CN107681916A - One kind collaboration irreversible electroporation device of pulse - Google Patents
One kind collaboration irreversible electroporation device of pulse Download PDFInfo
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- CN107681916A CN107681916A CN201710865337.2A CN201710865337A CN107681916A CN 107681916 A CN107681916 A CN 107681916A CN 201710865337 A CN201710865337 A CN 201710865337A CN 107681916 A CN107681916 A CN 107681916A
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- H—ELECTRICITY
- H03—ELECTRONIC CIRCUITRY
- H03K—PULSE TECHNIQUE
- H03K3/00—Circuits for generating electric pulses; Monostable, bistable or multistable circuits
- H03K3/02—Generators characterised by the type of circuit or by the means used for producing pulses
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- 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
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- 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
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- 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
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- 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
- A61B18/1402—Probes for open surgery
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- 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
- A61B2018/00577—Ablation
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- 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
- A61B2018/00589—Coagulation
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- 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
- A61B2018/00595—Cauterization
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- 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
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- 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
- A61B2018/00773—Sensed parameters
- A61B2018/00827—Current
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- 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
- A61B2018/00773—Sensed parameters
- A61B2018/00892—Voltage
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- 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
- A61B2018/1226—Generators therefor powered by a battery
Abstract
The invention discloses one kind to cooperate with the irreversible electroporation device of pulse, mainly including power-supply system, collaboration pulse shaping system, impulsive measurement system, control system and signal translating system.The irreversible electroporation device output collaboration pulse of collaboration pulse is melted to electrode needle, electrode needle to tumour cell.The present invention can effectively improve the lethal effect of tumour cell using collaboration pulse and expand the ablation area of biological tissue.
Description
Technical Field
The invention relates to the field of biological tissue ablation, in particular to a cooperative pulse irreversible electroporation device.
Background
Cancer is one of the major diseases that endanger human health. Traditional therapies for tumors and recently developed physical therapies for thermal ablation characterized by minimally invasive ablation are limited by indications, contraindications, side effects of treatment, heat sink, and the like. Therefore, the above method has a certain limitation in clinical application. In recent years, with the development of pulsed bioelectricity, electric field pulses have attracted extensive attention of researchers in the field of multinational bio-electromagnetism due to their non-thermal, minimally invasive biomedical effects. Among them, irreversible electroporation therapy for tumor has attracted much attention from researchers in bioelectricity fields at home and abroad due to its advantages and features of rapidness, controllability, visibility, selectivity and non-thermomechanics, and is gradually applied to clinical treatment of tumor.
At present, irreversible electroporation technology (typical pulse parameters are: field intensity is 1500-3000V/cm, pulse width is 100 mus, repetition frequency is 1Hz, and pulse number is 90-120) has been applied to the treatment of clinical tumor, and has achieved very good curative effect. Clinical tests prove that the technology has good effect on treating tumors such as pancreatic cancer, liver cancer, kidney cancer, prostate cancer and the like.
Angio Dynamics, USA, invests to produce a commercial irreversible electroporation tumor therapy apparatus Nano Knife, and obtains US FDA clinical trial approval in 2009. The company developed the first irreversible electroporation ablation clinical trial of prostate cancer worldwide in 2010 and obtained FDA approval in the united states for formal clinical use in 2012. In 2015, 6 months, the company obtained the clinical application permission of mainland China, and developed the first clinical application treatment of China in Guangzhou multiple tumor hospitals. By the beginning of 2017, hundreds of tumor patients are successfully cured by the therapeutic apparatus in continental China.
Therefore, the irreversible electroporation technology has good development prospect in the treatment of tumors as a safe and feasible local solid tumor treatment method.
By analyzing the effectiveness and safety of IRE in treating 221 patients with liver cancer, pancreatic cancer, lung cancer, lymph cancer and the like, scheffer et al find that IRE can safely ablate small-sized tumors near blood vessels or bile ducts.
Although the irreversible electroporation technology based on electric field pulse achieves exciting therapeutic effects in clinical applications at home and abroad, significant problems still remain in clinical applications.
For example, for tumor ablation, optimization of pulse parameters has always attracted extensive attention from researchers in the field of bioelectricity at home and abroad.
Generally, the physical therapy method of irreversible electroporation caused by electric field pulse is effective only for solid tumors with a size of less than 3cm, and the effectiveness of irreversible electroporation technology is gradually reduced as the tumor size increases. On the one hand, although large-sized tumors can be completely ablated by increasing the intensity (such as voltage, pulse width and the like) of the electric field pulse, the high-intensity electric field pulse can cause thermal effect and can also cause irrecoverable damage to normal tissues such as blood vessels, thereby breaking the non-thermal treatment principle of irreversible electroporation. On the other hand, increasing and optimizing the number of electrodes, while also effective in ablating large-sized tumors, can increase treatment complexity and medical risk, and even increase the invasiveness of the treatment.
From the mechanism of tumor research, the greater the damage to the cell membrane of tumor cells, the greater the probability of cell death,
where E is the applied pulse field strength, r is the cell membrane radius, θ represents the angle between the field strength direction and the cell membrane radial direction, t represents the pulse width, C represents the cell membrane capacitance, se represents the extracellular fluid conductivity, and si represents the cytoplasmic conductivity.
It can be seen from equation (1) that the higher the field strength, the larger the perforated area of the cell membrane.
