.
  • Different pulse outputs can be combined by switching the conduction of different relays.
  • the control logic of the relay can be summarized as follows: First, a set of (two) relays whose normally open contacts are connected to each other cannot be turned on at the same time; and second, each row of relays (relays connected to each other at the common end) are selected to be turned on at least one .
  • the multi-output switching unit of the present application also adopts a plug-in self-locking plug, which avoids the falling off of the electrode needle caused by the operator's mistake and improves the reliability of the system.
  • the microcomputer unit 26 mainly includes a microcomputer host, a touchable liquid crystal display, a hardware device such as a keyboard and a mouse, an adapter for supplying power to the microcomputer host, and supporting software and drivers.
  • the touchable liquid crystal display is connected through a display cable and a microcomputer host for displaying information such as treatment information, treatment progress, and the like, and the operator can also input information by clicking a corresponding icon of the control software displayed on the liquid crystal display.
  • the LCD monitor can be connected to the host computer using a VGA, DVI, HDMI or DP interface.
  • the host computer is connected to the keyboard and mouse via a USB port.
  • the power adapter is connected to the host computer through a specific power interface to supply power to the host computer.
  • the operator can also input parameters through the mouse and keyboard.
  • the operator can transmit the human-computer interaction communication and the control of the entire device by sending a parameter command or the like to the control unit 24 through the control software interface.
  • the microcomputer unit 26 is connected to the communication module of the control unit 24 through a serial port, a CAN bus or a Bluetooth communication method, and various communication modes can ensure stable, reliable and timely data transmission between the microcomputer unit 26 and the control unit 24.
  • the auxiliary control unit 27 is provided with an ECG module and a foot switch control module, and the ECG module is powered by a 220V, 50 Hz power supply provided by the unit after passing through the filter kit.
  • ECG module for compound steep pulse tumor treatment The treatment device measures the ECG signal of the patient during treatment, and outputs a control signal to the control unit 24 after the R wave of the patient ECG signal, so that the control unit 24 generates a control signal at that time and outputs it to the IGBT (MOSFET device) or the vacuum relay, thereby Accurate control of the output timing of the pulse voltage.
  • the output signal of the ECG module is connected through the first set of fiber isolation circuits and the control unit in the fiber isolation circuit, so as to avoid mutual interference between the ECG module and the control unit.
  • the pedal module of the present application is connected to a corresponding control terminal of the second group of fiber isolation modules and control modules in the fiber isolation circuit.
  • the pulse voltage cannot be output to the patient, but only acts on the internal non-inductive resistance.
  • the foot switch can be released by releasing the foot switch, and then the output pulse is applied to the internal load to disconnect the output of the patient, thereby achieving the purpose of suspending treatment.
  • the operator starts and pauses the treatment by stepping on and releasing the foot switch, and liberates the operator's hands and simplifies the operation of the instrument.
  • the operator controls the output of the pulse signal through the foot switch, which can quickly disconnect the circuit in an emergency, thereby avoiding damage to the patient and damage to the instrument.
  • the optical fiber isolation unit 25 of the composite steep pulse tumor treatment apparatus shown in FIG. 11 includes a filter circuit, an AC/DC conversion circuit, an electro-optical conversion module, and a photoelectric conversion module.
  • the filter circuit in the optical fiber isolation unit 25 obtains 220V, 50Hz alternating current from the power supply filter device in the power supply unit, and the alternating current outputted by the filter is converted into direct current after being converted by the AC/DC (AC to DC) power conversion module, and is provided.
  • the electro-optical conversion circuit the optical signal output by the electro-optical conversion circuit is transmitted to the photoelectric conversion circuit through the optical fiber, and the photoelectric conversion circuit converts the received optical signal into an electrical signal and outputs it to the control circuit board.
  • the ECG signal and the foot switch signal of the auxiliary control unit can be connected to the control unit after passing through the optical fiber, so as to avoid interference between signals and isolation to ensure the safety of the operator.
  • the filter type of the fiber isolation unit can be HT402-1-P21-P2, the input voltage is 220V, 50Hz, the rated current is 1A, and the leakage current is about 0.5mA.
  • the model of the AC/DC power module can be, for example, LH05-10B05, which allows an input voltage range of 85 to 264 VAC, an output voltage of 5 V, and an output current capability of 1000 mA, with short-circuit protection.
  • the electro-optical conversion chip used in this module is, for example, HFBR-1414TZ, and the photoelectric conversion chip uses HFBR-2412TZ.
  • the electro-optical conversion chip and the photoelectric conversion chip adopt ST interface, and the installation is firm and reliable.
  • the tumor treatment device of the present application is also equipped with a complete automatic protection device, which can detect the output voltage and current. When the voltage current exceeds the set value, the output can be cut off by software or hardware to protect the person. Safety of personnel and equipment.
  • the composite steep pulse tumor treatment device is also equipped with an emergency switch. In the state where the emergency switch is not pressed (closed), the compound steep pulse tumor treatment device works normally, and in the event of an emergency, the operator When the emergency switch is pressed, the emergency switch is turned off, and the compound steep pulse tumor treatment device reduces the voltage and stops the external output. Safeguard personnel and instruments. When the emergency stop switch is not pressed, the closed mode can avoid the out-of-control phenomenon in the case of the open circuit of the emergency stop switch, and fully ensure the safety of personnel and instruments.
  • the pulse generated by the tumor treatment device of the present application is a bipolar composite steep pulse train.
  • the amplitude of the output pulse voltage can be changed by adjusting the output voltage of the high voltage DC power supply.
  • parameters such as the on-time, the breaking frequency, and the number of breaking times of the switching device in the full-bridge inverter circuit by the control unit.
  • parameters such as the pulse width, the pulse interval, the frequency, and the number of the output pulse can be changed.
  • the amplitude of the bipolar composite steep pulse generated by the device is continuously adjustable from 0 to 3kV
  • the pulse width is continuously adjustable from 100ns to 500us
  • the frequency within the string is up to 2MHz
  • the frequency outside the string is adjustable from 0 to 10Hz
  • the rise time is 30ns. Time is 30ns.
  • the specific pulse parameters output by the tumor treatment device provided by the present application can be adjusted according to actual needs.
  • the device of the present application achieves precise control of the output energy of the compound steep pulse tumor treatment device by adjusting the above parameters, and these parameters are independent of each other and do not interfere with each other, so that a good therapeutic effect can be achieved.
  • Figure 12 is a schematic diagram showing exemplary waveforms of the output of the bipolar composite steep pulse tumor treatment device of the present application. It should be understood that the waveforms output by the device can be varied to accommodate different tumor tissues and are not limited to the illustrated species.
  • Figure 13 is a diagram showing an example of the actual output voltage and current waveform of the bipolar composite steep pulse tumor treatment apparatus of the present application. It can be seen from the figure that the bipolar waveform has a small overshoot and a small top drop, and the preface is steep. It is very suitable for the treatment of tumor tissue.
  • Another aspect of the present application relates to a biological tissue ablation method.
  • the patient's biological tissue is ablated by a corresponding procedure using an ablation electrode.
  • FIG. 14 is a schematic flow diagram of a biological tissue ablation method in accordance with the present application.
  • ablation parameters for the biological tissue to be ablated are determined.
  • Ablation parameters include selection of ablation electrodes and determination of ablation pulse parameters.
  • a splint electrode or an adsorption electrode may be selected, and for the biological tissue in the body, a needle electrode may be selected.
  • the needle ablation electrode can be a two-electrode needle, two electrode needles, three electrode needles or a plurality of electrode needles.
  • the shape and arrangement of the ablation electrode can be selected according to the position and shape of the ablated biological tissue, and the like.
  • the configuration of the fusion electrode includes, for example, an insertion position of the ablation electrode, an insertion depth, and an exposure length.
  • the ablation pulse parameter for example, the amplitude of the pulse, the polarity of the pulse, the pulse width, the pulse interval, the number of pulses, and the number of pulses can be determined according to the nature of the biological tissue to be ablated.
  • those skilled in the art can understand, according to the shape and arrangement of the electrodes used, the distance between the electrodes, the parameters of the ablation pulse used, and the estimated or measured conductivity and dielectric constant of the biological tissue to be ablated.
  • the intensity of the electric field generated by the applied bipolar pulse in the biological tissue to be ablated can be calculated. The range of parameters for the ablation pulse is discussed above in this specification and will not be repeated here.
  • step S102 the ablation parameters for the biological tissue to be ablated determined in step S101 are set in the irreversible electroporation device, and the determined ablation parameters are provided to the control unit 13 through the user interface 14 or the like so as to be Under the control of the control unit 13, the biological tissue is ablated by the bipolar pulse of the set parameters.
  • step S103 ablation is started and started.
  • the ablation electrode is placed to the patient's tissue to be ablated according to the type of ablation electrode selected in step S101 and the configuration of the ablation electrode, and the irreversible electroporation ablation procedure is initiated automatically or by the user manually.
  • a bipolar pulse conforming to the set pulse parameter is generated, and the generated bipolar pulse is applied to the patient's tissue to be ablated through the electrode to initiate ablation.
  • step S104 it is determined whether the ablation is completed, that is, whether all of the tissue to be ablated has been ablated.
  • the manner of determining whether the ablation is completed may include, for example, the user performing the ablation operation directly determines whether the ablation is completed by observation, and generates an image of the ablated biological tissue by an optical imaging device such as a microscope to determine whether the ablation is completed, such as by ultrasound imaging, optical coherence tomography.
  • a medical imaging method such as scanning (OCT) generates an image of the ablated biological tissue to determine whether ablation is completed, and determines ablation by measuring physiological parameters (eg, biological activity, electrical conductivity, dielectric constant, impedance, etc.) of the ablated biological tissue. Whether it is completed, etc.
  • the determination of whether or not to complete the ablation may be automatically made by the irreversible electroporation device of the present application or manually by the user.
  • step S104 If it is judged at step S104 that the ablation of all the tissue to be ablated has been completed, the process proceeds to step S105, the ablation process is ended, the output of the pulse signal is stopped, and the user ablation may be prompted by the user interface 14 or the like.
  • step S104 If it is judged at step S104 that the ablation of all the ablated biological tissues has not been completed, the process returns to step S104, and it is waited for again to judge whether or not the ablation is completed.
  • irreversible electroporation of the cell membrane is induced by applying an electric field pulse sufficient to form an irreversible perforation on the biological tissue, thereby causing cell death, and at the same time, having a rapid (treatment)
  • the application of pulse time is only tens of seconds, the whole process only takes a few minutes), controllable (the treatment parameters can be obtained by 3D modeling electric field calculation, the treatment range is accurate and safe), visible (the treatment process can be in ultrasound/CT) /MRI guided completion, efficacy can be assessed by ultrasound / CT / MRI), selective (does not damage the bile duct, blood vessels and nerves in the ablation zone) and non-thermal mechanism (no thermal effect, can overcome the heat caused by thermal therapy The advantages of damage 'and 'heat sink').
  • the cell membrane can fully complete the irreversible electroporation process, and the pulse electric field is greatly improved in the cell.
  • the uniformity of distribution in the tissue can break through the resting potential of the cell membrane, the capacitive effect, and the uneven distribution of the internal electric field caused by the anisotropy of the biological tissue, thereby realizing effective coverage of the electric field of the target tissue region to achieve the irreversible electroporation dose.
  • step S106 may be performed to measure and determine whether the parameter of the generated pulse is the same as the parameter of the set bipolar pulse. If the parameters of the generated pulse are the same as the parameters of the set bipolar pulse, the process proceeds to step S104, where it is judged that the ablation of all the biological tissues to be ablated has been completed. Otherwise, the process returns to step S102 to correspondingly change the ablation parameters set in the irreversible electroporation device such that the generated pulse parameters are identical to the parameters of the set bipolar pulse.
  • one aspect of the present application is directed to a biological tissue ablation method comprising the steps of:
  • the generated bipolar pulse is applied to the biological tissue to be ablated.
  • the pulse width of each of the positive polarity pulse and each of the negative polarity pulses is at least a period of time enabling the cell membrane of the biological tissue to reach a stable state of charge.
  • the pulse width of each of the positive polarity pulse and each of the negative polarity pulses is at least 4 to 5 times the charging time constant of the cells of the biological tissue, respectively.
  • the pulse width of each of the positive polarity pulse and each of the negative polarity pulses is 5 to 50 microseconds.
  • the pulse width of each of the positive polarity pulses and each of the negative polarity pulses is 5 microseconds.
  • the bipolar pulse sufficient to generate irreversible electroporation on the cell membrane of the biological tissue produces an electric field intensity in the biological tissue of 1.5 kV/cm to 3 kV/cm.
  • the total pulse width of the bipolar pulse sufficient to generate irreversible electroporation on the cell membrane of the biological tissue is from 50 microseconds to 150 microseconds.
  • the biological tissue ablation method according to the present application further comprises a pulse measuring step in which the parameters of the generated bipolar pulse are measured and adjusted to produce a bipolar having the determined parameter according to the measured parameter.
  • the bipolar pulse is a bipolar square wave pulse.
  • the bipolar pulse is repeatedly generated and the repeatedly generated bipolar pulse is applied to the biological tissue.
  • the present application also provides an example of the method of operation of the bipolar complex steep pulse tumor treatment device described above.
  • the microcomputer After the total power of the device of the present application is turned on, the microcomputer automatically turns on, and after the power is turned on, the operator controls the software by clicking the icon of the supporting control software on the desktop of the computer.
  • the control software first initializes; then checks whether the communication connection is normal. After the control software communication connection is passed, the control software performs a self-test on the compound steep pulse tumor treatment device to determine whether the device is normal. After the self-test is passed, the boost test is first performed; in the boost test, it is mainly detected whether the device can reach the specified voltage range within a specified time; after the boost test is passed, the control software performs the buck test, if Within the specified time, the output voltage can be reduced to within the specified range, and the buck test passes. After the buck test is passed, the initialization of the entire composite steep pulse tumor treatment device is passed.
  • the operator can enter the basic information input interface of the control software (the set parameters include patient serial number, patient name, patient gender, patient age, surgeon, case record, patient characteristics, tumor) Information, lesion size, margin margin, and clinical data).
  • the control software will check the legality of the parameters of the input data to determine whether the parameter is within the allowable range. If the legality of the parameter is detected, the next step of inputting the treatment parameter may be entered. If the legality of the parameter cannot be detected, the control software prompts the operator to re-enter the information until the operator enters the correct information or presses the exit button.
  • the operator first needs to refer to the patient's characteristics (physical condition, age, gender, etc.) and the specific conditions of the tumor tissue (type, degree of malignancy, size, etc.) Number) formulate the corresponding treatment plan and determine the parameters of the output square wave pulse (ie pulse amplitude, intra-string repetition frequency, pulse width, number of pulses in the string, polarity and number of pulse groups), and exposure length of the electrode needle , the insertion position and depth of the electrode needle and the pulse output trigger mode (fixed string frequency, ECG trigger mode); the control software saves the input parameters to the hard disk of the microcomputer, and the pulse amplitude of the square wave pulse, within the string
  • the parameters such as frequency, pulse width and number of pulses in the string and the number of pulse groups are calculated to form corresponding control commands to be sent to the control unit of the device through serial port, CAN bus or Bluetooth communication.
  • the operator determines the number of the electrode needle according to the step (2), and adjusts the length of the insulating sheath of the electrode needle according to the determined exposure length of the electrode needle, so that the exposed length of the electrode needle meets the requirements.
  • the operator then inserts the electrode tip into the patient's tumor tissue according to the set insertion position and depth of the electrode tip. During the insertion process, it is necessary to ensure that the electrode pins are inserted in parallel and cannot be short-circuited.
  • the operator clicks the release pre-pulse button of the control software interface, and the compound steep pulse device generates a pulse voltage of a certain parameter to act on the internal resistance of the system, and further detects the pulse parameter.
  • the prompt window of the control software will prompt the operator to step on the foot switch to start the treatment.
  • the pulse voltage of the specified parameter will be output to the patient's tumor tissue.
  • the operator can release the foot switch at any time to pause the pulse output to the patient.
  • the treatment progress data will still be saved in the control software.
  • the operator re-presses the foot switch, the compound steep pulse tumor treatment
  • the device continues to electrically pulse the patient until the treatment is complete or the operator releases the foot switch again.
  • the operator can also press the emergency stop button to pause the output to ensure the safety of the therapist and device.
  • the treatment device can also record the parameters during the treatment at any time, and the recorded parameters mainly include current waveform and voltage waveform during the treatment, and treatment information input in step (2). These data are stored in a certain form on the hard disk of the microcomputer.
  • the control software can generate a treatment list for the operator and the patient to view. The operator can also perform statistical and examination of the saved treatment parameters after the end of treatment. In order to optimize the treatment process, parameters and devices in the later stages.
  • control software will display the end of treatment and prompt the operator to remove the electrode needle from the patient's tumor tissue, and then the control software will send a corresponding command to reduce the voltage of the high-voltage DC power supply.
  • the residual charge on the storage capacitor is drained to ensure the safety of personnel and instruments. At this point, the operator can close The compound steep pulse tumor treatment device is ready for the next use, and the treatment process is officially ended.
  • the pulse waveform used in this application is a bipolar composite steep pulse, which mainly acts on the cell membrane of tumor cells, causing irreversible electroporation of the cell membrane, destroying the structure and living conditions of tumor cells, and allowing tumor cells to enter apoptotic state through self-regulation. And eventually kill the tumor cells.
  • This application does not use chemotherapy drugs, can completely avoid the toxic side effects of chemotherapy and chemotherapy drugs in electrochemical therapy, and significantly reduce the risk of recurrence.
  • the composite steep pulse tumor treatment device and method of the present application can accurately control the treatment range without affecting the surrounding normal tissue; has the advantage of non-thermal effect, and the curative effect is not affected by blood flow; the treatment time of the device is short, no pain It can be completed in a few minutes; the electrodes can be flexibly arranged according to the characteristics of the tumor; the treatment process and the therapeutic effect can be visualized, and the whole process can be observed under the monitoring of medical imaging equipment such as medical ultrasound and magnetic resonance imaging.
  • the composite steep pulse tumor treatment device of the present application has complete safety guarantee measures for possible misoperations in the treatment process, which can completely ensure the safety of the treatment object and ensure the treatment device is not damaged.
  • the treatment using the compound steep pulse tumor treatment device of the present application can reduce the muscle contraction of the patient, reduce the amount of muscle relaxant and anesthetic used during the treatment, improve the convenience of treatment and reduce the treatment cost.
  • the device of the present application is convenient to use, and the method of the present application is simple to operate.
  • the present application can be widely applied to the treatment of tumors of humans and animals, and is particularly suitable for treating tumors of the human body.
  • the present application also provides another example of the method of operation of the bipolar complex steep pulse tumor treatment device described above.
  • the operation flow chart of the bipolar composite steep pulse tumor treatment apparatus according to this embodiment is as shown in FIG. 15, and according to the operation flow, the purpose of safe treatment and rapid treatment can be achieved. The respective steps are specifically explained below with reference to FIG.
  • step S201 initialization is performed. After the tumor treatment device is powered on, the microcomputer is turned on, and other system modules such as a high-voltage DC power source are turned on.
  • the system control software installed on the microcomputer is automatically initialized after startup; the initialization includes detecting whether the communication connection between the host computer control software and the control board of the lower computer is normal, and then performing boost detection, and whether the detection instrument can be specified.
  • the specified time (for example: 30 seconds)
  • the output voltage range for example, 490-510V
  • the buck detection is performed, and the test instrument can drop the voltage to a specified voltage range within a specified time, for example, 0 to 20V, if the buck detection passes, Then the initialization of the instrument is completed. If any of these tests are not completed within the specified time, the operator is prompted to inspect the instrument under the direction of a professional.
  • treatment information is input.
  • patient information such as patient serial number, patient name, patient gender, and age
  • treatment information at the treatment information interface, including the operation time, the surgeon, Case records, input patient characteristics, tumor information in the clinical data column.
  • the length, width, thickness and margin margin parameters of the tumor were entered in the lesion area to determine the size of the treatment area.
  • the control software automatically determines whether the input parameters are correct. If the parameters of these inputs are correct, you can click to enter the next parameter setting phase.
  • a pulse parameter is input.
  • the parameters set include the trigger type of the pulse output (external frequency mode or ECG synchronization mode), pulse type (bipolar or unipolar). ), intra-string frequency, single pulse width, dead time, number of pulses in the string, total high time, and the number of electrode pins and the distribution of the electrode pins.
  • the control software further checks the legality of these parameters. After the parameter detection is legal, the control software automatically converts the input pulse parameters into corresponding control commands and sends them to the control system for preparation for treatment.
  • step S204 it is judged whether or not the output parameter is within the allowable range.
  • the operator clicks the "release pre-pulse" button of the control software to cause the device to release the pre-pulse, and the system determines whether the device is normal according to the parameters of the pre-pulse. If the output parameter of the instrument is within the allowable range, indicating that the device is normal, then The system prompts the operator to perform treatment, and the parameters such as the pulse amplitude, the repetition frequency, the pulse width and the number of pulses of the determined square wave pulse are calculated and sent to the microcomputer system in the apparatus of the first or second embodiment. The control system, the control system enters the pre-treatment preparation phase. If it is judged at S204 that the output parameter is not within the allowable range, the operation returns to S203 to re-enter the pulse parameter.
  • step S205 it is judged whether or not the emergency switch is pressed. If the emergency switch is pressed during the treatment, the emergency stop signal is directly sent to the high-voltage DC power supply, so that the output voltage of the high-voltage DC power supply is zero, and the pulse output is also stopped; after the error is eliminated, after the emergency switch is released, the treatment continues. The pulse output phase of the treatment process is not completed until the specified number of burst outputs are completed.
  • the emergency switch is directly connected to the control terminal of the high-voltage DC power supply to improve the response speed of the device to an emergency, and can effectively protect the safety of the patient and the device.
  • the foot switch it is judged whether or not the foot switch is depressed.
  • the operator inserts the electrode needle in parallel into the tumor tissue inserted into the patient, and determines that the electrode needle is not There is a short circuit, and then click the "Start Treatment" button on the control software.
  • the device starts outputting the pulse in step S207. At this point the pulse acts only on the internal non-inductive resistor. If the foot switch is depressed, the pulse begins to be output to the patient's tumor tissue and the control software counts the number of pulses output to the tumor tissue.
  • the control signal for releasing the foot switch is first transmitted to the fiber isolation module.
  • the signal is converted by electro-optical conversion, the signal is converted into an optical signal and transmitted to the photoelectric conversion chip in the fiber isolation module.
  • the electro-optical conversion chip converts the optical signal into an electrical signal and outputs it to the control module.
  • the control unit processes the pedal switch signal, the corresponding IGBT (or MOSFET) and the vacuum relay are controlled to be turned on or off, thereby making the composite steep.
  • the pulse output is suspended.
  • the count output to the tumor tissue is also suspended and the information is transmitted to the microcomputer unit for display and recording.
  • the composite tissue is outputted to the tumor tissue to continue the treatment, and the counting of the output pulse is resumed.
  • step S208 it is determined whether the number of output pulses reaches a preset value. If not, the process returns to step S205; if it is reached, the process ends at S209, and the liquid crystal display prompts "end of treatment".
  • the microcomputer automatically saves key data such as voltage data, current data, and treatment waveform during the treatment, and sends a buck command to make the output of the high-voltage DC power supply zero, and at the same time, the discharge circuit is turned on, so that the storage capacitor is turned on. After the charge is released, the storage capacitor voltage drops to zero, and a shutdown command is sent to reset the associated circuit, and the operator is prompted to pull the electrode needle from the patient's tumor tissue. After the above procedure, the treatment is over.
  • the square wave pulse generated in this embodiment is a bipolar composite steep pulse. Adjusting the square wave pulse output voltage is realized by controlling the output voltage of the high voltage power supply through the DAC module of the control unit.
  • the output signal waveform form can be controlled by the microcomputer computer unit and the control unit generating different combinations of control signals.
  • the amplitude of the bipolar square wave pulse is adjustable from 0-3kV; the square wave pulse width is adjustable from 100ns to 500 ⁇ s; the intra-string frequency of the square wave pulse is up to 2MHz, and the single pulse width of the square wave pulse is the smallest. It is 100ns.
  • the extra-sequence frequency of the square wave pulse is adjustable from 0-10 Hz.
  • the device of the present application realizes precise control of the output square wave pulse energy through flexible adjustment of the above parameters.
  • the device of the present application is equipped with a powerful software system, in addition to independent and accurate adjustment of various parameters of the output, it can also save parameters and data during the treatment process, facilitate the evaluation of the treatment effect after treatment and improve the treatment process.
  • the device is equipped with a complete protection device to ensure the safety of patients and devices. This device is very suitable for the treatment of tumor tissue in the human body.
  • the inventors of the present application conducted the following verification experiments with respect to the prior art unipolar irreversible electroporation apparatus and the bipolar irreversible electroporation apparatus according to the embodiment of the present application.
  • the inventors conducted research using rabbit liver tissue as a biological tissue, and applied electrical pulses to rabbit liver tissue through a splint electrode. Studies have shown that the charging time constant of cells in rabbit liver tissue is about 1 ⁇ s. Therefore, the applied unipolar pulse produces an electric field intensity of 1.5 kV/cm in rabbit liver tissue, a pulse width of 100 ⁇ s, and a pulse repetition number of 90 times, while the applied bipolar pulse is positive.
  • the pulse of sex and negative polarity produces an electric field intensity of 2 kV/cm in rabbit liver tissue, the pulse width is five times the charging time constant (ie, 5 ⁇ s), and the positive and negative polarity pulses are applied 10 times in each cycle. , repeat 90 cycles. Thereafter, the ablated biological tissue is magnified with a microscope to observe the presence of residual un-ablated hepatocytes.
  • FIG. 16 is the result of the above experiment, in which FIG. 16A is an enlarged view of a result of applying a conventional unipolar pulse, and FIG. 16B is an enlarged view of a result of applying a bipolar pulse according to an embodiment of the present application.
  • FIG. 16A is an enlarged view of a result of applying a conventional unipolar pulse
  • FIG. 16B is an enlarged view of a result of applying a bipolar pulse according to an embodiment of the present application.
  • the irreversible electroporation device and the biological tissue ablation method according to the embodiments of the present application can reduce the ablation dead zone and improve the ablation effect.
  • the Applicant compares the ablation effect when the pulse width is less than 4 to 5 times the charging time constant of the cells of the biological tissue and equals the time period in the case of using the bipolar pulse.
  • the rabbit liver tissue with a cell charge time constant of about 1 ⁇ s is still taken as an example.
  • the positive and negative polarity pulses produce an electric field intensity of 2 kV/cm in rabbit liver tissue, and the pulse width is 1 times the charging time constant (ie, 1 ⁇ s), each The positive polarity and negative polarity pulses were applied 50 times in the cycle, respectively, and repeated for 90 cycles.
  • the positive and negative polarity pulses produce an electric field intensity of 2 kV/cm in rabbit liver tissue, and the pulse width is 5 times the charging time constant (ie, 5 ⁇ s).
  • the positive polarity and negative polarity pulses were applied 10 times in each cycle, and repeated for 90 cycles. Thereafter, the ablated biological tissue is magnified with a microscope to observe the presence of residual un-ablated hepatocytes.
  • FIG. 17 is a result of the above experiment, in which FIG. 17A is an enlarged view of a result of applying a bipolar pulse having a pulse width of 1 ⁇ s, and FIG. 17B is an enlarged view of a result of applying a bipolar pulse having a pulse width of 5 ⁇ s.
  • FIG. 17A is an enlarged view of a result of applying a bipolar pulse having a pulse width of 1 ⁇ s
  • FIG. 17B is an enlarged view of a result of applying a bipolar pulse having a pulse width of 5 ⁇ s.
  • the irreversible electroporation device and the biological tissue ablation method set the pulse width of the bipolar pulse to be sufficient to cause irreversible electroporation on the cell membrane of the biological tissue.
  • the pores for example, 4 to 5 times the charging time constant of cells larger than or equal to the biological tissue, can reduce the ablation blind zone and improve the ablation effect.
  • the present application proposes an irreversible electroporation device comprising: a pulse forming unit configured to generate a bipolar pulse; and an electrode configured to receive a bipolar pulse from the pulse forming unit and adapted to bipolar Sex pulses are applied to biological tissue.
  • the pulse width of the bipolar pulse and the electric field intensity generated in the biological tissue are set to be sufficient to cause irreversible electroporation on the cell membrane of the biological tissue.
  • Another aspect of the present application relates to a biological tissue ablation method comprising the steps of determining a bipolar pulse to be applied according to a biological tissue to be ablated, a pulse width of the bipolar pulse and an electric field generated in the biological tissue
  • the intensity is set to be sufficient to produce irreversible electroporation on the cell membrane of the biological tissue; a bipolar pulse having the set parameters is generated; the generated bipolar pulse is applied to the biological tissue to be ablated.
  • the bipolar pulse according to an embodiment of the present application can effectively increase the uniformity of the ablation electric field, and the pulse width of the bipolar pulse and the electric field intensity generated in the biological tissue are sufficient to generate irreversible electroporation on the cell membrane of the biological tissue. Thereby reducing the ablation blind zone.
  • the present disclosure is embodied as a system, apparatus, method, or computer readable medium as a computer program product. Accordingly, the present disclosure may be embodied in various forms, such as a complete hardware embodiment, a complete software embodiment (including firmware, resident software, microprogram code, etc.), or as an implementation of software and hardware, The following will be referred to as "circuit,” “module,” or “system.” Furthermore, the present disclosure may also be embodied in any tangible media form as a computer program product having computer usable program code stored thereon.