Although high voltage, narrow pulses can produce a large perforated area on the cell membrane, the size of the generated micropores is small due to the narrow pulse width, and the micropores are easily restored, so that the occurrence of irreversible electroporation is difficult. Weaver et al found that low voltage, wide pulse can create large pore sizes in cell membranes. But the damage of the cell membrane caused by low voltage and wide pulse is also small due to the limit of threshold field intensity. And the cooperative pulse combines the respective advantages of high voltage, narrow pulse, low voltage and wide pulse, namely: the high voltage, narrow pulses create a large perforated area on the cell membrane, while the subsequent low voltage, wide pulses are not limited by the threshold field strength, thus enabling the creation of large-sized micropores within the existing perforated area of the cell membrane, which in turn can greatly damage the cell membrane, rendering the cell extremely lethal.
For biological tissue, high voltage, narrow pulses applied to the tissue can produce a large perforated area, but due to the short pulse width, the ablation zone is only present near the electrodes. Low voltage, wide pulses can only produce a small range of puncture regions due to threshold field strength limitations, but can essentially turn the puncture region into an ablation region due to the longer pulse width.
Disclosure of Invention
The purpose of the invention is: aiming at the problem that the existing irreversible electroporation therapy has small ablation area in clinical tests, a device and a method for ablating biological tissues by cooperating with pulses are provided and are used for ablating tumor tissues and other biological tissues.
The invention divides the pulse waveform of the traditional irreversible electroporation electric field into a high voltage, narrow pulse, a low voltage and wide pulse form. The high voltage, narrow pulse acts on the tissue to produce a large perforated area, but the ablation area exists only near the electrode due to the short pulse width, the low voltage, wide pulse can only produce a small range of perforated area due to the limitation of threshold field strength, and the perforated area can be basically changed into the ablation area due to the long pulse width. The electric field pulse is adopted to act on tumors or other biological tissues to induce cells to generate irreversible electroporation and die, so that the purpose of expanding a tumor ablation area and other biological tissues is achieved, the limitation of the tumor volume in an irreversible electroporation treatment method can be effectively solved, and the method can be applied to the treatment of tumors of human bodies and animals.
The technical scheme adopted for achieving the aim of the invention is that the coordinated pulse irreversible electroporation device mainly comprises a power supply system, a coordinated pulse forming system, a pulse measuring system, a control system and a signal conversion system.
The power supply system supplies power to the cooperative pulse forming system, the pulse measuring system, the control system and the signal conversion system.
The input end of the cooperative pulse forming system comprises an input terminal A1, an input terminal A2, an input terminal B1 and an input terminal B2.
The output of the collaborative pulse forming system includes an output terminal E1 and an output terminal E2.
The power supply system is connected between the input terminal A1 and the input terminal A2.
The input terminal A1 is connected with the input terminal A2 after being sequentially connected with the charging resistor R1 and the capacitor C1 in series.
The input terminal A1 is sequentially connected with a resistor R1 and an inductor L1 in series and then connected with the D pole of the semiconductor switch MOSFET/IGBT S1 in series.
The S pole of the semiconductor switch MOSFET/IGBT S1 is connected in series with the anode of the diode D1. The negative electrode of the diode D1 is connected in series with a load and then connected to the input terminal A2. The negative electrode of the diode D1 is connected in series with a load and then connected to the input terminal B2.
The power supply system is connected between the input terminal B1 and the input terminal B2.
The input terminal B1 is connected with the input terminal B2 after being sequentially connected with a resistor R2 and a capacitor C2 in series.
And the input terminal B1 is sequentially connected with an inductor L2 and a resistor R2 in series and then is connected with the D pole of a semiconductor switch MOSFET/IGBT S2.
The S pole of the semiconductor switch MOSFET/IGBT S2 is connected in series with the anode of the diode D2. The negative electrode of the diode D2 is connected in series with a load and then connected to the input terminal A2. The negative electrode of the diode D2 is connected in series with a load and then connected to the input terminal B2.
The load is connected between the output terminal E1 and the output terminal E2.
Further, the pulse measurement system mainly comprises a voltage divider, a current sensor and a processing circuit.
The voltage divider measures the voltage at the output of the co-pulse forming system.
The current sensor measures the current at the output of the pulse forming system.
The processing circuit receives a voltage signal measured by the voltage divider. The processing circuit receives the current signal measured by the current sensor.
Furthermore, the control system mainly comprises an FPGA module, a switch control module and the singlechip module.
And the FPGA module receives a voltage signal and a current signal at the output end of the processing circuit. And the voltage signal and the current signal are subjected to operation processing and then exchange data with the singlechip module.
The single chip microcomputer module controls the cooperative pulse irreversible electroporation device through the switch control module.
The control system may be provided with characteristic parameters of the pulses. The control system converts the set parameters into electric signals through an algorithm. The control system monitors the voltage signal and the current signal in the signal conversion system in real time, and the accuracy of the output pulse parameters is ensured.
The signal conversion system mainly includes the optical/electrical converter K1, the optical/electrical converter K2, the electrical/optical converter J1, and the electrical/optical converter J2.
And the electric signals are respectively transmitted to the power supply system, the cooperative pulse forming system and the pulse measuring system through the signal conversion system.
And the electric/optical converter J1 converts the electric signal received by the FPGA module into an optical signal.
The optical/electrical converter K1 converts an optical signal of the electrical/optical converter J1 into an electrical signal. The optical/electrical converter K1 transmits the converted electrical signal to the power supply system.
And the electric/optical converter J2 converts the electric signal received by the FPGA module into an optical signal.
The optical/electrical converter K2 converts the optical signal of the electrical/optical converter J2 into an electrical signal. The optical/electrical converter K2 transfers the converted electrical signal into the cooperative pulse forming system.
Furthermore, the power supply system mainly comprises a power supply, a power supply filtering device, a high-voltage direct current module and a switching power supply module.
The power supply is 220V alternating current.
The switching power supply module converts 220V alternating current into 12V direct current.
And the power supply filtering device filters the signal of the switching power supply module to obtain a power supply signal with specific frequency.