Landscapes

  • Health & Medical Sciences (AREA)
  • Surgery (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Plasma & Fusion (AREA)
  • Physics & Mathematics (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Medical Informatics (AREA)
  • Otolaryngology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Electrotherapy Devices (AREA)
  • Apparatus Associated With Microorganisms And Enzymes (AREA)

Abstract

不可逆电穿孔设备（1，2），其包括：脉冲形成装置（10），其被配置为产生双极性脉冲；和电极（20），其被配置为从脉冲形成装置（10）接收双极性脉冲并适于将双极性脉冲施加到生物组织。其中，双极性脉冲的脉冲宽度和在生物组织中产生的电场强度被设置为足以在生物组织的细胞膜上产生不可逆电穿孔。该双极性脉冲可以有效地增加消融电场的均匀性，并且双极性脉冲的脉冲宽度和在生物组织中产生的电场强度足以在生物组织的细胞膜上产生不可逆电穿孔，从而减小消融盲区。

Description

不可逆电穿孔设备及其操作方法 技术领域
本申请涉及不可逆电穿孔设备，更具体地，本申请涉及用于在生物组织的细胞上产生不可逆穿孔从而消融生物组织的设备以及生物组织消融方法。
背景技术
癌症是危害人类健康的主要疾病。肿瘤的传统疗法以及新近发展起来的以微创消融为特征的热消融物理疗法，由于受适应症、禁忌症、治疗副作用、热效应等因素的限制，使得其临床应用存在一定的局限性。近年来，随着脉冲生物电学的不断发展，电场脉冲以其非热、微创的生物医学效应引起了研究人员的关注，而其中的不可逆电穿孔治疗肿瘤以其快捷、可控、可视、选择性和非热机理等的优势和特色更是引起国内外生物电学领域研究人员的广泛关注，并逐渐应用于肿瘤的临床治疗。
目前，不可逆电穿孔技术已应用于临床肿瘤的治疗，取得了非常好的疗效，对多种癌症，如胰腺癌、肝癌、肾癌，前列腺癌、宫颈癌等癌症的前期肿瘤的治疗具有良好的效果。美国AngioDynamics公司投资生产出商业化的不可逆电穿孔肿瘤治疗仪NanoKnife，并于2009年获得美国FDA临床试验许可。但是由于其输出的脉冲是单极性的脉冲，单极性的脉冲作用于人体组织时容易导致肌肉收缩，加大患者的痛苦以及加大治疗的难度，并且单极性的脉冲的电场也不均匀，存在消融盲区，使得消融效果不甚良好。
因此，虽然不可逆电穿孔技术在国内外的临床应用中取得了令人振奋的治疗效果，但是由于生物组织的复杂性导致了组织中实际电场分布不均匀，使得肿瘤组织不能够完全被不可逆电穿孔有效电场覆盖，导致在临床试验中有部分患者需要二次或多次重复治疗。
如何能够找到一种能在生物组织中实现电场均匀分布的电场脉冲消融方法就成为解决上述难题的关键。
发明内容
鉴于现有技术中存在的一个或多个问题，本申请提出一种双极性复合陡脉冲肿瘤治疗装置，其可以减小肌肉收缩，使得脉冲电场更加均匀，进一步提高治疗效果。
本申请的一个方面涉及一种不可逆电穿孔设备，其包括：脉冲形成装置，其被配置为产生双极性脉冲；和电极，其被配置为从脉冲形成装置接收双极性脉冲并适于将双极 性脉冲施加到生物组织。其中，双极性脉冲的脉冲宽度和在生物组织中产生的电场强度被设置为足以在生物组织的细胞膜上产生不可逆电穿孔。
本申请的另一个方面涉及一种生物组织消融方法，包括以下步骤：根据待消融的生物组织来确定待施加的双极性脉冲，该双极性脉冲的脉冲宽度和在生物组织中产生的电场强度被设置为足以在生物组织的细胞膜上产生不可逆电穿孔；产生具有所设置的参数的双极性脉冲；将所产生的双极性脉冲施加到待消融的生物组织。
本申请的又一方面提供了一种不可逆电穿孔设备的操作方法，其包括：通过脉冲形成装置产生双极性脉冲；和通过电极将双极性脉冲施加到生物组织，所述电极从所述脉冲形成装置接收双极性脉冲，其中，双极性脉冲的总脉冲宽度和在生物组织中产生的电场强度被设置为足以在生物组织的细胞膜上产生不可逆电穿孔。
本申请的再一方面提供了一种肿瘤治疗装置，包括：电源单元，用于为所述装置供电；脉冲形成单元，包括全桥逆变电路，所述脉冲形成单元输出脉冲电流信号；测量单元，配置为测量由脉冲形成单元产生的脉冲的参数，并提供给控制单元；控制单元，根据所述测量单元提供的所述参数和用户输入参数来控制脉冲形成单元，通过改变脉冲形成单元中的全桥逆变电路中的开关器件的导通时间、开断频率以及开断次数等来改变输出脉冲的极性、脉宽、脉冲间隔、频率及脉冲个数。
根据本申请的实施方式的双极性脉冲可以有效地增加消融电场的均匀性，并且双极性脉冲的脉冲宽度和在生物组织中产生的电场强度足以在生物组织的细胞膜上产生不可逆电穿孔，并且脉冲之间的零电平脉冲间隔能够使细胞膜上的穿孔得到进一步发展，从而减小消融盲区，提高治疗效率，减少重复治疗。
附图说明
图1是根据本申请的第一实施方式的不可逆电穿孔设备的示意性框图。
图2A和2B是由根据本申请的第一实施方式的不可逆电穿孔设备形成的双极性脉冲的示意图。
图3是根据本申请的第一实施方式的脉冲产生单元12的构造的示意性框图。
图4是根据本申请的一种可替代实施方式的双极性脉冲的波形图。
图5是根据本申请的另一种可替代实施方式的不可逆电穿孔设备的示意性框图。
图6是根据本申请的第二实施方式的双极性复合陡脉冲肿瘤治疗装置的示意性框图。
图7是根据本申请的第二实施方式的双极性复合陡脉冲肿瘤治疗装置的结构示意图。
图8示出了根据本申请的复合陡脉冲肿瘤治疗装置中主电路中的全桥逆变电路的一个例子。
图9示出了根据本申请的复合陡脉冲肿瘤治疗装置中的控制单元的一个例子。
图10示出了根据本申请的复合陡脉冲肿瘤治疗装置的多路输出切换单元的一个例子。
图11示出了根据本申请的复合陡脉冲肿瘤治疗装置的光纤隔离单元的一个例子。
图12示出了本申请的双极性复合陡脉冲肿瘤治疗装置输出的示例性波形的示意图。
图13示出了本申请的双极性复合陡脉冲肿瘤治疗装置的实际输出电压电流波形图的例子。
图14是根据本申请的第三实施方式的生物组织消融方法的示意流程图。
图15示出了根据本申请的第五实施方式的双极性复合陡脉冲肿瘤治疗装置的操作流程图。
图16是对兔肝脏组织的细胞进行消融实验的结果的示意图，其中，图16A是施加传统单极性脉冲的结果的放大图，图16B是施加根据本申请的实施方式的双极性脉冲的结果的放大图。
图17是对兔肝脏组织的细胞进行消融实验的结果的示意图，其中图17A是施加脉冲宽度为1μs的双极性脉冲的结果的放大图，图17B是施加脉冲宽度为5μs的双极性脉冲的结果的放大图。
具体实施方式
现在将参照附图来详细描述本申请的各种示例性实施例。应注意到：除非另外具体说明，否则在这些实施例中阐述的部件和步骤的相对布置、数字表达式和数值不限制本申请的范围。
同时，应当明白，为了便于描述，附图中所示出的各个部分的尺寸并不是按照实际的比例关系绘制的。
以下对至少一个示例性实施例的描述实际上仅仅是说明性的，决不作为对本申请及其应用或使用的任何限制。
对于相关领域普通技术人员已知的技术、方法和设备可能不作详细讨论，但在适当情况下，所述技术、方法和设备应当被视为授权说明书的一部分。
在这里示出和讨论的所有示例中，任何具体值应被解释为仅仅是示例性的，而不是作为限制。因此，示例性实施例的其它示例可以具有不同的值。
第一实施方式
图1是根据本申请的第一实施方式的不可逆电穿孔设备的示意性框图。
根据该实施方式的不可逆电穿孔设备1包括脉冲形成装置10和电极20。该脉冲形成装置10用来产生根据本实施方式的不可逆电穿孔设备1所需的脉冲，电极20用来从脉冲形成装置10接收所产生的脉冲，并将所产生的脉冲施加到生物组织的细胞，诸如肿瘤细胞。
根据本申请的实施方式的脉冲形成装置10包括电源11、脉冲产生单元12、控制单元13和用户界面14等。电源11用来为不可逆电穿孔设备1以及其中的各个单元供电。脉冲产生单元12用来产生根据本实施方式的不可逆电穿孔设备1所需的脉冲。控制单元13用来对不可逆电穿孔设备1的各个单元的操作进行控制和监测。用户界面14用来提供用户输入、监视不可逆电穿孔过程和显示不可逆电穿孔结果等。
控制单元13可以至少部分以数字电子电路、模拟电子电路或者计算机硬件、固件、软件或其组合来实施。控制单元13可以实施为特定目的逻辑电路，例如FPGA(现场可编程门阵列)或者ASIC(专用集成电路)。另外，控制单元13可以实施作为计算机程序产品，即，有形地嵌入信息载体，例如机器可读存储设备或者产生的信号至的计算机程序，可由数据处理装置，例如可编程处理器、计算机或多计算机执行或控制操作。计算机程序可以以任何编程语言编写，包括编辑或编译语言，并且其可以以任何形式布置，包括作为独立程序或者作为模块、组件、子例程或适于在计算环境中使用的其他单元。计算机程序可以布置为在一个地点或分布在多个地点处的一个计算机上或者多个计算机上执行并且由通信网络互联。并且，控制单元13还可以包括存储器等，用来存储用户设置、各个参数以及监测结果等。
用户界面14用于输入命令和显示状态、信息等，并且可以包括各种输入/输出设备。例如，输入设备可以使用触摸屏、小键盘或全键盘，并且包括各种输入接口、磁盘驱动器等。输出设备包括各种视觉、听觉、触觉输出设备，例如，显示器、LED灯、振动器等。
下文中对由根据本实施方式的脉冲产生单元12产生的脉冲进行说明。
当在生物组织的细胞膜上施加强脉冲时，在强脉冲所产生的强电场的作用下，在细胞膜上建立起的足够大的跨膜电位分布，从而在细胞膜的磷脂双分子层上产生纳米量级的小孔，并且通过该小孔可以输送分子进出细胞膜，即，发生电穿孔。在电穿孔对细胞膜的伤害较小的情况下，当电脉冲停止时，小孔关闭并且细胞可以存活，这样的情况被称作为可逆性电穿孔(Reversible electroporation，RE)。而当电穿孔对细胞膜的伤害达到一定程度之后，细胞内物质通过小孔泄漏过度严重或是小孔的关闭过度缓慢，对细胞造成不可逆的伤害，从而使得细胞因此自然凋亡，而不是其他消融系统通过热能或是辐射造成的坏死，这样的情况被称作为不可逆电穿孔(Inreversible electroporation，IRE)。
本申请的发明人认识到，生物组织的细胞的细胞膜存在约-90mV的静息跨膜电位，因此，当对生物组织的细胞施加单一极性电脉冲时，由于细胞膜的静息跨膜电位的存在，由单一极性的电脉冲在细胞膜上建立起的跨膜电位分布可能是不均匀的。这样的不均匀可能导致当细胞的细胞膜的部分区域的跨膜电位超过不可逆电穿孔阈值时，细胞膜的其余大部分区域的跨膜电位仍然未能达到不可逆电穿孔阈值，使得跨膜电位未能达到不可逆电穿孔阈值的细胞膜区域不会形成不可逆电穿孔。另外，电穿孔过程存在随机性，即，即使细胞膜的某一区域的跨膜电位达到了不可逆电穿孔阈值，细胞膜的该区域也不一定能发生完全的不可逆电穿孔。因此，由于细胞膜的静息跨膜电位的存在，使得细胞膜的跨膜电位超过不可逆电穿孔阈值的区域变得不均匀，这将极大地降低使单个细胞的细胞膜发生不可逆电穿孔的概率，从而导致通过施加单一极性的脉冲来进行不可逆电穿孔时可能存在消融盲区。另外，考虑到实际生物组织中的细胞的形态是不规则的，而非简单的球形，所以细胞膜的静息电位对细胞整体产生不可逆电穿孔效率的影响会更加严重。
本申请的发明人在进行以上考虑之后，提出了本申请的不可逆电脉冲消融设备，其中，采用了双极性脉冲，该双极性脉冲的总脉冲宽度和由该双极性脉冲在生物组织中产生的电场强度被设置为足以在生物组织的细胞膜上产生不可逆电穿孔。总脉冲宽度指的是正极性脉冲和负极性脉冲的高电平时间之和，而由该双极性脉冲在生物组织中产生的电场强度指的是通过电极施加正极性脉冲和负极性脉冲而在生物组织中产生的电场强度。由该双极性脉冲在生物组织中产生的电场强度可以根据所施加的脉冲的幅值、用于施加脉冲的电极的构造和电极间距离以及生物组织的电导率、介电常数等来确定。本申请中提到的“双极性脉冲的总脉冲宽度和由该双极性脉冲在生物组织中产生的电场强度足以在生物组织的细胞膜上产生不可逆电穿孔”指的是在施加产生该电场强度和总脉冲 宽度的电压脉冲时，能够在生物组织的细胞膜上产生不可逆电穿孔，从而使得该细胞最终死亡。在本申请的实施方式中，通过施加上述双极性脉冲，避免了在施加单一极性电场脉冲时，由于细胞膜静息电位的存在导致的跨膜电位超过不可逆电穿孔阈值的分布不均匀问题，从而使细胞膜大部分区域达到不可逆电穿孔阈值跨膜电位，提高单个细胞发生不可逆电穿孔概率，最大限度地减小了消融盲区。
针对不同类型的生物组织，足以在细胞膜上产生不可逆电穿孔的双极性脉冲总脉冲宽度和由该双极性脉冲在生物组织中产生的电场强度可能存在区别。
根据本申请的发明人针对不同的细胞、生物组织和动物进行实验的结果，足以在生物组织的细胞膜上产生不可逆电穿孔的双极性脉冲在生物组织中产生的电场强度例如在1.5kV/cm以上，总脉冲宽度例如在50μs以上。另外，考虑到生物组织对于高电压脉冲的承受能力以及治疗过程中的舒适程度，一般来说，所施加的双极性脉冲在生物组织中产生的电场强度例如可以在3kV/cm以下，总脉冲宽度例如可以在150μs以下。
根据生物电介质理论，细胞可以等效为膜电容与离子电导构成的电容、电阻串联模型。在本申请的实施方式中，本申请的发明人将一阶电路阶跃响应的特征应用到生物电介质细胞模型，发现在对生物组织的细胞施加电脉冲时，在充电时间常数的4～5倍的充电持续时间之后，细胞就能达到稳定的充电状态，从而在细胞膜上产生较强的不可逆电穿孔效应以达到较好的组织消融效果。因此，在本申请的一个实施方式中，单个正极性和负极性脉冲的脉冲宽度至少为生物组织的细胞的充电时间常数的4到5倍。例如，对于充电时间常数为1μs左右的细胞膜，单个正极性和负极性的脉冲的脉冲宽度都至少为约5μs。通过将单个正极性和负极性脉冲的脉冲宽度设置为生物组织的细胞的充电时间常数的4到5倍以上，可以避免过度减小脉冲宽度导致的消融效果下降的问题，从而减小消融盲区。另外，同样考虑到生物组织对于高电压脉冲的承受能力以及治疗过程中的舒适程度，以及治疗过程中发热等情况，一般来说，正极性和负极性的脉冲的脉冲宽度例如可以在约50μs以下。
在改变单个正极性和负极性脉冲的脉冲宽度的同时，为了保证总脉冲宽度足以在生物组织的细胞膜上产生不可逆电穿孔，需要相应地改变正极性脉冲和负极性脉冲的个数，以将双极性脉冲的总脉冲宽度基本保持在所需值。
在本申请的实施方式中，双极性脉冲的总脉冲宽度，即，正极性和负极性的脉冲的脉冲宽度之和，可以与传统的单极性脉冲的不可逆电穿孔设备中的单个脉冲的脉冲宽度相当。例如，在传统的单极性脉冲的不可逆电穿孔设备中，单个脉冲的脉冲宽度的典型 值为100μs，参考该参数，在本申请的实施方式中正极性和负极性的脉冲的脉冲宽度之和可以为100μs。通过参考传统的单极性脉冲的不可逆电穿孔设备的参数，可以保持不可逆电穿孔典型脉冲电场的参数特征，使得更容易将传统现有技术中的参数应用到本申请的实施方式中。
另外，为了保证不可逆电穿孔的效果，根据本申请的实施方式的双极性脉冲可以被重复施加多次。例如，在本申请的一个实施方式中，双极性脉冲可以周期性地例如每1秒施加一次并重复施加例如90个周期。本领域技术人员也可以认识到，可以根据具体情况来非周期性地产生任意次数的双极性脉冲。
图2是由根据本申请的第一实施方式的不可逆电穿孔设备1形成的双极性脉冲的示意图。
图2A示出了其中正、负极性的脉冲交替施加的情况，如图2A所示，正负交替的脉冲之间有零电平的脉冲间隔。通过在一个电极上施加这样的双极性脉冲，当电极作用在生物组织的细胞时，由于电极上的脉冲的正负极性是交替变化的，那么电极周围产生的电场也是交替性变化的，这就避免了单一极性的电脉冲在细胞膜上建立起的跨膜电位分布不均匀而存在消融盲区的问题。由于在正脉冲之后，有一零电平的脉冲间隔，因此在正极性电场驱使正负离子产生运动之后，在该零电平的脉冲间隔期间，由于电场为零，正负离子可以继续运动，运动的累积使得细胞上的电穿孔得以发展；在脉冲间隔期间结束后，再施加负脉冲，通过这样的方式，能够大大提高穿孔效率。换言之，如果正脉冲造成细胞电穿孔之后，马上施加负脉冲，则电场方向立即改变，那么正负离子立即受到相反的作用力，使得电穿孔不能继续发展，因此治疗效果不好。通过使用本申请提出的这种正负极交替并且脉冲间有零电平间隔的双极性脉冲，可以使得所产生的电场充分作用于细胞膜使其发生不可逆电穿孔，提高治疗效率，减少患者需要重复治疗的次数。
可选地，施加到电极上的脉冲的极性不限于一正一负交替变化，而可以是两个正极性脉冲、两个负极性脉冲交替，或者可以是多个正极性脉冲、多个负极性脉冲交替，图2B中示出了多个正极性脉冲和多个负极性脉冲交替的一个例子。图2B示出了其中先施加正极性的脉冲，再施加负极性的脉冲，并且每个脉冲之间有零电平的脉冲间隔的情况。通过在电极上施加图2B所示的脉冲，当电极作用在生物组织的细胞时，由于电极上的脉冲的若干正极性脉冲和若干负极性脉冲交替变化的，那么电极周围产生的电场也是交替性变化的，这就避免了单一极性的电脉冲在细胞膜上建立起的跨膜电位分布不均匀而存在消融盲区的问题。由于在每两个脉冲之间都有零电平的脉冲间隔，因此在正负 离子由于受到电场驱动而产生运动之后，在零电平的脉冲间隔期间，由于电场为零，正负离子可以继续运动，运动的累积使得细胞上的电穿孔得以发展；由于脉冲间隔之后还是同样极性的脉冲，这就使得没有停下来的正负离子得以继续加速，在相同方向上继续运动，细胞上的电穿孔进一步发展；在若干个同极性脉冲后的脉冲间隔期间结束后，再施加相反极性的脉冲，通过这样的方式，能够提高穿孔效率。在这种情况下，脉冲宽度和交替的正负极性脉冲的个数以及脉冲间隔的长度可以根据实际需要来设定。通过使用本申请提出的这种多个正极性脉冲和多个负极性脉冲交替并且每两个脉冲间有零电平间隔的双极性脉冲，可以使得所产生的电场充分作用于细胞膜使其发生不可逆电穿孔，提高治疗效率，减少患者需要重复治疗的次数。
如图2A和2B所示，在本申请的该实施方式中，总脉冲宽度为正、负极性的脉冲宽度之和，即正、负极性的脉冲宽度与正、负极性的脉冲个数的乘积，并且总脉冲宽度可以被设置为100μs。从图2A和2B中可以看到，在本申请的实施方式中，为了便于说明和解释的目的，所采用的双极性脉冲为双极性方波脉冲。
但是，由于不同的生物组织的性质(例如，生物组织的类型、在身体上所处位置、整体形状、组织微环境，以及构成细胞的类型、形状、含水率、电解质浓度、电导率、介电常数等)之间存在较大差异，所以可以根据不同的生物组织等的具体情况，对双极性脉冲的参数进行适当设置。
因此，本领域技术人员可以认识到，在本申请的实施方式中正极性和负极性的脉冲的脉冲宽度之和不一定要参考传统的单极性脉冲的不可逆电穿孔设备的参数，而是可以根据具体情况来适当地设置。例如，总脉冲宽度可以被设置为50μs到150μs的范围中的各个数值，例如，50μs、60μs、70μs、80μs、90μs、100μs、110μs、120μs、130μs、140μs和150μs等。
另外，本领域技术人员还可以认识到，在本申请的实施方式中所施加的正极性和负极性脉冲的排列方式不仅仅局限于图2A和2B中示出的两种排列方式，而是可以根据具体情况来适当地设置。例如，正极性和负极性的脉冲不需要交替施加，而是可以以任意顺序施加等。
另外，本领域技术人员还可以认识到，在本申请的实施方式中正极性和负极性脉冲的个数的比率不一定是1:1的关系，而是可以根据具体情况来适当地设置，只要向生物组织施加的脉冲既包括正极性脉冲又包括负极性脉冲即可。例如，正极性和负极性脉冲的个数的比率可以是在1:2到2:1的范围中的任意数值，例如，1:2、2:3、4:5、1:1、5:4、 3:2、2:1等。
因此，在本申请的实施方式中，可以针对生物组织施加脉冲宽度和在生物组织中产生的电场强度足够使得生物组织的细胞膜产生不可逆电穿孔的若干双极性脉冲，此时所产生电场可充分作用于细胞膜使其发生不可逆电穿孔，使得电场对于生物组织的每个细胞而言分布得更加均匀，从而减小消融盲区。
图3是根据本实施方式的脉冲产生单元12的构造的示意图。脉冲产生单元12包括储能元件121和开关电路122。储能元件121储存由电源11提供的能量，并通过开关电路122将能量释放给电极20。开关电路122被配置为按照用户设定的脉冲宽度、脉冲间隔以及脉冲个数，以脉冲形式进行相应的开关动作，从而产生所需的脉冲波形。开关电路122的一个示例为全桥电路，通过控制全桥电路中的开关的断开和接通的状态、顺序、频率以及次数等，可以形成所需要的正极性的脉冲和负极性的脉冲。当然，根据本申请的实施方式的开关电路122也可以操作来产生单极性的电脉冲。
通过本申请的实施方式，通过施加高场强的电场脉冲作用与生物组织，诱导细胞膜出现不可逆电穿孔，从而导致细胞死亡，同时，具有快捷(治疗施加脉冲时间仅为几十秒，全过程也仅需几分钟)，可控(治疗参数可通过三维建模电场计算获取，治疗范围精确、安全)，可视(治疗过程可在超声/CT/MRI引导下完成，疗效可通过超声/CT/MRI评估)，可选择性(不损伤消融区的胆管，血管及神经等)和非热机理(无热效应，可克服热疗法带来的‘热损伤’与‘热沉’)的优点。
进一步地，通过施加脉冲宽度和在生物组织中产生的电场强度足以在生物组织的细胞膜上产生不可逆电穿孔的双极性脉冲，可以使得细胞膜充分完成不可逆电穿孔过程，并且大大改善脉冲电场在细胞及组织中的分布均匀性，可以突破细胞膜的静息电位、电容效应以及生物组织各向异性带来的内部电场分布不均匀的障碍，实现目标组织区域实现不可逆电穿孔剂量的电场有效覆盖，从而解决了不可逆电穿孔临床应用的消融盲区的问题。
进一步地，通过将正极性和负极性脉冲的脉冲宽度设置为至少为生物组织的细胞的充电时间常数的4到5倍，可以避免过度减小脉冲宽度所导致的消融效果下降的问题，从而减小消融盲区。
在通过不可逆电穿孔技术消融技术治疗例如癌症等疾病时，越来越将患者的舒适程度等作为重要的内容进行考虑。因此，在对人体等活体生物组织进行不可逆电穿孔消融治疗时，除了考虑减小消融盲区之外，还可以考虑人体的承受能力、舒适程度以及消融 区域的发热情况等。
有鉴于此，在本申请的一种可替代实施方式中，可以适当地减小每个极性的脉冲的脉冲宽度，并且在一些情况下，可以将每个极性的脉冲的脉冲宽度设置为约等于被消融的生物组织的细胞的充电时间常数的4到5倍，从而保证了在减小了消融盲区的同时，减少给患者带来的痛苦感和不适感。
在本申请的该可替代实施方式中，可以将由不可逆电穿孔设备形成的每个极性的脉冲的脉冲宽度限定为约5μs。图4是根据本申请的该可替代实施方式的双极性脉冲的波形图。
相比于传统的单极性脉冲不可逆电穿孔消融技术，本申请的该实施方式有利地在保证消融效果的同时尽可能地缩短每个极性的脉冲的脉冲宽度，进一步减少了给患者带来的痛苦感和不适感。
图5是图1所示的实施方式的另一个可替代实施方式的不可逆电穿孔设备2的示意图。
在该实施方式中，如图5所示的不可逆电穿孔设备2与如图1所示的不可逆电穿孔设备1的区别在于脉冲形成装置10还可以包括脉冲测量单元15。
脉冲测量单元15被配置为测量由脉冲产生单元12产生的脉冲的参数，并将所获得的参数提供给控制单元13。脉冲测量单元15所测量的脉冲的参数可以包括例如：脉冲的幅值、脉冲的极性、脉冲宽度、脉冲间隔、脉冲个数以及脉冲串个数等。控制单元13可以监视将所获得的参数并可以将所获得的参数通过用户界面14提供给用户。
之后，控制单元13可以自动地或在用户的控制下根据需要对脉冲产生单元12进行相应的调节，从而确保输出脉冲参数的准确性。
第二实施方式
以下描述本申请的第二实施方式。本申请提供了一种双极性复合陡脉冲肿瘤治疗装置。该装置采用结合了软开关技术的全桥逆变技术来产生双极性复合陡脉冲，在控制单元及控制软件的精确控制下，使脉冲电路按照指定的要求产生所需要的脉冲电压并作用于人体肿瘤组织，从而达到治疗肿瘤的目的。
图6是根据本申请的第二实施方式的双极性复合陡脉冲肿瘤治疗装置的示意性框图，图7是该装置的结构示意图。如图6所示，该肿瘤治疗装置包括：电源单元21、高频复合陡脉冲形成单元22、测量单元23、控制单元24、光纤隔离单元25、微型电脑 单元26和辅助控制单元27和多路输出切换单元28。
在该实施方式中，高频复合陡脉冲形成单元22、多路输出切换单元28、测量单元23、电源单元21、微型电脑单元26、辅助控制单元27、光纤隔离单元25、控制单元24及其配套软件程序具有数据采集、过流保护、安全预警等功能，可以确保患者和治疗装置安全。
电源单元21可包括，例如，市电电源、总开关、保险丝、电源滤波装置、高压直流电源(例如，输入为220V/50Hz交流电，输出最高电压幅值3000V、最大电流幅值100mA的直流电)、隔离变压器(例如，电压、频率变比均为1：1)和开关电源模块，其中开关电源模块可包括变压和整流装置，例如，将220V/50Hz交流输入变为12V直流输出。滤波器的选择主要考虑能够隔离市电电源中的谐波干扰，并且防止仪器产生的谐波干扰传输到市电电源中污染市电电源。隔离变压器是一个等电压、等频率的变压器，其主要是用于隔离电压，从而使得患者在治疗的时候可以不需要与大地进行悬浮，使治疗过程更加简单。高压直流电源的最大输出电压大于或等于最终输出的脉冲电压的幅值，高压直流电源的最大输出电流需要在装置输出最高频率、最大脉宽和最小阻抗的条件下满足电压顶降满足允许值。开关电源模块需要输出后续电路所需的电压，其输出电流应该满足大于其上所接的所有用电的设备消耗的电流的总和。市电电源一般为220V、50Hz交流电源，市电电源的接地线不能接到隔离变压器上，也不能接到隔离变压器后的用电设备的地上，而是直接紧密连接到该双极性复合陡脉冲治疗装置的金属外壳上，这样可以减少来自地线的电磁干扰，使得仪器电源更加稳定。该市电电源首先与总开关的输入端连接，经过总开关之后的交流电的火线连接到保险丝的一端，该交流电的零线和经过保险丝之后的火线与滤波器的输入端相连接。保险丝的作用是在当发生超载情况或者短路情况下可以迅速地切断供电电源，防止对仪器设备的损害。需要注意的是，保险丝需根据仪器输出的总体功率进行选择。经过滤波器之后的市电电源通过端子排与隔离变压器的输入端、ECG模块的输入端、液晶显示器的电源输入端、微型电脑的电源适配器的输入端、光纤隔离单元的电源输入端相连。隔离变压器的输出端与高压直流电源的输入端和开关电源模块的输入端相连接，高压直流电源的输出端通过导线与高频复合陡脉冲形成单元22的全桥逆变电路进行连接。开关电源模块将220V交流电转换为12V的直流电，其输出端通过导线和高频复合陡脉冲形成单元22中的脉冲产生电路的驱动芯片的电源输入端、散热风扇的电源输入端、控制单元的电源输入端相连接。其中，散热风扇用于将装置内部产生的热量通过强制对流的方式散发到外部空间中，从而降低 机体内部的温度。电源单元21为本申请的装置的其余组成部分提供安全、稳定的电能，保障装置的正常工作。
在该实施方式中，高频复合脉冲形成单元22由储能电容、全桥逆变电路及其驱动电路、外部负载切换电路、放电电路和内部放电电阻构成。储能电容并联在电源单元21中的高压直流电源输出端，全桥逆变电路的两端通过导线与电源单元21的高压直流电源的输出端相连接，也就是同时并联在储能电容的两端。全桥逆变电路的每个桥臂单元由耐压足够高的单个IGBT或者多个MOSFET串联构成。全桥逆变电路还配置有相应的驱动电路、旁路二极管和均压电路(如果是多个MOSFET串联的情况)。在每个桥臂单元中，旁路二极管的阴极通过导线与IGBT的C极或者MOSFET的D极连接，阳极通过导线与IGBT的E极或者MOSFET的S极连接，固态开关器件的G极通过导线与驱动芯片的输出端连接，驱动芯片的输入端与控制单元中的相应的控制接口相连接。放电电路和内部放电电阻串联后并联在储能电容两端，放电电路的控制端通过导线和控制单元的相应的控制接口相互连接。在执行降压指令或者关机指令时，控制单元让放电电路导通，储能电容上面的电荷通过放电电路进行泄放，从而达到降压、关机的目的。外部负载切换电路的控制端通过导线与控制单元的控制接口相连接，以便将脉冲输出到装置外部，对患者进行治疗。
如图7中所示的装置结构示意图中的储能电容器可以采用，例如，型号MMJ5kV-100μF(其最大耐压5000V，电容值100μF)，用于存储能量，复合陡脉冲主电路从该储能电容获取能量。隔离变压器最大隔离电压需至少满足该仪器的最大输出电压，隔离变压器的功率需大于该装置的最大消耗功率。
图8示出了复合陡脉冲肿瘤治疗装置中主电路中的全桥逆变电路的一个例子，其中的IGBT可以选用IXEL40N400型号，最大反向击穿电压为4000V，25℃时最大连续导通电流为90A，开通时间不大于300ns，典型关断时间为425ns。在该实例中，复合陡脉冲形成主电路中的无感电阻阻值可以为300Ω，主电路的放电电阻可以采用阻值为20kΩ的大功率电阻。主电路中的真空继电器可以采用GL81C235型号，最大工作电压为10kV，最大连续负载电流为5A，最大接触电阻为0.05Ω，最大工作时间和最大释放时间均为10ms，机械寿命2000000次。电阻分压器的电阻可以选型为：1206封装，分压臂电阻分别为6MΩ和10kΩ，根据电阻分压原理，可以得到在脉冲变压器最大输出电压3000V下，电阻分压器的最大输出电压为4.992V，约为5V,可以输入给AD模块进行测量。复合陡脉冲形成主脉冲产生电路的Pearson线圈型号可以为411，变比参数 0.1V/A，带宽20MHz，可以准确的测量主电路产生的脉冲电流。
如图8所示，当该主电路的IGBT1和IGBT4导通，并且IGBT3和IGBT2关断的时候，复合陡脉冲形成主电路输出正极性脉冲；当电路的IGBT1和IGBT4关断，IGBT3和IGBT2导通的时候，复合陡脉冲形成主电路输出负极性脉冲，通过上面两种控制模式的交替，就可以实现双极性复合陡脉冲的输出。当继电器81关断的时候，脉冲产生电路停止向外部输出，全桥逆变电路的输出的脉冲并联在无感电阻的两端，无感电阻的阻值为300Ω。无感电阻连接的导线从Pearson线圈的中心穿过，这样Pearson线圈就可以准确的测量输出的脉冲电流的大小，再结合无感电阻的阻值，就可以计算出脉冲电压的大小。无感电阻除了形成测量输出脉冲电压和电流的功能之外，还可以避免脉冲输出端的悬空，使得脉冲输出波形更加理想。复合陡脉冲形成主电路的放电电路采用IGBT5开关器件控制，当接收到放电或者降压信号的时候，IGBT5导通，从而使得电容上面的电荷得以通过放电回路释放掉。
测量单元23包括电阻分压器、Pearson电流传感器及其配套处理电路。电阻分压器的电阻并联在储能电容的两端。电阻分压电路的分压比需要满足将高电压转换到后续处理电路可以承受的范围之内，分压器的输出端通过同轴电缆和控制单元的模数转换模块的输入端连接。电流传感器采用Pearson线圈。Pearson线圈的带宽需满足该复合陡脉冲装置的脉冲电压的频带范围，该线圈的输出电压需要在控制单元的电压测量范围内。全桥逆变电路的输出端穿过Pearson线圈的中心的圆孔，和一个合适阻值的无感电阻进行串联。电流传感器(Pearson线圈)的输出端通过同轴电缆与控制单元的相应接口进行连接。通过Pearson线圈测量到的电流以及根据串联的无感电阻的大小可以计算得到脉冲电压的大小。电流测量电路和电压测量电路还增加了必要的处理电路(保护电路)，用于对电流传感器和分压器采集到的超量程的信号经过限压，防止其对后面控制单元的损害。
该肿瘤治疗装置的控制单元可包括现场可编程逻辑门整列(FPGA)，ARM(STM32)和微型电脑以及配套的软件程序、代码、帮助文档及硬件设备等。控制单元的微型电脑上面可安装有配套的控制软件，操作人员可以通过控制软件设置病人的基本信息、肿瘤的基本信息、医生的信息、治疗的信息等基本参数。通过运行该控制软件，可以根据输入的肿瘤信息、脉冲参数的特定频率、幅值、串内频率、极性和个数等数据产生与之相对应的控制指令。该控制指令可以通过串口、CAN总线或蓝牙的通讯方式传输到控制单元的ARM上，ARM经过处理后将数据传送给FPGA，FPGA产生与之对应的触发波 形，并作用于驱动芯片输入端，驱动芯片的输出端的输出驱动信号连接到开关器件的控制端，从而达到控制开关器件导通和关断，从而控制高频复合陡脉冲形成单元和多路输出切换单元产生指定参数的脉冲。