And the grounding end of the power supply filtering device is directly grounded. And the power supply filter device provides the obtained power supply signal to the high-voltage direct current module.
And the high-voltage direct current module supplies power to the input end of the collaborative pulse forming system.
Further, the device also comprises a PC. The power supply system supplies power to the PC. And the PC monitors the voltage signal and the current signal received by the control system in real time.
The high-voltage pulse amplitude of the cooperative pulse is continuously adjustable between 0 kV and 3 kV. The interval time of the high voltage pulse is between 1 and 200 s. The low-voltage pulse amplitude of the cooperative pulse is continuously adjustable between 0 kV and 3 kV. The interval time of the low-voltage pulse is between 1 and 200 s.
The sub-pulse width is continuously adjustable between 0.2 and 100 mu s. The pulse period is adjustable between 0.1 and 10 s. The rise time of the co-pulse is 30ns. The falling time of the co-pulse is 30ns.
The capacitance of the capacitor C1 and the capacitance of the capacitor C2 are determined by the total pulse width, the amplitude of the output pulse voltage, the allowable drop value of the output pulse voltage, the load resistance value and the discharge time constant.
Let the maximum total pulse width be tau and the output pulse voltage amplitude be V 0 The allowable drop value of the output pulse voltage is DeltaV d Load resistance value of R L Then the minimum capacitance of the capacitor C1 and the capacitor C2 is calculated according to the following formula:
after the discharge of each pulse train is finished, the voltage of the capacitor C1 and the capacitor C2 is reduced by 5% at most.
The withstand voltage values of the capacitor C1 and the capacitor C2 are determined by the maximum amplitude of the required pulse.
The device can accurately and reliably generate the synergistic pulse, can induce the transmembrane potential of the tumor cell membrane to be larger than a perforation threshold value, so that the cell membrane is subjected to irreversible electroporation, and the tumor cell is dead.
Meanwhile, the novel electric field pulse application mode provided by the invention is that high voltage and narrow pulse are applied before the irreversible electroporation parameters of the traditional low voltage and wide pulse, so that the influence of threshold field intensity is reduced and eliminated, and the tumor ablation area can be further expanded, namely, the high voltage and narrow pulse generate a larger perforated area on the tissue, and the subsequent low voltage and wide pulse have no limitation of the threshold field intensity, so that a larger ablation area is generated in the existing perforated area.
The invention can apply high-field electric field pulse to biological tissue to induce cell membrane to generate irreversible electroporation, thereby leading to cell death, and the cells generate irreversible electroporation under the action of the high-field pulse, thereby achieving the treatment effect without applying chemotherapeutic drugs and avoiding side effects brought by the chemotherapeutic drugs. Meanwhile, the invention has the advantages of rapidness (the pulse applying time for treatment is only dozens of seconds, the whole process is only a few minutes), controllability (treatment parameters can be obtained by calculating a three-dimensional modeling electric field, the treatment range is accurate and safe), visibility (the treatment process can be completed under the guidance of ultrasound/CT/MRI, the curative effect can be evaluated by ultrasound/CT/MRI), selectivity (bile ducts, blood vessels, nerves and the like in an ablation area are not damaged), and nonthermal mechanism (no thermal effect, and thermal damage and thermal sink brought by the thermal therapy can be overcome).
Drawings
FIG. 1 is a schematic block diagram of a coordinated pulse irreversible electroporation apparatus according to the method of the present invention;
FIG. 2 is a schematic block circuit diagram of a coordinated pulse forming system of the method of the present invention;
FIG. 3 is a diagram of a synergistic pulsed cell and tissue assay (pulse application method and assay platform) according to the present invention;
figure 4 is a graph of the synergistic pulse cell killing rate of the method of the invention (. P < 0.05);
FIG. 5 is a diagram of an experimental electrode needle for animal tissues used in the method of the present invention;
fig. 6 is a graph of tissue ablation results of the inventive method ([ p <0.05, [ p <0.01, [ p < 0.001) ];
FIG. 7 is a graph showing the results of H & E staining of tissues according to the method of the present invention;
in the figure: the device comprises a power supply system 1, a cooperative pulse forming system 2, a pulse measuring system 3, a control system 4, a signal conversion system 5, a power supply 11, a power supply filtering device 12, a high-voltage direct current module 13, a switching power supply module 14, a PC (personal computer) 6, a voltage divider 31, a current sensor 32, a processing circuit 33, an FPGA (field programmable gate array) module 41, a switching control module 42 and a singlechip module 43.
Detailed Description
The present invention will be further described with reference to the following examples, but it should be understood that the scope of the subject matter described above is not limited to the following examples. Various substitutions and modifications can be made without departing from the technical idea of the invention and the scope of the invention according to the common technical knowledge and the conventional means in the field.
Example 1:
a cooperative pulse irreversible electroporation device is disclosed, and referring to fig. 1, the cooperative pulse irreversible electroporation device mainly comprises a power supply system 1, a cooperative pulse forming system 2, a pulse measuring system 3, a control system 4 and a signal conversion system 5.
The power supply system 1 supplies power to the cooperative pulse forming system 2, the pulse measuring system 3, the control system 4 and the signal conversion system 5.
Further, the power supply system 1 mainly includes a power supply 11, a power supply filter 12, a high voltage dc module 13, and a switching power supply module 14.
The power supply 11 is 220V alternating current.
The switching power supply module 14 converts 220V ac power to 12V dc power.
The power filter 12 filters the signal of the switching power supply module 14 to obtain a power signal with a specific frequency.
The ground terminal of the power filter apparatus 12 is directly grounded. The power filter 12 provides the obtained power signal to the high voltage dc module 13.