图9示出了图6中的复合陡脉冲肿瘤治疗装置中的控制单元24的一个例子。控制单元24包括通讯模块31、ARM模块32、DAC模块33、PWM模块34、FPGA模块35、ADC模块36、电源模块37、电平转换模块38和光耦模块39。其中电源模块37可以输出不同幅值的电压，用于为肿瘤治疗装置中的其余模块供电。ARM模块32与通讯模块31、DAC模块33以及FPGA模块35进行连接，FPGA模块35与PWM模块34、ADC模块36、ARM模块32以及电平转换模块38相连接。其中通讯模块31由串口通讯模块、CAN总线模块和蓝牙通讯模块组成，可以保障需要的信号能够准确快速地在控制单元24和微型电脑单元26之间传输。ARM芯片32负责对通讯模块31从微型电脑26接收到的数据进行预处理。FPGA模块35用于接收ARM模块32的指令以产生相应的PWM控制信号，并且FPGA模块35通过ADC模块36测量电路中的电压信号和脉冲电流信号。FPGA模块35和电平转换模块38相连，用于控制主电路和脉冲输出切换电路的固态开关器件和真空继电器的导通和关断。电平转换模块38是用于转换FPGA的输出电压到光耦模块39允许的信号电压范围之内，以实现其互相通讯。光耦模块39用于将控制电路板的弱信号控制电压和主电路以及切换电路等设备的高电压进行隔离。ADC模块36接收从测量单元23的处理电路的输出端传输的高频复合脉冲形成单元输出的电压和高频陡脉冲电流信号，经过模数转换后发送到的FPGA模块35，FPGA模块35将ADC模块36发送来的数据进行计算处理之后发送给ARM模块32，ARM模块32在接收到数据后将数据通过通讯模块31传输给微型电脑用于显示和保存等工作。当ARM模块32通过通讯模块31接收到微型电脑单元的指令的时候，ARM模块32首先对发送来的指令进行判断，产生与之对应的控制信号，并将控制信号发送给FPFA模块35用于产生不同的PWM控制信号以输出不同的脉冲波形。ARM模块32在接收到调节高压直流电源输出电压和最大输出电流指令时，根据控制指令输出相应的信号到DAC模块33，以调节DAC模块33的输出电压，从而调节高压直流电源的输出电压。FPGA模块35通过电平转换模块38和光耦模块39与高频复合陡脉冲形成单元的全桥逆变电路的开关驱动的控制端、放电电路的控制端、内外部负载切换电路的控制端以及多路输出切换单元的控制端进行连接，从而实现对输出波形的控制。FPGA模块35通过光耦模块39和多路输出切换单元进行控制。ARM模块32通过光电转换模块、光纤 和电光转换模块和辅助控制单元27中的ECG模块和脚踏开关进行数据通讯，从而使得操作人员可以通过脚踏开关踩下与否来对该装置进行控制，辅助控制单元中的ECG模块也可以通过调节脉冲的产生时间从而达到降低肌肉收缩的目的。通讯模块31用多芯屏蔽线或者无线通讯的方式和微型电脑单元的电脑主机进行连接，实现控制单元24和微型电脑单元26间的通信；光耦模块39的光耦芯片的输出管脚用导线与复合陡脉冲主电路的固态开关器件的驱动芯片的控制端、真空继电器的控制端，以及多路输出切换电路的真空继电器的控制端进行连接。DAC模块33通过输出不同的模拟电压值实现对高压直流电源模块的输出电压和最大输出电流进行控制，从而达到控制复合陡脉冲肿瘤治疗装置输出的脉冲电压的目的。
举例来说，如图9所示的复合陡脉冲肿瘤治疗装置中的控制单元24中，FPGA模块可以采用Altera公司的cycloneⅢ系列的芯片，ARM可以采用STMICROELECTRONICS公司的STM32F4系列ARM芯片，光耦模块可以采用BROADCOM LIMITED公司的光耦芯片，电平转换模块可以采用Philips Semiconductor公司的电平转换芯片。通讯模块中的串口通讯可以采用ANALOG DEVICES公司的RS232串口芯片，通讯模块中的CAN通讯可以采用ANALOG DEVICES公司的CAN总线收发器，通讯模块中的蓝牙芯片采用高通公司的蓝牙数据传输芯片。应理解，以上具体实例仅用来提供实现本发明的细节用以帮助理解本发明，但不以任何方式构成对本发明的限制。本领域技术人员可以根据实际需要选用具体的模块或芯片来实现本发明的不同实施方式。
图10示出了根据本申请的复合陡脉冲肿瘤治疗装置的多路输出切换单元的一个例子。复合陡脉冲肿瘤治疗装置的多路输出切换单元28采用的真空继电器可以使用与复合脉冲形成主电路中相同型号的继电器。图10中示出了采用12个真空继电器的例子，但应理解，其他数量也是可行的，本申请对此不作限制。12个真空继电器采用如图10所示的连接方式，构成六组真空继电器组。在控制真空继电器时，使得常开触点相连的继电器不能同时处于导通状态，如，继电器1和继电器2、继电器3和继电器4、…、继电器11和继电器12不能同时导通，如果常开触点相连的继电器同时导通，则会导致复合陡脉冲形成主电路短路，对治疗人员和仪器造成损害。如果继电器1和继电器4同时导通，则在脉冲输出接口1和脉冲输出接口2之间输出复合陡脉冲电压，如果继电器1和继电器4、继电器6同时导通，则在电极针1和电极针2之间以及电极针1和电极针3之间输出复合陡脉冲电压。通过不同的继电器的组合，可以得到多种形式的输 出脉冲，从而形成不同的脉冲电场，适用于多种形式的肿瘤组织。
多路输出切换单元28主要包括真空继电器、三极管、去耦电容、磁珠和光耦器件等元件。多路输出切换单元28将全桥逆变电路输出的脉冲电压经过不同的真空继电器输出到不同的外部电极上，从而达到形成不同形式、不同形状的脉冲电场作用区域的目的。多路输出切换系统输出的脉冲可以在肿瘤组织上产生不同的消融范围、区域，从而实现对肿瘤的精准消融。继电器1，继电器2，继电器3，继电器4，继电器5，继电器6，继电器7，继电器8，继电器9，继电器10，继电器11，继电器12等部件构成了多路输出切换电路的主电路。其中，继电器1，继电器3，继电器5，继电器7，继电器9，继电器11的公共端和复合陡脉冲产生主电路的高电位端相连，继电器2，继电器4，继电器6，继电器8，继电器10，继电器12的公共端和复合陡脉冲产生电路的地电位端相连。所有继电器的控制端都通过相应的三极管和光耦隔离芯片后通过导线和所述控制单元相应管脚的连接。在没有收到控制信号的时候，继电器的公共端和常闭触点相互连接；当收到控制信号的时候，继电器的公共端和其常开触点相互连接。通过切换不同的继电器的导通可以组合形成不同的脉冲输出。继电器的控制逻辑可以概括为：第一、常开触点相互连接的一组(两个)继电器不能同时导通；第二、每一排继电器(公共端相互连接的继电器)至少选择导通一个。本申请的多路输出切换单元还采用了插拔自锁插头，其避免了由于操作人员的失误造成的电极针的脱落，提高了系统的可靠性。
微型电脑单元26主要包括微型电脑主机、可触摸液晶显示器、键盘、鼠标等硬件设备、给微型电脑主机供电的适配器，以及配套的软件、驱动等。可触摸液晶显示器通过显示电缆和微型电脑主机进行连接，用于显示治疗信息、治疗进度等信息，并且操作人员也可以通过点击显示在液晶显示器上面的控制软件的相应图标进行信息输入。液晶显示器可使用VGA、DVI、HDMI或者DP等接口和电脑主机进行连接，电脑主机通过USB插口和键盘、鼠标进行连接。电源适配器通过特定的电源接口和电脑主机相连给电脑主机进行供电。除了通过点击触摸液晶屏的输入方式之外，操作人员还可以通过鼠标和键盘进行参数的输入。操作人员可以通过控制软件界面设置参数命令等发送给控制单元24而实现人机交互通信以及对整个装置的控制。微型电脑单元26通过串口、CAN总线或者蓝牙通讯方式与控制单元24的通讯模块连接，多种通讯方式可以确保微型电脑单元26和控制单元24之间数据传输稳定、可靠、及时。
辅助控制单元27设置有ECG模块和脚踏开关控制模块，ECG模块的供电采用本机提供的经过滤波器套件之后的220V、50Hz电源。ECG模块用于复合陡脉冲肿瘤治 疗装置治疗时测量患者的ECG信号，并且在病人ECG信号的R波之后输出控制信号给控制单元24，使控制单元24在该时刻产生控制信号并输出给IGBT(MOSFET器件)或者真空继电器，从而准确控制脉冲电压的输出时机。因为在ECG信号的R波之后，存在不应期，所以在此时输出脉冲可以降低患者在治疗时刻的肌肉收缩程度，从而降低对肌松剂、麻醉剂以及呼吸机等医疗设备的依赖。ECG模块的输出信号通过光纤隔离电路中的第一组光纤隔离电路和控制单元进行连接，这样可以避免ECG模块和控制单元两个模块之间的相互干扰。本申请的脚踏模块通过和光纤隔离电路中的第二组光纤隔离模块和控制模块的相应的控制端相连。在治疗时，当操作人员踩下脚踏开关的时候，脉冲可以输出到患者，如果松开脚踏开关，则脉冲电压不能输出到患者，而仅仅是作用在内部的无感电阻上面。在治疗的过程中操作人员需要临时暂停治疗时，可以通过松开脚踏开关，这时输出脉冲就会作用到内部负载上，断开对患者的输出，从而达到暂停治疗的目的。操作人员通过脚踏开关的踩下与松开来开始和暂停治疗，还可以解放操作人员的双手，简化仪器的操作。操作人员通过脚踏开关来控制脉冲信号的输出，可以使得在紧急情况下快速断开电路，从而避免对患者造成伤害及仪器造成损害。
如图11所示的复合陡脉冲肿瘤治疗装置的光纤隔离单元25包括滤波电路、AC/DC转换电路、电光转换模块和光电转换模块。光纤隔离单元25中的滤波电路从电源单元中的电源滤波器器件中后获取220V、50Hz交流电，滤波器输出的交流电经过AC/DC(交流转直流)电源转换模块之后变为直流电，并被提供到电光转换电路，电光转换电路输出的光信号经过光纤传输给光电转换电路，光电转换电路把接收到的光信号转换成为电信号后输出给控制电路板。这样可以把辅助控制单元的ECG信号和脚踏开关信号经过光纤之后连接到控制单元中，可以避免信号之间的干扰以及隔离保障操作人员的安全。
举例来说，光纤隔离单元的滤波器型号可以为HT402-1-P21-P2，输入电压220V、50Hz，额定电流1A，漏电流约为0.5mA。使用这种滤波器可以有效抑制差模和共模电磁干扰。AC/DC电源模块采用的型号可以是，例如，LH05-10B05，其允许输入电压范围为85～264VAC，输出电压为5V，输出电流能力为1000mA，具有短路保护功能。该模块采用的电光转换芯片为，例如，HFBR-1414TZ，光电转换芯片采用HFBR-2412TZ。电光转换芯片和光电转换芯片采用ST接口，安装牢固、可靠。
另外，本申请的肿瘤治疗装置还配备有完善的自动保护装置，可以检测输出电压、电流的大小，当电压电流超过设定值的时候，可以通过软件或者硬件切断输出，保护人 员和设备的安全。除此之外，本复合陡脉冲肿瘤治疗装置还配备了紧急开关，在平时紧急开关未按下(闭合)的状态，复合陡脉冲肿瘤治疗装置工作正常，在有紧急情况发生的时候，操作人员按下紧急开关，紧急开关断开，复合陡脉冲肿瘤治疗装置降低电压，并且停止对外输出。保障人员和仪器的安全。紧急停止开关在未按下时采用闭合的方式可以避免紧急停止开关的导线的断路情况下的失控现象，充分保障人员和仪器的安全。
本申请的肿瘤治疗装置所产生的脉冲为双极性复合陡脉冲串。通过调节高压直流电源的输出电压可以改变输出的脉冲电压的幅值。通过控制单元改变全桥逆变电路中的开关器件的导通时间、开断频率以及开断次数等参数可以达到改变输出脉冲的脉宽、脉冲间隔、频率及个数等参数。该装置产生的双极性复合陡脉冲幅值在0～3kV连续可调，脉冲宽度100ns～500us连续可调，串内频率最高达2MHz，串外频率0～10Hz可调，上升时间30ns，下降时间30ns。应理解，本申请提供的肿瘤治疗装置输出的具体脉冲参数可以根据实际需要来调节。本申请的装置通过对上述参数的调节实现了对复合陡脉冲肿瘤治疗装置输出能量的精确控制，并且这些参数之间相互独立，互不干扰，因此可以实现良好的治疗效果。
图12示出了本申请的双极性复合陡脉冲肿瘤治疗装置输出的示例性波形的示意图。应理解，该装置输出的波形可以有多种变化，以适应于不同的肿瘤组织，而不限于图示的种类。
图13示出了本申请的双极性复合陡脉冲肿瘤治疗装置的实际输出电压电流波形图的例子，从图中可以看出该双极性波形过冲很小，顶降很小，前言陡峭，非常适合于肿瘤组织的治疗。
第三实施方式
本申请的另一个方面涉及一种生物组织消融方法。利用本申请的不可逆电穿孔设备，使用消融电极通过相应的程序对患者的生物组织进行消融。
图14是根据本申请的生物组织消融方法的示意流程图。
首先，在步骤S101处，确定用于待消融的生物组织的消融参数。消融参数包括消融电极的选择以及消融脉冲参数的确定。对于消融电极来说，例如，对于体表的生物组织，可以选择使用夹板式电极或吸附式电极，对于体内的生物组织，可以选择使用针式电极。针式消融电极可以是一个两极电极针、两个电极针、三个电极针或多个电极针。另外，可以根据被消融生物组织的位置和形状等来选择消融电极的形状和配置方式。消 融电极的配置方式例如包括：消融电极的插入位置、插入深度以及暴露长度等。对于消融脉冲参数来说，可以根据待消融的生物组织的性质来确定例如：脉冲的幅值、脉冲的极性、脉冲宽度、脉冲间隔、脉冲个数以及脉冲串个数等。另外，本领域技术人员可以理解，根据所使用的电极的形状和配置方式、电极间的距离、所采用的消融脉冲的参数以及估计或测量得到的待消融的生物组织的电导率、介电常数，可以计算出由所施加的双极性脉冲在待消融的生物组织中产生的电场强度。消融脉冲的参数的范围参见本说明书上文中的讨论，在此不再进行重复。
之后，在步骤S102处，在不可逆电穿孔设备中设置在步骤S101中确定的用于待消融的生物组织的消融参数，将所确定的消融参数通过用户界面14等提供给控制单元13，以便在控制单元13的控制下，通过所设置的参数的双极性脉冲对生物组织进行消融。
之后，在步骤S103处，启动并开始消融。按照在步骤S101选择的消融电极的类型以及消融电极的配置方式来将消融电极布置到患者的待消融生物组织，并自动地或者通过用户手动地启动不可逆电穿孔消融程序。通过本申请的不可逆电穿孔设备，产生符合所设置脉冲参数的双极性脉冲，并将所产生的双极性脉冲通过电极施加到患者的待消融生物组织，开始消融。
之后，在步骤S104处，判断消融是否完成，即，是否已经将全部待消融生物组织消融。判断消融是否完成的方式可以包括例如：进行消融操作的用户直接通过观察判断消融是否完成，通过显微镜等光学成像设备生成被消融生物组织的图像来判断消融是否完成，通过诸如超声波成像、光学相干断层扫描(OCT)等的医学成像方式生成被消融生物组织的图像来判断消融是否完成，通过测量被消融生物组织的生理参数(例如，生物活性、电导率、介电常数、阻抗等)来判断消融是否完成等。另外，是否完成消融的判断可以由本申请的不可逆电穿孔设备自动做出，或者由用户来手动地做出。
如果在步骤S104处判断已经完成全部待消融生物组织的消融，那么处理进行到步骤S105，结束消融过程，停止输出脉冲信号并可以通过用户界面14等提示用户消融已经结束。
如果在步骤S104处判断尚未完成全部待消融生物组织的消融，那么处理返回到步骤S104之前，等待再次判断消融是否完成。
通过本申请的实施方式，通过将足以在生物组织上形成不可逆穿孔的电场脉冲施加到生物组织，诱导细胞膜出现不可逆电穿孔，从而导致细胞死亡，同时，具有快捷(治 疗施加脉冲时间仅为几十秒，全过程也仅需几分钟)，可控(治疗参数可通过三维建模电场计算获取，治疗范围精确、安全)，可视(治疗过程可在超声/CT/MRI引导下完成，疗效可通过超声/CT/MRI评估)，可选择性(不损伤消融区的胆管，血管及神经等)和非热机理(无热效应，可克服热疗法带来的‘热损伤’与‘热沉’)的优点。
进一步地，通过施加脉冲宽度和在生物组织中产生的电场强度足以在生物组织的细胞膜上产生不可逆电穿孔的双极性脉冲，可以使得细胞膜充分完成不可逆电穿孔过程，并且大大改善脉冲电场在细胞及组织中的分布均匀性，可以突破细胞膜的静息电位、电容效应以及生物组织各向异性带来的内部电场分布不均匀的障碍，实现目标组织区域实现不可逆电穿孔剂量的电场有效覆盖，从而解决了不可逆电穿孔临床应用的消融盲区的问题。
此外，在本申请的一个实施方式中，在步骤S103之后，可以进行步骤S106来测量并判断所产生的脉冲的参数是否与所设置的双极性脉冲的参数相同。如果所产生的脉冲的参数与所设置的双极性脉冲的参数相同，则处理进行到步骤S104，判断已经完成全部待消融生物组织的消融。否则，处理返回到步骤S102，对在不可逆电穿孔设备中设置的消融参数进行相应更改，以使得所产生的脉冲参数与所设置的双极性脉冲的参数相同。
因此，本申请的一个方面涉及一种生物组织消融方法，包括以下步骤：
根据待消融的生物组织来确定待施加的双极性脉冲的参数，使得该双极性脉冲的脉冲宽度和在生物组织中产生的电场强度被确定为足以在生物组织的细胞膜上产生不可逆电穿孔；
产生具有所确定的参数的双极性脉冲；
将所产生的双极性脉冲施加到待消融的生物组织。
优选地，在根据本申请的生物组织消融方法中，每个正极性脉冲和每个负极性脉冲的脉冲宽度分别至少为能够使得生物组织的细胞膜达到稳定充电状态的时间段。
优选地，在根据本申请的生物组织消融方法中，每个正极性脉冲和每个负极性脉冲的脉冲宽度分别至少为生物组织的细胞的充电时间常数的4到5倍。
优选地，在根据本申请的生物组织消融方法中，每个正极性脉冲和每个负极性脉冲的脉冲宽度为5到50微秒。
优选地，在根据本申请的生物组织消融方法中，每个正极性脉冲和每个负极性脉冲的脉冲宽度为5微秒。
优选地，在根据本申请的生物组织消融方法中，足以在生物组织的细胞膜上产生不可逆电穿孔的双极性脉冲在生物组织中产生的电场强度为1.5kV/cm到3kV/cm。
优选地，在根据本申请的生物组织消融方法中，足以在生物组织的细胞膜上产生不可逆电穿孔的双极性脉冲的总脉冲宽度为50微秒到150微秒。
优选地，在根据本申请的生物组织消融方法还包括脉冲测量步骤，在该步骤中，测量所产生的双极性脉冲的参数并且根据所测量的参数来调整产生具有所确定的参数的双极性脉冲的步骤，以产生具有所确定的参数的双极性脉冲。
优选地，在根据本申请的生物组织消融方法中，双极性脉冲为双极性方波脉冲。
优选地，在根据本申请的生物组织消融方法中，重复地产生双极性脉冲并将重复地产生的双极性脉冲施加到生物组织。
第四实施方式
本申请还提供了上述双极性复合陡脉冲肿瘤治疗装置的操作方法的一个例子。
(1)初始化
本申请装置的总电源接通后，微型电脑自动开机，待开机后通过操作人员点击电脑桌面上的配套控制软件的图标，启动控制软件。控制软件首先进行初始化；然后检查通讯连接是否正常，待控制软件通讯连接通过之后，控制软件对复合陡脉冲肿瘤治疗装置进行自检，判断装置是否正常。待自检通过后进行首先进行升压测试；升压测试中，主要检测该装置能否在指定的时间内达到指定的电压范围内；升压测试通过之后，控制软件进行降压测试，如果在指定的时间之内，输出电压可以降低到指定的范围内，则降压测试通过。待降压测试通过之后，则整个复合陡脉冲肿瘤治疗装置的初始化通过。
(2)确定治疗参数
在第(1)步装置的初始化完成之后，操作人员可以进入控制软件的基本信息输入界面(设置的参数包括病人序号、病人姓名、病人性别、病人年龄、手术医师、病例记录、病人特征、肿瘤信息、病变区尺寸、边缘裕度和临床数据等信息)。待数据输入完成后，控制软件会对输入的数据进行参数的合法性检测，判断参数是否在允许的范围之内，如果参数的合法性检测通过，则可以进入到输入治疗参数的下一步，如果参数的合法性检测不能通过，则控制软件提示操作人员重新输入信息，直到操作人员输入正确信息或者按下退出按钮为止。在上面的参数输入完成之后，操作人员首先需要根据患者的特点(身体状况、年龄、性别等)及肿瘤组织的具体情况(种类、恶性程度、尺寸等参 数)制定相应的治疗方案，并确定输出方波脉冲的参数(即脉冲幅值、串内重复频率、脉冲宽度、串内脉冲个数、极性和脉冲群个数)、电极针的暴露长度、电极针的插入位置和深度以及脉冲输出触发模式(固定串外频率、ECG触发模式)；控制软件将输入的参数保存到微型电脑的硬盘中，并将方波脉冲的脉冲幅值、串内频率、脉冲宽度和串内脉冲个数和脉冲群个数等参数经过计算后形成相应的控制指令通过串口、CAN总线或蓝牙通讯方式发送给本申请装置的控制单元。
(3)进行治疗
在第(2)步完成后，操作人员根据第(2)步确定电极针的数量、按照确定的电极针的暴露长度，调节电极针的绝缘外皮的长度，使得电极针的暴露长度符合要求，然后按照设定的电极头的插入位置和深度，操作人员将电极头插入患者的肿瘤组织中。在插入的过程中，需要保证电极针平行插入并且不能短路。待检查电极针插入无误后，操作人员点击控制软件界面的释放预脉冲按钮，复合陡脉冲装置会产生一定参数的脉冲电压作用在系统内部的电阻上，通过对该脉冲的参数进行检测，进一步检测装置是否正常。判断装置正常后，控制软件的提示窗口会提示操作人员可以踩下脚踏开关开始治疗，当操作人员踩下脚踏开关的时候，指定参数的脉冲电压就会输出到患者的肿瘤组织。在治疗过程中，操作人员可以随时松开脚踏开关，以暂停对患者输出脉冲，治疗进度数据仍然会保存在控制软件中，待操作人员重新踩下脚踏开关的时候，复合陡脉冲肿瘤治疗装置继续对患者进行电脉冲治疗，直到治疗完成或操作人员再次松开脚踏开关为止。在治疗过程中如果出现紧急情况，操作人员还可以按下紧急停止按钮，从而暂停输出，以保障治疗人员和装置的安全。
(4)治疗参数统计
该治疗装置还可以随时对治疗过程中的参数进行记录，记录的参数主要包括治疗过程中的电流波形和电压波形，步骤(2)中输入的治疗信息等数据。这些数据都以一定的形式保存在微型电脑的硬盘上。在第(3)步治疗完成后，该控制软件可以生成治疗单，方便操作人员和患者进行查看。操作人员在治疗结束之后也可以对保存的治疗参数进行统计和检查。以便在后期优化治疗流程、参数以及装置。
(5)治疗结束
在第(4)步的所有流程完成后，该控制软件会显示治疗结束并提示操作人员从患者的肿瘤组织中拔出电极针，然后控制软件会发送相应的指令降低高压直流电源的电压，泄放掉储能电容上面残存的电荷，确保人员和仪器安全。这时，操作人员可以关闭 该复合陡脉冲肿瘤治疗装置，以备下一次的使用，治疗过程正式结束。
本申请采用的上述技术方案，主要有以下有益效果：
1.本申请采用的脉冲波形为双极性复合陡脉冲，主要作用于肿瘤细胞的细胞膜，致使细胞膜发生不可逆电穿孔，破坏肿瘤细胞的结构和生存条件，使肿瘤细胞通过自我调控进入凋亡状态，最终杀死肿瘤细胞。本申请不使用化疗药物，能够完全避免化疗方法及电化学疗法中化疗药物的毒副作用,并显著降低复发的风险。
2.采用本申请的复合陡脉冲肿瘤治疗装置及方法，能够精确控制治疗范围，且不影响周围正常组织；具有非热效应优点，疗效不受血流的影响；本装置的治疗时间短，无痛苦，一般几分钟即可完成；电极可根据肿瘤的特征灵活布置；治疗过程及治疗效果可视化，全过程能在医学超声及核磁共振成像等医疗成像设备监控下观察。
3.采用本申请的复合陡脉冲肿瘤治疗装置，对人卵巢腺SKOV3癌细胞、人肺癌细胞L9981和A549、荷瘤BALB/c小鼠进行了实验。结果表明，复合陡脉冲能导致肿瘤细胞发生不可逆电穿孔而死亡，明显抑制了肿瘤的生长、增殖，治疗效果好，并从根本上避免了化疗药物的副作用对患者身体的危害，显示出良好的临床应用前景。
4.采用本申请的复合陡脉冲肿瘤治疗装置，对于治疗过程可能发生的误操作，均具有完备的安全保障措施，可完全保证治疗对象的安全，同时确保治疗装置不受损害。
5.使用本申请的复合陡脉冲肿瘤治疗装置进行治疗，可以降低患者的肌肉收缩，降低治疗期间对肌松剂和麻醉剂的使用量，提高治疗的便利性和降低治疗成本。
6.本申请的装置使用方便，本申请的方法操作简单。
本申请可广泛应用于治疗人体和动物的肿瘤，特别适用于治疗人体的肿瘤。
第五实施方式
本申请还提供了上述双极性复合陡脉冲肿瘤治疗装置的操作方法的另一个例子。
根据该实施方式的双极性复合陡脉冲肿瘤治疗装置的操作流程图如图15所示，按照该操作流程，可以达到安全治疗，快速治疗的目的。下面结合图15具体解释各个步骤。
在步骤S201，进行初始化。肿瘤治疗装置接通电源后，微型电脑开机，高压直流电源等其它系统模块开机。安装在微型电脑上面的系统控制软件启动后自动进行初始化；初始化的内容包括检测上位机控制软件和下位机的控制板之间的通讯连接是否正常，然后进行升压检测，检测仪器能否在指定的时间(例如：30秒)内达到指定的输 出电压范围，例如490～510V，升压检测通过后，进行降压检测，测试仪器能否在指定的时间之内将电压下降到指定的电压范围，例如0～20V，如果降压检测通过，则仪器的初始化自检工作完成。如果其中有任意一项检测没有在规定时间内完成，则提示操作人员需要在专业人士的指导下检查仪器。
在步骤S202，输入治疗信息。在S201的初始化完成之后，操作人员在仪器的控制系统软件的信息界面输入病人信息，例如，病人序号、病人姓名、病人性别和年龄，在治疗信息界面输入治疗信息，包括手术时间、手术医师、病例记录，在临床数据栏输入病人特征、肿瘤信息。在病变区输入肿瘤的长、宽、厚尺寸以及边缘裕度参数，确定治疗区域的大小。控制软件自动判断输入的参数是否正确，如果这些输入的参数都是正确的，则可以点击进入下一步参数设置阶段。
在步骤S203，输入脉冲参数。在S202的治疗信息输入完成之后，操作人员可以在液晶显示屏中设置参数，设置的参数包括脉冲输出的触发类型(串外频率模式还是ECG同步模式)、脉冲类型(双极性还是单极性)、串内频率、单脉冲宽度、死区时间、串内脉冲个数、总高电平时间，以及电极针数量和电极针的分布方式。待输入完成之后，控制软件进一步对这些参数进行合法性检测，在参数检测合法之后，控制软件会自动将输入的脉冲参数转换成为相应的控制指令发送到控制系统，准备进行治疗。
在步骤S204，判断输出参数是否在允许范围。在S203完成后，操作者点击控制软件的“释放预脉冲”按钮使装置释放出预脉冲，系统根据预脉冲的参数判断装置是否正常，如果仪器的输出参数在允许范围内，表明装置正常，则系统提示操作人员可以进行治疗，通过第一或第二实施方式的装置中的微型电脑系统将确定的方波脉冲的脉冲幅值、重复频率、脉冲宽度和脉冲个数等参数经过计算后发送给控制系统，控制系统进入治疗前的准备阶段。如果在S204判断输出参数不在允许范围，则操作返回S203重新输入脉冲参数。
在步骤S205，判断紧急开关是否按下。在治疗过程中如果按下紧急开关，紧急停止信号直接被发送给高压直流电源，使得高压直流电源的输出电压为零，并且脉冲输出也停止；直到排除错误之后，松开紧急开关后，治疗继续进行，直到指定个数的脉冲串输出完成后，治疗过程的脉冲输出阶段才完成。紧急开关直接接到高压直流电源的控制端是可以提高装置对紧急事件的反应速度，可以有效地保护患者和装置的安全。
在S206，判断脚踏开关是否踩下。在S204完成后，按照计划好的电极针的插入位置和深度，操作人员将电极针平行地插入到插入患者的肿瘤组织中，并且确定电极针没 有短路，然后点击控制软件上的“开始治疗”按钮，在紧急开关没有被按下的情况下，在步骤S207，装置开始输出脉冲。此时脉冲仅仅作用在内部的无感电阻上。如果踩下脚踏开关，则脉冲开始输出到患者的肿瘤组织上，并且控制软件对输出到肿瘤组织的脉冲个数进行计数。如果在治疗过程中，脚踏开关松开，则脚踏开关松开的控制信号首先传输到光纤隔离模块，该信号通过电光转换之后，转换成为光信号传递给光纤隔离模块中的光电转换芯片，电光转换芯片将该光信号转换成为电信号之后输出到控制模块，控制单元对该脚踏开关信号进行处理后，控制相应的IGBT(或者MOSFET)和真空继电器导通或者关断，从而使得复合陡脉冲输出暂停。同时，输出到肿瘤组织的计数也暂停，并将该信息传送给微型电脑单元用于显示和记录。此时，如果踩下脚踏开关，则对肿瘤组织输出复合陡脉冲继续进行治疗，并且恢复对输出脉冲的计数。
在步骤S208，判断输出脉冲个数是否达到预设值，如果未达到，则返回步骤S205；如果达到，则在S209治疗结束，液晶显示屏提示“治疗结束”。微型电脑自动对治疗过程中的关键数据比如电压数据、电流数据以及治疗波形等数据进行保存，并且发送降压指令使得高压直流电源的输出为零，同时使得放电回路导通，使得储能电容上面的电荷释放完毕，储能电容电压降为零，同时发送关机指令使得相关电路复位，并且提示操作人员从患者的肿瘤组织中拔出电极针。经过上述的操作流程后，治疗结束。
本实施例所产生的方波脉冲为双极性复合陡脉冲。调节方波脉冲输出电压是通过控制单元的DAC模块来控制高压电源的输出电压来实现的，通过微型电脑单元和控制单元产生不同组合的控制信号，可以控制输出脉冲波形的形式。双极性方波脉冲的幅值在0-3kV可调；方波脉冲脉宽在100ns-500μs可调；方波脉冲的串内频率最高可达2MHz，方波脉冲的串内单脉冲宽度最小为100ns。方波脉冲的串外频率在0-10Hz可调。本申请装置正是通过上述参数的灵活调节调节实现对输出方波脉冲能量的精确控制。本申请装置配备有强大的软件系统，除了能对输出的各个参数进行独立准确调节外，还可以对治疗过程中的参数和数据进行保存，方便治疗后对治疗效果进行评估以及对治疗流程进行改进。同时该装置还配备了完善的保护装置，可以完全保证患者和装置的安全。本装置非常适合于人体的肿瘤组织的治疗。
实验结果
针对现有技术的单极性不可逆电穿孔设备和根据本申请的实施方式的双极性不可逆电穿孔设备，本申请的发明人进行了以下验证实验。
发明人以兔肝脏组织作为生物组织来进行研究，通过夹板电极对兔肝脏组织施加电脉冲。通过研究表明，兔肝脏组织的细胞的充电时间常数约为1μs。因此，所施加的传统单极性脉冲的在兔肝脏组织中产生的电场强度为1.5kV/cm，脉冲宽度为100μs，脉冲的重复次数为90次，而所施加的双极性脉冲中，正极性和负极性的脉冲在兔肝脏组织中产生的电场强度为2kV/cm，脉冲宽度为充电时间常数的五倍(即，5μs)，每个周期内正极性和负极性的脉冲分别施加10次，重复90个周期。之后，用显微镜放大被消融的生物组织，观察是否存在残留的未被消融的肝细胞。
图16是以上实验的结果，其中图16A是施加传统单极性脉冲的结果的放大图，图16B是施加根据本申请的实施方式的双极性脉冲的结果的放大图。通过比较可以看出，在施加传统单极性脉冲的情况下，肝脏组织的胆管周边仍存在完整肝细胞，消融不彻底并且存在消融盲区，而在施加根据本申请的实施方式的双极性脉冲的情况下，肝脏组织的胆管周边的肝细胞全部死亡，消融较为彻底并且不存在消融盲区。
因此，通过该比较，可以看到，根据本申请的实施方式的不可逆电穿孔设备以及生物组织消融方法可以减小消融盲区，提高消融效果。
另外，申请人比较了在采用双极性脉冲的情况下，当脉冲宽度小于生物组织的细胞的充电时间常数的4到5倍时和等于该时间段时的消融效果。
仍然以细胞的充电时间常数约为1μs的兔肝脏组织为例。所施加的第一种双极性脉冲中，正极性和负极性的脉冲在兔肝脏组织中产生的电场强度为2kV/cm，脉冲宽度为充电时间常数的1倍(即，1μs)，每个周期内正极性和负极性的脉冲分别施加50次，重复90个周期。另外，在所施加的第二种双极性脉冲中，正极性和负极性的脉冲在兔肝脏组织中产生的电场强度为2kV/cm，脉冲宽度为充电时间常数的5倍(即，5μs)，每个周期内正极性和负极性的脉冲分别施加10次，重复90个周期。之后，用显微镜放大被消融的生物组织，观察是否存在残留的未被消融的肝细胞。
图17是以上实验的结果，其中图17A是施加脉冲宽度为1μs的双极性脉冲的结果的放大图，图17B是施加脉冲宽度为5μs的双极性脉冲的结果的放大图。通过比较可以看出，在施加脉冲宽度为1μs的双极性脉冲的情况下，未被消融的区域较多，消融不彻底并且存在消融盲区，而在施加脉冲宽度为5μs的双极性脉冲的情况下，未被消融的区域很少，消融较为彻底并且不存在消融盲区。
因此，通过该比较，根据本申请的实施方式的不可逆电穿孔设备以及生物组织消融方法通过将双极性脉冲的脉冲宽度设置为足以在生物组织的细胞膜上产生不可逆电穿 孔，例如，大于或等于生物组织的细胞的充电时间常数的4到5倍，可以减小消融盲区，提高消融效果。
总结
本申请提出了一种不可逆电穿孔装置，其包括：脉冲形成单元，其被配置为产生双极性脉冲；和电极，其被配置为从脉冲形成单元接收双极性脉冲并适于将双极性脉冲施加到生物组织。其中，双极性脉冲的脉冲宽度和在生物组织中产生的电场强度被设置为足以在生物组织的细胞膜上产生不可逆电穿孔。
本申请的另一个方面涉及一种生物组织消融方法，包括以下步骤：根据待消融的生物组织来确定待施加的双极性脉冲，该双极性脉冲的脉冲宽度和在生物组织中产生的电场强度被设置为足以在生物组织的细胞膜上产生不可逆电穿孔；产生具有所设置的参数的双极性脉冲；将所产生的双极性脉冲施加到待消融的生物组织。
根据本申请的实施方式的双极性脉冲可以有效地增加消融电场的均匀性，并且双极性脉冲的脉冲宽度和在生物组织中产生的电场强度足以在生物组织的细胞膜上产生不可逆电穿孔，从而减小消融盲区。
本说明书中“实施例”或类似表达方式的引用是指结合该实施例所述的特定特征、结构、或特性系包括在本公开的至少一具体实施例中。因此，在本说明书中，“在本公开的实施例中”及类似表达方式的用语的出现未必指相同的实施例。
本领域技术人员应当知道，本公开被实施为一系统、装置、方法或作为计算机程序产品的计算机可读媒体。因此，本公开可以实施为各种形式，例如完全的硬件实施例、完全的软件实施例(包括固件、常驻软件、微程序代码等)，或者也可实施为软件与硬件的实施形式，在以下会被称为“电路”、“模块”或“系统”。此外，本公开也可以任何有形的媒体形式实施为计算机程序产品，其具有计算机可使用程序代码存储于其上。
本公开的相关叙述参照根据本公开具体实施例的系统、装置、方法及计算机程序产品的流程图和/或方块图进行了说明。可以理解每一个流程图和/或方块图中的每一个方块，以及流程图和/或方块图中方块的任何组合，可以使用计算机程序指令来实施。这些计算机程序指令可供通用型计算机或特殊计算机的处理器或其它可编程数据处理装置所组成的机器来执行，而指令经由计算机或其它可编程数据处理装置处理以便实施流程图和/或方块图中所说明的功能或操作。
在附图中示出了根据本公开各种实施例的系统、装置、方法及计算机程序产品可实施的架构、功能及操作的流程图及方块图。应当注意，在某些其它的实施例中，方块所述的操作可以不按图中所示的顺序进行。举例来说，两个图示相连接的方块事实上也可以同时执行，或根据所涉及的功能在某些情况下也可以按图标相反的顺序执行。此外还需注意，每个方块图和/或流程图的方块，以及方块图和/或流程图中方块的组合，可藉由基于专用硬件的系统来实施，或者藉由专用硬件与计算机指令的组合，来执行特定的功能或操作。