Further, the power filter device 12 is a passive bidirectional network. The larger the impedance adaptation of the input end and the output end of the power supply filtering device to a power supply and a load is, the more effective the signal filtering is.
The high-voltage direct current module 13 supplies power to the input end of the collaborative pulse forming system 2.
Further, the pulse measuring system 3 mainly includes a voltage divider 31, a current sensor 32, and a processing circuit 33.
The voltage divider 31 measures the voltage at the output of the co-pulse forming system 2.
The current sensor 32 measures the current at the output of the co-pulse forming system 2.
The processing circuit 33 receives the voltage signal measured by the voltage divider 31. The processing circuit 33 receives the current signal measured by the current sensor 32.
Further, the control system 4 mainly includes an FPGA module 41, a switch control module 42, and the single chip module 43.
The FPGA module 41 receives the voltage signal and the current signal at the output of the processing circuit 33. The voltage signal and the current signal are subjected to operation processing and then perform data exchange with the single chip microcomputer module 43.
The single chip microcomputer module 43 controls the cooperative pulse irreversible electroporation device through the switch control module 42.
The control system 4 can be provided with characteristic parameters of the pulses. The control system 4 converts the set parameters into electric signals through an algorithm. The control system 4 monitors the voltage signal and the current signal in the signal conversion system 5 in real time, and the accuracy of the output pulse parameters is ensured.
The signal conversion system 5 mainly includes the optical/electrical converter K1, the optical/electrical converter K2, the electrical/optical converter J1, and the electrical/optical converter J2.
The electric signals are transmitted to the power supply system 1, the cooperative pulse forming system 2 and the pulse measuring system 3 through the signal conversion system 5.
The electrical/optical converter J1 converts the electrical signal received by the FPGA module 41 into an optical signal.
The optical/electrical converter K1 converts an optical signal of the electrical/optical converter J1 into an electrical signal. The optical/electrical converter K1 transmits the converted electrical signal to the power supply system 1.
The electric/optical converter J2 converts the electric signal received by the FPGA module 41 into an optical signal.
The optical/electrical converter K2 converts the optical signal of the electrical/optical converter J2 into an electrical signal. The optical/electrical converter K2 passes the converted electrical signal into the cooperative pulse forming system 2.
Further, the cooperative pulse irreversible electroporation apparatus further includes a PC 6.
The power supply system 1 supplies power to the PC 6. And the PC 6 monitors the voltage signal and the current signal received by the control system 4 in real time.
The regulation of the pulses is performed by regulating the output voltage of the power supply system 1 and the conduction time, the turn-on and turn-off time sequence and the turn-on and turn-off times of the solid state switches in the high-voltage and low-voltage circuits.
The high-voltage pulse amplitude of the cooperative pulse is continuously adjustable between 0 kV and 3 kV. The interval time of the high voltage pulse is between 1 and 200 s. The low-voltage pulse amplitude of the cooperative pulse is continuously adjustable between 0 kV and 3 kV. The interval time of the low-voltage pulse is between 1 and 200 s.
The sub-pulse width is continuously adjustable between 0.2 and 100 mu s. The pulse period is adjustable between 0.1 and 10 s. The rise time of the co-pulse is 30ns. The falling time of the co-pulse is 30ns.
The capacitance of the capacitor C1 and the capacitance of the capacitor C2 are determined by the total pulse width, the amplitude of the output pulse voltage, the allowable drop value of the output pulse voltage, the load resistance value and the discharge time constant.
Let the maximum total pulse width be tau and the output pulse voltage amplitude be V 0 The allowable drop value of the output pulse voltage is DeltaV d Load resistance value of R L Then the minimum capacitance of the capacitor C1 and the capacitor C2 is calculated according to the following formula:
after the discharge of each pulse train is finished, the voltage of the capacitor C1 and the capacitor C2 is reduced by 5% at most.
The withstand voltage values of the capacitor C1 and the capacitor C2 are determined by the maximum amplitude of the required pulse.
Example 2:
an input terminal of the cooperative pulse forming system 2 includes an input terminal A1, an input terminal A2, an input terminal B1, and an input terminal B2, see fig. 2.
The output of the cooperative pulse forming system 2 includes an output terminal E1 and an output terminal E2.
The power supply system 1 is connected between the input terminal A1 and the input terminal A2.
The input terminal A1 is connected with the input terminal A2 after being sequentially connected with a charging resistor R1 and a capacitor C1 in series.
Further, the high-voltage direct current module 13 charges the energy storage capacitor C1 through the charging resistor R1 according to the set pulse amplitude. After the charging is finished, the energy storage capacitor C1 releases energy to the load.
The input terminal A1 is sequentially connected with a resistor R1 and an inductor L1 in series and then connected with the D pole of the semiconductor switch MOSFET/IGBT S1 in series.
The S pole of the semiconductor switch MOSFET/IGBT S1 is connected in series with the anode of the diode D1. The negative electrode of the diode D1 is connected in series with a load and then connected to the input terminal A2. The negative electrode of the diode D1 is connected in series with a load and then connected to the input terminal B2.
The power supply system 1 is connected between the input terminal B1 and the input terminal B2.
The input terminal B1 is connected with the input terminal B2 after being sequentially connected with a resistor R2 and a capacitor C2 in series.
Further, the high voltage dc module 13 charges the energy storage capacitor C2 through the charging resistor R2 according to the set pulse amplitude. After the charging is finished, the energy storage capacitor C2 releases energy to the load.
And the input terminal B1 is sequentially connected with an inductor L2 and a resistor R2 in series and then is connected with the D pole of a semiconductor switch MOSFET/IGBT S2.
The S pole of the semiconductor switch MOSFET/IGBT S2 is connected in series with the anode of the diode D2. The negative electrode of the diode D2 is connected in series with a load and then connected to the input terminal A2. The negative electrode of the diode D2 is connected in series with a load and then connected to the input terminal B2.