Claims (30)

  1. 一种不可逆电穿孔设备，其包括：
    脉冲形成装置，其被配置为产生双极性脉冲；和
    电极，其被配置为从脉冲形成装置接收双极性脉冲并适于将双极性脉冲施加到生物组织，
    其中，双极性脉冲的总脉冲宽度和在生物组织中产生的电场强度被设置为足以在生物组织的细胞膜上产生不可逆电穿孔。
  2. 根据权利要求1所述的不可逆电穿孔设备，其中，所述双极性脉冲是正负极性的脉冲交替的，并且脉冲之间有零电平的脉冲间隔。
  3. 根据权利要求2所述的不可逆电穿孔设备，其中，所述双极性脉冲是单个正极性脉冲和单个负极性脉冲交替的，并且每两个脉冲之间有零电平的脉冲间隔。
  4. 根据权利要求2所述的不可逆电穿孔设备，其中，所述双极性脉冲是多个正极性脉冲和多个负极性脉冲交替的，并且每两个脉冲之间有零电平的脉冲间隔。
  5. 根据权利要求1所述的不可逆电穿孔设备，其中，每个正极性脉冲和每个负极性脉冲的脉冲宽度分别至少为能够使得生物组织的细胞膜达到稳定充电状态的时间段。
  6. 根据权利要求1所述的不可逆电穿孔设备，其中，每个正极性脉冲和每个负极性脉冲的脉冲宽度分别至少为生物组织的细胞的充电时间常数的4到5倍。
  7. 根据权利要求1所述的不可逆电穿孔设备，其中，每个正极性脉冲和每个负极性脉冲的脉冲宽度为5到50微秒。
  8. 根据权利要求7所述的不可逆电穿孔设备，其中，每个正极性脉冲和每个负极性脉冲的脉冲宽度为5微秒。
  9. 根据权利要求1所述的不可逆电穿孔设备，其中，足以在生物组织的细胞膜 上产生不可逆电穿孔的双极性脉冲在生物组织中产生的电场强度为1.5kV/cm到3kV/cm。
  10. 根据权利要求1所述的不可逆电穿孔设备，其中，足以在生物组织的细胞膜上产生不可逆电穿孔的双极性脉冲的总脉冲宽度为50微秒到150微秒。
  11. 根据权利要求1所述的不可逆电穿孔设备，还包括脉冲测量装置，其被配置为测量由脉冲形成装置产生的双极性脉冲的参数，并且所述脉冲消融设备根据由脉冲测量装置所测量的参数来控制脉冲形成装置，以产生具有期望参数的双极性脉冲。
  12. 根据权利要求1所述的不可逆电穿孔设备，其中，双极性脉冲为双极性方波脉冲。
  13. 根据权利要求1-12所述的不可逆电穿孔设备，其中，脉冲形成装置重复产生双极性脉冲并通过电极将重复产生的双极性脉冲施加到生物组织。
  14. 一种不可逆电穿孔设备的操作方法，其包括：
    通过脉冲形成装置产生双极性脉冲；和
    通过电极将双极性脉冲施加到生物组织，所述电极从所述脉冲形成装置接收双极性脉冲，
    其中，双极性脉冲的总脉冲宽度和在生物组织中产生的电场强度被设置为足以在生物组织的细胞膜上产生不可逆电穿孔。
  15. 根据权利要求14所述的方法，其中，通过脉冲形成装置产生正负极性的脉冲交替的双极性脉冲，并且脉冲之间有零电平的脉冲间隔。
  16. 根据权利要求15所述的方法，其中，通过脉冲形成装置产生单个正极性脉冲和单个负极性脉冲交替的双极性脉冲，并且每两个脉冲之间有零电平的脉冲间隔。
  17. 根据权利要求15所述的方法，其中，通过脉冲形成装置产生多个正极性脉冲 和多个负极性脉冲交替的双极性脉冲，并且每两个脉冲之间有零电平的脉冲间隔。
  18. 根据权利要求14所述的方法，其中，每个正极性脉冲和每个负极性脉冲的脉冲宽度分别至少为能够使得生物组织的细胞膜达到稳定充电状态的时间段。
  19. 根据权利要求14所述的方法，其中，每个正极性脉冲和每个负极性脉冲的脉冲宽度分别至少为生物组织的细胞的充电时间常数的4到5倍。
  20. 根据权利要求14所述的方法，其中，每个正极性脉冲和每个负极性脉冲的脉冲宽度为5到50微秒。
  21. 根据权利要求20所述的方法，其中，每个正极性脉冲和每个负极性脉冲的脉冲宽度为5微秒。
  22. 根据权利要求14所述的方法，其中，足以在生物组织的细胞膜上产生不可逆电穿孔的双极性脉冲在生物组织中产生的电场强度为1.5kV/cm到3kV/cm。
  23. 根据权利要求14所述的方法，其中，足以在生物组织的细胞膜上产生不可逆电穿孔的双极性脉冲的总脉冲宽度为50微秒到150微秒。
  24. 根据权利要求14所述的方法，还包括通过脉冲测量装置来测量由脉冲形成装置产生的双极性脉冲的参数，并且根据由脉冲测量装置所测量的参数来控制脉冲形成装置，以产生具有期望参数的双极性脉冲。
  25. 根据权利要求14所述的方法，其中，双极性脉冲为双极性方波脉冲。
  26. 根据权利要求14-25所述的方法，其中，通过脉冲形成装置重复产生双极性脉冲并通过电极将重复产生的双极性脉冲施加到生物组织。
  27. 一种肿瘤治疗装置，包括：
    电源单元，用于为所述装置供电；
    脉冲形成单元，包括全桥逆变电路，所述脉冲形成单元输出脉冲电流信号；
    测量单元，配置为测量所述由脉冲形成单元输出的脉冲的参数，并提供给控制单元；
    控制单元，根据所述测量单元提供的所述参数和用户输入参数来控制所述脉冲形成单元，通过改变脉冲形成单元中的全桥逆变电路中的开关器件的导通时间、开断频率以及开断次数等来改变输出脉冲的极性、脉宽、脉冲间隔、频率及脉冲个数。
  28. 如权利要求27所述的装置，还包括多路输出切换单元，将所述全桥逆变电路输出的脉冲电压经过不同的真空继电器输出到不同的外部电极上。
  29. 如权利要求27所述的装置，还包括脚踏板，设置为当脚踏板被松开时，暂停对患者输出脉冲，当脚踏板被踩下时，继续输出脉冲。
  30. 如权利要求27所述的装置，其中，当测量单元测得的脉冲个数达到预定个数时，所述控制单元使所述脉冲形成单元停止。
PCT/CN2017/092591 2016-07-12 2017-07-12 不可逆电穿孔设备及其操作方法 WO2018010659A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201780007234.0A CN109661210B (zh) 2016-07-12 2017-07-12 不可逆电穿孔设备

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201610545618.5A CN106388932B (zh) 2016-07-12 2016-07-12 不可逆电穿孔设备
CN201610545618.5 2016-07-12

Publications (1)

Publication Number Publication Date
WO2018010659A1 true WO2018010659A1 (zh) 2018-01-18

Family

ID=58006917

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2017/092591 WO2018010659A1 (zh) 2016-07-12 2017-07-12 不可逆电穿孔设备及其操作方法

Country Status (2)

Country Link
CN (2) CN106388932B (zh)
WO (1) WO2018010659A1 (zh)

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112294425A (zh) * 2019-07-30 2021-02-02 上海睿刀医疗科技有限公司 用于治疗肿瘤的电脉冲设备
CN112294424A (zh) * 2019-07-30 2021-02-02 上海睿刀医疗科技有限公司 用于治疗肿瘤的电脉冲设备
CN112568989A (zh) * 2019-12-03 2021-03-30 伯恩森斯韦伯斯特(以色列)有限责任公司 用于不可逆电穿孔的脉冲发生器
CN113054960A (zh) * 2021-03-29 2021-06-29 杭州维那泰克医疗科技有限责任公司 电信号输出设备、系统、输出方法及存储介质
CN113180818A (zh) * 2021-05-06 2021-07-30 上海玄宇医疗器械有限公司 一种高压电脉冲消融与电生理记录仪协同工作的装置
CN113346876A (zh) * 2021-06-11 2021-09-03 成都飞云科技有限公司 一种脉冲发生装置及脉冲控制方法
CN113616312A (zh) * 2021-08-11 2021-11-09 杭州维纳安可医疗科技有限责任公司 协同脉冲发生装置、系统及发生方法
CN113842200A (zh) * 2020-11-30 2021-12-28 杭州德诺电生理医疗科技有限公司 一种脉冲消融仪及其控制方法
CN114041873A (zh) * 2021-11-10 2022-02-15 上海玄宇医疗器械有限公司 一种不对称波形的高频不可逆电穿孔脉冲消融装置
CN114209413A (zh) * 2021-12-09 2022-03-22 杭州睿笛生物科技有限公司 多级可控的复合脉冲发生控制系统
CN114259296A (zh) * 2021-12-23 2022-04-01 心航路医学科技(广州)有限公司 一种脉冲电场发生器
CN114271931A (zh) * 2021-12-23 2022-04-05 心航路医学科技(广州)有限公司 一种脉冲消融系统
CN114469308A (zh) * 2021-12-23 2022-05-13 心航路医学科技(广州)有限公司 一种脉冲电场消融系统
CN114533249A (zh) * 2022-02-11 2022-05-27 重庆千恩医疗科技有限公司 一种自适应随动式脉冲消融系统和方法
CN114948185A (zh) * 2022-06-09 2022-08-30 北京三春晖医疗器械有限公司 一种脉冲控制电路及脉冲消融装置
EP4011307A4 (en) * 2019-08-06 2022-10-12 Shenzhen Neumann Technology Co., Ltd. REAL-TIME PULSE MONITORING CIRCUIT AND TUMOR TREATMENT APPARATUS
US11497541B2 (en) 2019-11-20 2022-11-15 Boston Scientific Scimed, Inc. Systems, apparatuses, and methods for protecting electronic components from high power noise induced by high voltage pulses
WO2023009586A1 (en) * 2021-07-27 2023-02-02 Acutus Medical, Inc. Energy delivery systems with lesion index
US11589921B2 (en) 2016-01-05 2023-02-28 Boston Scientific Scimed, Inc. Systems, apparatuses and methods for delivery of ablative energy to tissue
US11684408B2 (en) 2019-11-20 2023-06-27 Boston Scientific Scimed, Inc. Systems, apparatuses, and methods for protecting electronic components from high power noise induced by high voltage pulses
US11786300B2 (en) 2021-04-07 2023-10-17 Btl Medical Technologies S.R.O. Pulsed field ablation device and method
US11896298B2 (en) 2021-07-06 2024-02-13 Btl Medical Development A.S. Pulsed field ablation device and method
US11938317B2 (en) 2017-12-26 2024-03-26 Galvanize Therapeutics, Inc. Optimization of energy delivery for various applications
US12076067B2 (en) 2022-10-05 2024-09-03 Btl Medical Development A.S. Pulsed field ablation device and method
US12076071B2 (en) 2020-08-14 2024-09-03 Kardium Inc. Systems and methods for treating tissue with pulsed field ablation