The load is connected between the output terminal E1 and the output terminal E2.
Further, the cooperative pulse forming system 2 forms a high voltage and a narrow pulse, and then forms a low voltage and a wide pulse. High voltage and narrow pulses, low voltage and wide pulses occur in sequence.
By the cooperative pulse forming system 2, a novel electric field pulse application mode can be formed, namely, the high voltage and narrow pulse are applied before the irreversible electroporation parameters of the traditional low voltage and wide pulse, so that the influence of threshold field intensity is reduced and eliminated, and the tumor ablation area is further enlarged. That is, a high voltage, narrow pulse produces a larger perforated area on the tissue, while a subsequent low voltage, wide pulse, without the limitation of threshold field strength, can produce a larger ablation zone within the existing perforated area.
Example 3:
the procedure for using the co-pulse irreversible electroporation apparatus was as follows:
1) The device is initialized.
2) The form and application of the electrodes and the characteristic parameters of the co-pulse are determined to ensure effective coverage of the electric field area.
3) The pulse width, pulse interval and number of pulses are set.
4) The pulse parameters of the synergic pulse device and the application mode of the electrodes are adjusted according to the characteristics of the patient and the specific condition of the tumor tissue. Notably, splint electrodes or suction electrodes are used for body surface type tumor tissues. For in vivo tumors, needle electrodes are used, the insertion position of which is determined by the position of the tumor tissue and the depth of which is determined by the size of the tumor tissue. A commonly used combination of electrode needles for applying pulses is a two-needle electrode.
5) And setting the determined cooperative pulse characteristic parameter through a control system. The pulse width, the pulse interval and the number of pulses set by a user.
6) And performing corresponding switching action on the cooperative pulse irreversible electroporation device so as to control the pulse width, the number, the pulse interval and the like of output.
7) The electrode is applied to the tumor tissue of a patient, the cooperative pulse required by the patient is generated by the cooperative pulse irreversible electroporation device and is applied to the electrode, the tumor tissue of the patient is stimulated by a pulse electric field, and the irreversible electroporation is induced to the tumor tissue of the patient, so that the tumor cells are effectively killed and killed.
8) During the electrode application period, a user monitors the voltage signal and the current signal in real time through the control system, and the accuracy of the output pulse parameters is ensured.
9) After the treatment is completed, the user removes the electrodes from the patient's tumor tissue.
Example 4:
when the high-voltage narrow pulse output by the cooperative pulse irreversible electroporation device is used for ablating cells and tissues, the following devices are mainly needed: an oscilloscope, a synergic pulse irreversible electroporation device, a temperature sensor and an electrode cup.
The circuit of the coordinated pulse irreversible electroporation device outputs high-voltage narrow pulses.
A current probe of the oscilloscope detects a current signal of the load anode of the collaborative pulse irreversible electroporation device, and a voltage probe of the oscilloscope detects a voltage signal of the load anode of the collaborative pulse irreversible electroporation device; the oscilloscope converts the electric signals detected by the current probe and the voltage probe into a waveform curve which changes along with time.
The electrode needles have a pitch of 5 mm.
The optical fiber probe of the temperature sensor detects the temperature of the electrode needle; the temperature sensor converts the temperature detected by the fiber optic probe into a usable output signal.
One end of the electrode cup is connected with the negative electrode of the collaborative pulse irreversible electroporation device collaborative pulse forming system 2, and the other end of the electrode cup is connected with the positive electrode of the collaborative pulse generating device collaborative pulse forming system 2.
The electrode cup receives a pulse signal output by the pulse irreversible electroporation device.
Example 5:
when the low-voltage and wide-pulse output by the cooperative pulse irreversible electroporation device is used for ablating cells and tissues, the following devices are mainly needed: an oscilloscope, a synergic pulse irreversible electroporation device, a temperature sensor and an electrode cup.
The circuit of the cooperative pulse irreversible electroporation apparatus outputs a low voltage, wide pulse.
A current probe of the oscilloscope detects current signals at two ends of a load of the collaborative pulse irreversible electroporation device, and a voltage probe of the oscilloscope detects voltage signals at two ends of the load of the collaborative pulse irreversible electroporation device; the oscilloscope converts the electric signals detected by the current probe and the voltage probe into a waveform curve which changes along with time.
The electrode needles have a pitch of 5 mm.
The optical fiber probe of the temperature sensor detects the temperature of the electrode needle; the temperature sensor converts the temperature detected by the fiber optic probe into a usable output signal.
One end of the electrode cup is connected with the negative electrode of the collaborative pulse irreversible electroporation device collaborative pulse forming system 2, and the other end is connected with the positive electrode of the collaborative pulse generating device collaborative pulse forming system 2.
The electrode cup receives a pulse signal output by the pulse irreversible electroporation device.
Example 6:
in this example, when a cooperative pulse irreversible electroporation apparatus is used, human ovarian cancer cell SKOV-3 is used as an experimental subject, and an orthogonal experiment and CCK-8 activity detection means are adopted. The test procedure was as follows:
1) First, a modified RPMI-1640 medium (Hyaline) and a corresponding 1640 complete medium containing 10% of standard fetal bovine serum (Shanghai Eikesai Bioproducts Ltd.) and 1% of diabatic antibody (penicillin, streptomycin) (Genview Co.) were prepared. A BTX electrode cup was prepared, the electrode portion of which was 10mm in length, 4mm in width and 20mm in height.
2) Human ovarian carcinoma cells SKOV-3 (provided by Chongqing university of medicine) were grown adherent to the walls and modified RPMI-1640 medium was placed in a T25 cell culture flask (BeaverBio).