Families Citing this family (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106388932B (zh) * 2016-07-12 2017-10-10 上海睿刀医疗科技有限公司 不可逆电穿孔设备
CN106388933B (zh) * 2016-09-14 2017-10-10 上海睿刀医疗科技有限公司 用于不可逆电穿孔设备的电极
CN108186108A (zh) * 2017-10-12 2018-06-22 天津市鹰泰利安康医疗科技有限责任公司 多极双向高压陡脉冲放电系统及放电方法
CN109157280A (zh) * 2018-08-10 2019-01-08 重庆大学 不可逆电穿孔组织消融效果动态实时评估设备
CN109171947A (zh) * 2018-09-17 2019-01-11 重庆大学 靶向消融细胞装置、方法、介质及电子设备
US11903638B2 (en) * 2019-12-11 2024-02-20 Biosense Webster (Israel) Ltd. Regulating delivery of irreversible electroporation pulses according to transferred energy
WO2021114219A1 (zh) * 2019-12-13 2021-06-17 天津市鹰泰利安康医疗科技有限责任公司 一种高频双极性不可恢复电穿孔系统
CN110946642A (zh) * 2019-12-13 2020-04-03 天津市鹰泰利安康医疗科技有限责任公司 一种高频双极性不可恢复电穿孔系统
CN113317864A (zh) * 2020-02-28 2021-08-31 苏州博思得电气有限公司 一种细胞不可逆电穿孔装置以及细胞不可逆电穿孔方法
CN112451086A (zh) * 2020-12-09 2021-03-09 郑州大学 基于直流偏置型脉冲的靶向细胞消融系统
CN112869872B (zh) * 2021-01-11 2022-09-16 杭州维纳安可医疗科技有限责任公司 消融装置及其控制方法、装置、系统、存储介质
CN113229931A (zh) * 2021-06-18 2021-08-10 杭州维纳安可医疗科技有限责任公司 电极针、消融设备及消融方法、装置、存储介质
CN114259291A (zh) * 2021-12-23 2022-04-01 心航路医学科技(广州)有限公司 一种脉冲消融系统的控制方法及装置
CN114271930B (zh) * 2021-12-27 2022-07-29 天津市鹰泰利安康医疗科技有限责任公司 用于肿瘤治疗的高频双向脉冲治疗系统
CN114246664B (zh) * 2021-12-27 2022-08-23 天津市鹰泰利安康医疗科技有限责任公司 高频双极性肿瘤治疗系统
CN114305659B (zh) * 2021-12-27 2022-07-26 天津市鹰泰利安康医疗科技有限责任公司 高频双极性不可恢复电穿孔系统
CN114366280B (zh) * 2022-03-22 2022-11-08 上海睿刀医疗科技有限公司 脉冲处理装置、脉冲处理方法、电子设备和存储介质
CN115040233B (zh) * 2022-05-19 2024-06-18 杭州维纳安可医疗科技有限责任公司 不可逆电穿孔组织消融系统及其控制方法
CN115005961B (zh) * 2022-07-07 2023-05-12 上海普实医疗器械股份有限公司 心脏脉冲电场消融系统
CN117655440B (zh) * 2023-09-22 2024-09-20 新疆大学 双极性高低压复合脉冲电源
CN117883178A (zh) * 2024-01-17 2024-04-16 天津市鹰泰利安康医疗科技有限责任公司 一种基于不可逆电穿孔的泡沫细胞消融装置及应用

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101495055A (zh) * 2006-01-03 2009-07-29 安乔动力学公司 使用电穿孔治疗心房纤维性颤动的系统和方法
US20090281477A1 (en) * 2008-05-09 2009-11-12 Angiodynamics, Inc. Electroporation device and method
US20100023004A1 (en) * 2008-07-28 2010-01-28 David Francischelli Systems and methods for cardiac tissue electroporation ablation
CN101972168A (zh) * 2010-11-16 2011-02-16 重庆大学 不可逆电穿孔治疗肿瘤的装置及方法
US20120095459A1 (en) * 2010-10-13 2012-04-19 Peter Callas System and Method for Electrically Ablating Tissue of a Patient
CN104684500A (zh) * 2012-09-06 2015-06-03 麦德托尼克消融前沿有限公司 用于消融和电穿孔组织细胞的设备
US20160184003A1 (en) * 2013-08-06 2016-06-30 Memorial Sloan Kettering Cancer Center System, method and computer-accessible medium for in-vivo tissue ablation and/or damage
CN106388932A (zh) * 2016-07-12 2017-02-15 上海睿刀医疗科技有限公司 不可逆电穿孔设备

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB0411610D0 (en) * 2004-05-24 2004-06-30 Bioinduction Ltd Electrotherapy apparatus
US7655004B2 (en) * 2007-02-15 2010-02-02 Ethicon Endo-Surgery, Inc. Electroporation ablation apparatus, system, and method
WO2012065177A2 (en) * 2010-11-12 2012-05-18 Estech, Inc (Endoscopic Technologies, Inc) Stabilized ablation systems and methods
US9233241B2 (en) * 2011-02-28 2016-01-12 Ethicon Endo-Surgery, Inc. Electrical ablation devices and methods
US9439722B2 (en) * 2012-05-09 2016-09-13 Biosense Webster (Israel) Ltd. Ablation targeting nerves in or near the inferior vena cava and/or abdominal aorta for treatment of hypertension
EP3495018B1 (en) * 2014-05-07 2023-09-06 Farapulse, Inc. Apparatus for selective tissue ablation

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101495055A (zh) * 2006-01-03 2009-07-29 安乔动力学公司 使用电穿孔治疗心房纤维性颤动的系统和方法
US20090281477A1 (en) * 2008-05-09 2009-11-12 Angiodynamics, Inc. Electroporation device and method
US20100023004A1 (en) * 2008-07-28 2010-01-28 David Francischelli Systems and methods for cardiac tissue electroporation ablation
US20120095459A1 (en) * 2010-10-13 2012-04-19 Peter Callas System and Method for Electrically Ablating Tissue of a Patient
CN101972168A (zh) * 2010-11-16 2011-02-16 重庆大学 不可逆电穿孔治疗肿瘤的装置及方法
CN104684500A (zh) * 2012-09-06 2015-06-03 麦德托尼克消融前沿有限公司 用于消融和电穿孔组织细胞的设备
US20160184003A1 (en) * 2013-08-06 2016-06-30 Memorial Sloan Kettering Cancer Center System, method and computer-accessible medium for in-vivo tissue ablation and/or damage
CN106388932A (zh) * 2016-07-12 2017-02-15 上海睿刀医疗科技有限公司 不可逆电穿孔设备

Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11589921B2 (en) 2016-01-05 2023-02-28 Boston Scientific Scimed, Inc. Systems, apparatuses and methods for delivery of ablative energy to tissue
US11938317B2 (en) 2017-12-26 2024-03-26 Galvanize Therapeutics, Inc. Optimization of energy delivery for various applications
CN112294425A (zh) * 2019-07-30 2021-02-02 上海睿刀医疗科技有限公司 用于治疗肿瘤的电脉冲设备
WO2021018216A1 (zh) * 2019-07-30 2021-02-04 上海睿刀医疗科技有限公司 用于治疗肿瘤的电脉冲设备
CN112294424A (zh) * 2019-07-30 2021-02-02 上海睿刀医疗科技有限公司 用于治疗肿瘤的电脉冲设备
EP4011307A4 (en) * 2019-08-06 2022-10-12 Shenzhen Neumann Technology Co., Ltd. REAL-TIME PULSE MONITORING CIRCUIT AND TUMOR TREATMENT APPARATUS
US11931090B2 (en) 2019-11-20 2024-03-19 Boston Scientific Scimed, Inc. Systems, apparatuses, and methods for protecting electronic components from high power noise induced by high voltage pulses
US11684408B2 (en) 2019-11-20 2023-06-27 Boston Scientific Scimed, Inc. Systems, apparatuses, and methods for protecting electronic components from high power noise induced by high voltage pulses
US11497541B2 (en) 2019-11-20 2022-11-15 Boston Scientific Scimed, Inc. Systems, apparatuses, and methods for protecting electronic components from high power noise induced by high voltage pulses
CN112568989A (zh) * 2019-12-03 2021-03-30 伯恩森斯韦伯斯特(以色列)有限责任公司 用于不可逆电穿孔的脉冲发生器
US12076071B2 (en) 2020-08-14 2024-09-03 Kardium Inc. Systems and methods for treating tissue with pulsed field ablation
CN113842200A (zh) * 2020-11-30 2021-12-28 杭州德诺电生理医疗科技有限公司 一种脉冲消融仪及其控制方法
WO2022111735A1 (zh) * 2020-11-30 2022-06-02 杭州德诺电生理医疗科技有限公司 脉冲消融仪及其控制方法、装置、电子设备及介质
CN113054960A (zh) * 2021-03-29 2021-06-29 杭州维那泰克医疗科技有限责任公司 电信号输出设备、系统、输出方法及存储介质
US11786300B2 (en) 2021-04-07 2023-10-17 Btl Medical Technologies S.R.O. Pulsed field ablation device and method
US11832785B2 (en) 2021-04-07 2023-12-05 Btl Medical Development A.S. Pulsed field ablation device and method
CN113180818A (zh) * 2021-05-06 2021-07-30 上海玄宇医疗器械有限公司 一种高压电脉冲消融与电生理记录仪协同工作的装置
CN113180818B (zh) * 2021-05-06 2024-03-15 上海玄宇医疗器械有限公司 一种高压电脉冲消融与电生理记录仪协同工作的装置
CN113346876A (zh) * 2021-06-11 2021-09-03 成都飞云科技有限公司 一种脉冲发生装置及脉冲控制方法
WO2022258034A1 (zh) * 2021-06-11 2022-12-15 成都飞云科技有限公司 一种脉冲发生装置及脉冲控制方法
US11896298B2 (en) 2021-07-06 2024-02-13 Btl Medical Development A.S. Pulsed field ablation device and method
WO2023009586A1 (en) * 2021-07-27 2023-02-02 Acutus Medical, Inc. Energy delivery systems with lesion index
CN113616312A (zh) * 2021-08-11 2021-11-09 杭州维纳安可医疗科技有限责任公司 协同脉冲发生装置、系统及发生方法
CN114041873A (zh) * 2021-11-10 2022-02-15 上海玄宇医疗器械有限公司 一种不对称波形的高频不可逆电穿孔脉冲消融装置
CN114041873B (zh) * 2021-11-10 2023-12-26 上海玄宇医疗器械有限公司 一种不对称波形的高频不可逆电穿孔脉冲消融装置
CN114209413B (zh) * 2021-12-09 2024-09-03 杭州睿笛生物科技有限公司 多级可控的复合脉冲发生控制系统
CN114209413A (zh) * 2021-12-09 2022-03-22 杭州睿笛生物科技有限公司 多级可控的复合脉冲发生控制系统
CN114469308A (zh) * 2021-12-23 2022-05-13 心航路医学科技(广州)有限公司 一种脉冲电场消融系统
CN114271931A (zh) * 2021-12-23 2022-04-05 心航路医学科技(广州)有限公司 一种脉冲消融系统
CN114259296A (zh) * 2021-12-23 2022-04-01 心航路医学科技(广州)有限公司 一种脉冲电场发生器
CN114271931B (zh) * 2021-12-23 2023-09-12 心航路医学科技(广州)有限公司 一种脉冲消融系统
CN114533249A (zh) * 2022-02-11 2022-05-27 重庆千恩医疗科技有限公司 一种自适应随动式脉冲消融系统和方法
CN114533249B (zh) * 2022-02-11 2024-01-16 重庆千恩医疗科技有限公司 一种自适应随动式脉冲消融系统
CN114948185A (zh) * 2022-06-09 2022-08-30 北京三春晖医疗器械有限公司 一种脉冲控制电路及脉冲消融装置
US12076067B2 (en) 2022-10-05 2024-09-03 Btl Medical Development A.S. Pulsed field ablation device and method

Also Published As

Publication number Publication date
CN109661210A (zh) 2019-04-19
CN106388932B (zh) 2017-10-10
CN109661210B (zh) 2021-08-24
CN106388932A (zh) 2017-02-15

Similar Documents

Publication Publication Date Title
WO2018010659A1 (zh) 不可逆电穿孔设备及其操作方法
CN110382040B (zh) 堆叠电位电穿孔
Gerhard Surgical Electrotechnology: Quo Vadis?
EP3937812A1 (en) Waveform generator and control for selective cell ablation
JP2018075424A (ja) 神経筋刺激を最小にするための電気外科手術用ジェネレータ
CN109394334A (zh) 一种高压双极陡脉冲组肿瘤治疗装置及系统
KR101562998B1 (ko) 비만개선을 위한 전자 알에프와 고강도 집속형 초음파를 이용한 지방융해 의료장치
US20160228178A1 (en) Radio frequency treatment apparatus
KR20140010374A (ko) 피부 미용 치료를 위한 방법과 장치
JP2022512003A (ja) 非熱エネルギーの適用による皮膚腺の治療
US11351368B2 (en) Megahertz compression of nanosecond pulse bursts
EP3753516A1 (en) Electroporation device
WO2019223636A1 (zh) 一种冷等离子体射流针灸装置
US20190381310A1 (en) Systems and methods for delivering neuroregenerative therapy
WO2021108292A1 (en) Methods for controlling treatment volumes, thermal gradients, muscle stimulation, and immune responses in pulsed electric field treatments
WO2023078338A1 (zh) 消融系统
JP2022547233A (ja) エレクトロポレーション装置および方法
AU2018354250A1 (en) Systems and methods for delivering neuroregenerative therapy
CN217162274U (zh) 一种脉冲电场发生器
CN216221635U (zh) 一种用于自动监测及调整消融参数的复合陡脉冲治疗设备
CN102284132A (zh) 基于多针形电极的高压脉冲电场治疗装置
CN216962609U (zh) 一种脉冲消融系统
KR20180074465A (ko) 고주파 조사량 및 습도 조절량을 제어할 수 있는 고주파를 이용한 미용의료 장치
CN114209978A (zh) 电场发生装置、设备及电场的控制方法
CN207838030U (zh) 可动态调度电极板极性的三维动态治疗仪

Legal Events

Date Code Title Description
DPE1 Request for preliminary examination filed after expiration of 19th month from priority date (pct application filed from 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17826995

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205 DATED 03.06.2019)

122 Ep: pct application non-entry in european phase

Ref document number: 17826995

Country of ref document: EP

Kind code of ref document: A1