3) The T25 cell culture flasks were placed in a 5% CO2 cell culture chamber (Thermo) at 37 ℃.
4) The modified RPMI-1640 medium in the confluent T25 cell culture flasks was aspirated with glass pipettes in a clean bench (Suzhou clarification facility, inc.).
5) 1-2mL of PBS buffer (Beijing ancient Changsheng Biotechnology, LLC) is added into a T25 cell culture bottle, the PBS buffer is used for infiltrating and washing cells, and then the cells and the PBS buffer are sucked out.
6) 1mL of 0.25% trypsin is added into a T25 cell culture bottle, namely 0.25g of trypsin (Beijing Ding Guosheng Biotech, ltd.) powder and 0.033g of EDTA (domestic analytical purity) are weighed, and then PBS buffer is added until 100mL of trypsin liquid is prepared in the T25 cell culture bottle.
7) The cells in the flask (SKOV-3) were digested with trypsin solution and the pancreatin was aspirated after about 1 minute. Pancreatin was added to the medium and digestion was stopped.
8) The cells were diluted to 5X 10 by adding 5mL of 1640 complete medium to the medium to prepare a cell suspension 5 cells/mL。
9) Pulse signals are applied to the electrode cups during the experiment, and 100 mu L of cell suspension is added into the electrode cups for corresponding electrical stimulation in each experiment.
10 Different parameters of the co-pulse were studied separately, as shown in table 1. Untreated cell suspension and blank were used as controls. Each set of experiments was repeated three times.
TABLE 1
11 After the experiment is finished, the survival rate of the cells is detected by a CCK-8 method, namely, the cells treated in the experiment are added into a 96-well plate and are cultured in an incubator for 24 hours for CCK-8 determination. Wherein 5 multiple holes are arranged for each group of parameters.
12 Remove the medium and wash the cells with PBS, and add 20 μ L of CCK-8 (Changsheng Biotechnology, inc., beijing ancient China) reagent to each well of the 96-well plate. The serum-free medium was shaken up and incubated for 2-4 hours at 37 ℃ in the absence of light.
13 Carefully aspirate the medium, add dimethyl sulfoxide (DMSO, bekka biotechnology llc of beijing dingguosheng) to each well of a 96-well plate, and incubate for 20 minutes in a light-shielded shaker (wadd biomedical instrument division, six instruments, beijing).
14 Absorbance of each set of parameter well light was measured on a 450nm wavelength enzyme linked immunosorbent assay (BIO-RAD). The results were recorded and the kill rate of the cells was calculated. The experimental data are expressed as mean ± standard deviation (x ± s) and analyzed using GraphPad Prism 5 software, using a one-way analysis of variance comparative test.
With this embodiment, the following results can be obtained:
referring to fig. 4, the cell survival rate was 62.4% when a high voltage, narrow pulse was applied alone, and 68.8% when a low voltage, wide pulse width was applied alone.
However, cell viability was only 19.0% when co-pulses (high voltage, narrow pulse followed by low voltage, wide pulse) were applied. The synergistic pulse has significant difference in cell killing rate relative to the high voltage, narrow pulse, low voltage, wide pulse, respectively, and the survival rate is 3.28 times that of the high voltage, narrow pulse and 3.62 times that of the low voltage, wide pulse.
The results thus indicate that the synergistic pulse can increase the rate of cell killing, indirectly demonstrating the validity of the method of the invention, i.e. the high voltage, narrow pulse produces a large perforated area on the cell membrane, whereas the subsequent low voltage, wide pulse has no threshold and field strength limitations, so that the synergistic pulse can produce a large size of micropores in the already existing perforated area of the cell membrane, which in turn greatly damages the cell membrane, rendering the cell extremely lethal.
It can be seen from the figure that if the low voltage and the wide pulse are applied first, and then the high voltage and the narrow pulse are applied, the cell survival rate is 56.1%, but the cell survival rate is slightly decreased when the high voltage and the narrow pulse are applied separately from the low voltage and the wide pulse, but there is no significant difference. This indicates that the order of application can also affect its killing effect.
On the other hand, the time interval between the application of the high voltage, narrow pulse and low voltage wide pulse also affects the survival rate of cancer cells. When the application interval time of the high-voltage narrow pulse and the low-voltage wide pulse is prolonged to 100s, the damage degree of the synergistic pulse to the cells is more serious, the survival rate of the cells is only 7.9%, and compared with the synergistic pulse with the interval time of 1s, the synergistic pulse has a significant difference, which shows that the inhibition rate of the cells can be further improved by increasing the interval time.
Example 7:
the method for researching the law of the ablation effect of the cooperative pulse, the high-voltage narrow pulse, the low-voltage wide pulse and the tissue by utilizing the cooperative pulse irreversible electroporation device based on FPGA control comprises the following steps:
1) 8 New Zealand white rabbits (female, 6 months old, 2.5kg body weight. + -. 0.2 kg) were prepared, which were provided by the animal experiment center of Chongqing university of medicine. And 8 New Zealand white rabbits were bred in a clean and constant temperature animal breeding laboratory. The test of this example strictly performed the relevant regulations in the "regulations on laboratory animals management" of the people's republic of China.
2) 10 minutes prior to the pulse treatment, the ear edge vein (1 mL/kg) of New Zealand white rabbits was anesthetized with a 3% solution of sodium pentobarbital. The duration of anesthesia was about 60 minutes or more, which was sufficient for the experiment. The experiment is opened the abdomen through surgery, and during the experiment, the rabbit is fixed in the operating table with the mode of lying the appearance, opens 50 mm's opening in its abdominal cavity upper half to in with electrode needle disect insertion liver tissue, the experimental scene is as shown in fig. 5.
3) The electrode needle adopts the spacer, fixes its interval and is 5mm, fixes the electrode needle with the support and is located the picture abdominal cavity directly over, applys the pulse electric field in coordination of different parameters respectively to the electrode needle. The specific applied pulse parameters are shown in table 2.
TABLE 2
4) After the pulse treatment was completed, the abdominal wound of the new zealand white rabbit was sutured with a medical suture. And the sutured New Zealand white rabbits were kept in a sterile animal laboratory for three days.
5) After the animals are fed in the experimental rooms for 3 days, 3% sodium pentobarbital solution is adopted for anesthesia, the vital sign signals of the new zealand white rabbits are monitored in real time before euthanasia, and the liver tissues of the rabbits are taken out after euthanasia. After sampling, the samples were soaked in 10% formalin solution for 24 hours, fixed in paraffin, cut and H & E stained to prepare tissue sections.
6) Slices were scanned using an Aperio LV1 () numerical case slice scanner to obtain color scan images of the tissue slices.
As shown in fig. 6, taking high-voltage and narrow-pulse parameters of 20 pulses, 1600V and 2 μ s pulses, and low-voltage and narrow-pulse parameters of 60 pulses, 360V and 100 μ s pulses as examples, when the high-voltage and narrow pulses were applied alone, the ablation area of the rabbit liver tissue was 21.7mm2; when a low voltage and a wide pulse width are independently applied, the ablation area of the rabbit liver tissue is 23.8mm2.
However, when a synergistic pulse (high voltage, narrow pulse first, and low voltage, wide pulse second) was applied, the ablated area of the rabbit liver tissue was 50.7mm2. And the synergistic pulse has significant difference in ablation area relative to the high voltage and narrow pulse and the low voltage and wide pulse when applied respectively. The tissue ablation area was increased by 133.6% for the high voltage, narrow pulse and 113.0% for the high voltage, narrow pulse.
Therefore, the result shows that the synergistic pulse can effectively improve the ablation area of the tissue, and indirectly proves the correctness of the method, namely: the high voltage, narrow pulse produces a larger perforated area on the biological tissue, while the threshold field strength of the subsequent low voltage, wide pulse is reduced, thus enabling a further enlargement of the liver tissue ablation area.
On the other hand, the present example finds that the cooperative pulse can increase the ablation area by adjusting the voltage of the low-voltage, wide-pulse, i.e., the ablation area becomes larger and larger as the voltage of the low-voltage, wide-pulse increases. When the voltage of low voltage and wide pulse is added to 480V, the ablation area reaches 86.0mm2; when low-voltage and wide-pulse are applied independently, the ablation area is only 59.8mm2; when the synergistic pulse is applied, the ablation area is improved by 43.8 percent compared with that when the low-voltage and wide pulse is applied independently.
Example 8:
the H & E staining graph is shown in FIG. 7, and after H & E staining scanning of liver tissues, boundaries of ablation areas and normal tissues of the liver tissues can be observed more clearly and accurately. As shown in fig. 5, taking the synergistic pulses (20 high voltage and narrow pulse parameters, 1600V and 2 μ s pulses and 60 low voltage and narrow pulse parameters, 480V and 100 μ s pulses) as an example, the electrical parameters of the liver tissue are anisotropic due to the structural heterogeneity of liver lobules, blood vessels and bile ducts in the actual liver tissue, so the actual electric field distribution is not in a standard dumbbell shape or an ellipse shape, fig. 7 shows that the ablation boundary is very clear, the ablation boundary of the μm level is reached, and the bile ducts and cells near the blood vessels are completely ablated without residual liver cells.
Claims (5)
1. The coordinated pulse irreversible electroporation device is characterized by mainly comprising a power supply system (1), a coordinated pulse forming system (2), a pulse measuring system (3), a control system (4) and a signal conversion system (5);
the power supply system (1) supplies power to the cooperative pulse forming system (2), the pulse measuring system (3), the control system (4) and the signal conversion system (5);
the input end of the collaborative pulse forming system (2) comprises an input terminal A1, an input terminal A2, an input terminal B1 and an input terminal B2;
the output end of the cooperative pulse forming system (2) comprises an output terminal E1 and an output terminal E2;
the power supply system (1) is connected between the input terminal A1 and the input terminal A2;
the input terminal A1 is connected with the input terminal A2 after being sequentially connected with a charging resistor R1 and a capacitor C1 in series;
the input terminal A1 is sequentially connected with a resistor R1 and an inductor L1 in series and then connected with a D pole of a semiconductor switch MOSFET/IGBT S1 in series;
the S pole of the semiconductor switch MOSFET/IGBT S1 is connected with the anode of the diode D1 in series; the negative electrode of the diode D1 is connected with a load in series and then is connected with the input terminal A2; the negative electrode of the diode D1 is connected with a load in series and then is connected with the input terminal B2;
the power supply system (1) is connected between the input terminal B1 and the input terminal B2;
the input terminal B1 is connected with the input terminal B2 after being sequentially connected with a resistor R2 and a capacitor C2 in series;
the input terminal B1 is connected with the D pole of a semiconductor switch MOSFET/IGBT S2 after being sequentially connected with an inductor L2 and a resistor R2 in series;
the S pole of the semiconductor switch MOSFET/IGBT S2 is connected with the anode of the diode D2 in series; the negative electrode of the diode D2 is connected with a load in series and then is connected with the input terminal A2; the negative electrode of the diode D2 is connected with a load in series and then is connected with the input terminal B2;
the load is connected in series between the output terminal E1 and the output terminal E2;
the pulse measurement system (3) mainly comprises a voltage divider (31), a current sensor (32) and a processing circuit (33);
the voltage divider (31) measures the voltage at the output of the co-pulse forming system (2);
the current sensor (32) measures the current at the output of the co-pulse forming system (2);
-the processing circuit (33) receives the voltage signal measured by the voltage divider (31); -the processing circuit (33) receives the current signal measured by the current sensor (32);
the control system (4) mainly comprises an FPGA module (41), a switch control module (42) and the single chip microcomputer module (43);
the FPGA module (41) receives a voltage signal and a current signal at the output end of the processing circuit (33); the voltage signal and the current signal are subjected to operation processing and then exchange data with the singlechip module (43);
the singlechip module (43) controls the cooperative pulse irreversible electroporation device through the switch control module (42);
characteristic parameters of the pulse can be set in the control system (4); the control system (4) converts the set parameters into electric signals through an algorithm; the control system (4) monitors the voltage signal and the current signal in the signal conversion system (5) in real time to ensure the accuracy of the output pulse parameters;
the signal conversion system (5) mainly comprises the optical/electrical converter K1, the optical/electrical converter K2, the electrical/optical converter J1 and the electrical/optical converter J2;
the electric signals are respectively transmitted to the power supply system (1), the cooperative pulse forming system (2) and the pulse measuring system (3) through the signal conversion system (5);
the electric/optical converter J1 converts the electric signal received by the FPGA module (41) into an optical signal;
the optical/electrical converter K1 converts an optical signal of the electrical/optical converter J1 into an electrical signal; the optical/electrical converter K1 transmits the converted electrical signal to the power supply system (1);
the electric/optical converter J2 converts the electric signal received by the FPGA module (41) into an optical signal;
the optical/electrical converter K2 converts the optical signal of the electrical/optical converter J2 into an electrical signal; the optical/electrical converter K2 transmits the converted electrical signal to the cooperative pulse forming system (2).
2. A collaborative pulsed irreversible puncturing device according to claim 1, wherein: the power supply system (1) mainly comprises a power supply (11), a power supply filtering device (12), a high-voltage direct current module (13) and a switch power supply module (14);
the power supply (11) is 220V alternating current;
the switching power supply module (14) converts 220V alternating current into 12V direct current;
the power supply filtering device (12) filters the signal of the switching power supply module (14) to obtain a power supply signal with specific frequency;
the grounding end of the power supply filtering device (12) is directly grounded; the power supply filtering device (12) provides the obtained power supply signal to the high-voltage direct current module (13);
the high-voltage direct current module (13) supplies power to the input end of the collaborative pulse forming system (2).
3. The co-pulsing irreversible electroporation device according to claim 1, wherein: the system also comprises a PC (6); the power supply system (1) supplies power to the PC (6); and the PC (6) monitors the voltage signal and the current signal received by the control system (4) in real time.
4. A collaborative pulsed irreversible puncturing device according to claim 1, wherein:
the high-voltage pulse amplitude of the cooperative pulse is continuously adjustable between 0 and 3 kV; the interval time of the high-voltage pulse is between 1 and 200 s; the low-voltage pulse amplitude of the cooperative pulse is continuously adjustable between 0 and 3 kV; the interval time of the low-voltage pulse is between 1 and 200 s;
the sub-pulse width is continuously adjustable between 0.2 and 100 mu s; the pulse period is adjustable between 0.1 and 10 s; the rise time of the cooperative pulse is 30ns; the falling time of the co-pulse is 30ns.
5. A collaborative pulsed irreversible puncturing device according to claim 1, wherein: the capacitance of the capacitor C1 and the capacitance of the capacitor C2 are determined by the total pulse width, the amplitude of the output pulse voltage, the allowable drop value of the output pulse voltage, the load resistance value and the discharge time constant;
let the maximum total pulse width be tau and the output pulse voltage amplitude be V 0 The allowable drop value of the output pulse voltage is DeltaV d Load resistance value of R L Then the minimum capacitance of the capacitor C1 and the capacitor C2 is calculated according to the following formula:
after the discharge of each pulse train is finished, the voltage of the capacitor C1 and the capacitor C2 is reduced by 5% at most;
the withstand voltage values of the capacitor C1 and the capacitor C2 are determined by the maximum amplitude of the required pulse.
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| CN113098448A (en) * | 2021-04-01 | 2021-07-09 | 杭州维那泰克医疗科技有限责任公司 | Pulse generating method, pulse generating device, storage medium, and electronic apparatus |
| WO2022218312A1 (en) * | 2021-04-15 | 2022-10-20 | 杭州维纳安可医疗科技有限责任公司 | Pulse control method and apparatus, ablation device and system, and storage medium |
| WO2023016523A1 (en) * | 2021-08-11 | 2023-02-16 | 杭州维纳安可医疗科技有限责任公司 | Cooperative pulse generation apparatus, device and generation method |
| CN113855218A (en) * | 2021-09-26 | 2021-12-31 | 北京三春晖医疗器械有限公司 | Resistance evaluation tumor cell ablation system |
| CN114271930A (en) * | 2021-12-27 | 2022-04-05 | 天津市鹰泰利安康医疗科技有限责任公司 | High-frequency bidirectional pulse treatment system for tumor treatment |
| CN114448396A (en) * | 2022-03-07 | 2022-05-06 | 重庆大学 | Equipment and method for generating cooperative pulse |
| CN115385423A (en) * | 2022-08-22 | 2022-11-25 | 华中科技大学 | System design method for preventing and treating periphyton fouling by using pulsed electric field |
| CN115385423B (en) * | 2022-08-22 | 2023-09-29 | 华中科技大学 | System design method for preventing and treating sessile biological fouling by using pulse electric field |
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| Publication number | Publication date |
|---|---|
| CN109124760B (en) | 2020-12-29 |
| CN109124760A (en) | 2019-01-04 |
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